My action lasts longer: Potential link between subjective time and agency during voluntary action.

PubMed

Imaizumi, Shu; Asai, Tomohisa

2017-05-01

Time perception distorts across different phases of bodily movement. During motor execution, sensory feedback matching an internal sensorimotor prediction is perceived to last longer. The sensorimotor prediction also underlies sense of agency. We investigated association between subjective time and agency during voluntary action. Participants performed hand action while watching a video feedback of their hand with various delays to manipulate agency. The perceived duration and agency over the video feedback were judged. Minimal delay of the video feedback resulted in longer perceived duration than the actual duration and stronger agency, while substantial feedback delay resulted in shorter perceived duration and weaker agency. These fluctuations of perceived duration and agency were nullified by the feedback of other's hand instead of their own, but not by inverted feedback from a third-person perspective. Subjective time during action might be associated with agency stemming from sensorimotor prediction, and self-other distinction based on bodily appearance. Copyright © 2017 Elsevier Inc. All rights reserved.

Crataegus extract prolongs action potential duration in guinea-pig papillary muscle.

PubMed

Müller, A; Linke, W; Zhao, Y; Klaus, W

1996-11-01

Crataegus extract is used in cardiology for the treatment of moderate heart failure (NYHA II). Recently it was shown that Crataegus extract prolongs the refractory period in isolated perfused guinea pig hearts. In order to find out what mechanism is responsible for this prolongation of refractory period, we investigated the effects of Crataegus extract (LI 132) on the action potential of guinea pig papillary muscle with the help of conventional microelectrode techniques. Crataegus extract, when put in a concentration (10 mg/l) capable of inducing an inotropic effect of about 20%, significantly increased action potential duration at all investigated levels of repolarisation. Maximum prolongation was 8.5±2.3 ms, 12.5±2.6 ms and 11.7±2.9 ms at 20%, 50% and 90% repolarisation, respectively (control APD(90): 172±4 ms). Experiments on the time course of recovery of the maximum upstroke velocity (V(max)) of the action potential revealed that Crataegus extract increased the time constant of recovery of V(max) from 8.80±2.33 ms to 22.60±5.77 ms, indicating a weak Class I-like antiarrhythmic action. In addition, we observed a small reduction in V(max). In summary, our results show that Crataegus extract prolongs action potential duration and delays recovery of V(max). We, therefore, suggest that Crataegus extract possesses certain antiarrhythmic properties. Copyright © 1996 Gustav Fischer Verlag · Stuttgart · Jena · New York. Published by Elsevier GmbH.. All rights reserved.

Actions and mechanisms of action of novel analogues of sotalol on guinea-pig and rabbit ventricular cells.

PubMed Central

Connors, S. P.; Gill, E. W.; Terrar, D. A.

1992-01-01

1. The actions and mechanisms of action of novel analogues of sotalol which prolong cardiac action potentials were investigated in guinea-pig and rabbit isolated ventricular cells. 2. In guinea-pig and rabbit cells the compounds significantly prolonged action potential duration at 20% and 90% repolarization levels without affecting resting membrane potential. In guinea-pig but not rabbit cells there was an increase in action potential amplitude and in rabbit cells there was no change in the shape or position of the 'notch' in the action potential. 3. Possible mechanisms of action were studied in more detail in the case of compound II (1-(4-methanesulphonamidophenoxy)-3-(N-methyl 3,4 dichlorophenylethylamino)-2-propanol). Prolongation of action potential duration continued to occur in the presence of nisoldipine, and calcium currents recorded under voltage-clamp conditions were not reduced by compound II (1 microM). Action potential prolongation by compound II was also unaffected in the presence of 10 microM tetrodotoxin. 4. Compound II (1 microM) did not influence IK1 assessed from the current during ramp changes in membrane potential (20 mV s-1) over the range -90 to -10 mV. 5. Compound II (1 microM) blocked time-dependent delayed rectifier potassium current (IK) activated by step depolarizations and recorded as an outward tail following repolarization. When a submaximal concentration (50 nM) was applied there was no change in the apparent reversal potential of IK.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1393293

Choline-modulated arsenic trioxide-induced prolongation of cardiac repolarization in Guinea pig.

PubMed

Sun, Hong-Li; Chu, Wen-Feng; Dong, De-Li; Liu, Yan; Bai, Yun-Long; Wang, Xiao-Hui; Zhou, Jin; Yang, Bao-Feng

2006-04-01

Arsenic trioxide (As(2)O(3)) has been found to be effective for relapsed or refractory acute promyelocytic leukaemia, but its clinical use is burdened by QT prolongation, Torsade de pointes tachycardias, and sudden cardiac death. The aim of the present study was to elucidate the ionic mechanisms of As(2)O(3)-induced abnormalities of cardiac electrophysiology and the therapeutic action of choline on As(2)O(3)-caused QT prolongation in guinea pig. Intravenous administration of As(2)O(3) prolonged the QT interval in a dose- and time-dependent manner in guinea pig hearts, and the QT prolongation could be modulated by choline. By using whole-cell patch clamp technique and confocal laser scanning microscopy, we found that As(2)O(3) significantly lengthened action potential duration measured at 50 and 90% of repolarization, enhanced L-type calcium currents (I(Ca-L)), inhibited delayed rectifier potassium currents (I(K)), and increased intracellular calcium concentration ([Ca(2+)](i)) in guinea pig ventricular myocytes. Choline corrected As(2)O(3)-mediated alterations of action potential duration, I(Ca-L) and [Ca(2+)](i), but had no effect on the I(K) inhibition. As(2)O(3) markedly disturbed the normal equilibrium of transmembrane currents (increasing I(Ca-L) and suppressing I(K)) in guinea pig cardiomyocyte, and induced prolongation of action potential duration, further degenerated into QT prolongation. Choline normalized QT interval abnormality and corrected lengthened action potential duration by inhibiting the elevated I(Ca-L) and [Ca(2+)](i) in ventricular myocytes during As(2)O(3) application.

Effects of tacrolimus on action potential configuration and transmembrane ion currents in canine ventricular cells.

PubMed

Szabó, László; Szentandrássy, Norbert; Kistamás, Kornél; Hegyi, Bence; Ruzsnavszky, Ferenc; Váczi, Krisztina; Horváth, Balázs; Magyar, János; Bányász, Tamás; Pál, Balázs; Nánási, Péter P

2013-03-01

Tacrolimus is a commonly used immunosuppressive agent which causes cardiovascular complications, e.g., hypertension and hypertrophic cardiomyopathy. In spite of it, there is little information on the cellular cardiac effects of the immunosuppressive agent tacrolimus in larger mammals. In the present study, therefore, the concentration-dependent effects of tacrolimus on action potential morphology and the underlying ion currents were studied in canine ventricular cardiomyocytes. Standard microelectrode, conventional whole cell patch clamp, and action potential voltage clamp techniques were applied in myocytes enzymatically dispersed from canine ventricular myocardium. Tacrolimus (3-30 μM) caused a concentration-dependent reduction of maximum velocity of depolarization and repolarization, action potential amplitude, phase-1 repolarization, action potential duration, and plateau potential, while no significant change in the resting membrane potential was observed. Conventional voltage clamp experiments revealed that tacrolimus concentrations ≥3 μM blocked a variety of ion currents, including I(Ca), I(to), I(K1), I(Kr), and I(Ks). Similar results were obtained under action potential voltage clamp conditions. These effects of tacrolimus developed rapidly and were fully reversible upon washout. The blockade of inward currents with the concomitant shortening of action potential duration in canine myocytes is the opposite of those observed previously with tacrolimus in small rodents. It is concluded that although tacrolimus blocks several ion channels at higher concentrations, there is no risk of direct interaction with cardiac ion channels when applying tacrolimus in therapeutic concentrations.

Acute alteration of cardiac ECG, action potential, I{sub Kr} and the human ether-a-go-go-related gene (hERG) K{sup +} channel by PCB 126 and PCB 77

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Mi-Hyeong; Park, Won Sun; Jo, Su-Hyun, E-mail: suhyunjo@kangwon.ac.kr

2012-07-01

Polychlorinated biphenyls (PCBs) have been known as serious persistent organic pollutants (POPs), causing developmental delays and motor dysfunction. We have investigated the effects of two PCB congeners, 3,3′,4,4′-tetrachlorobiphenyl (PCB 77) and 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) on ECG, action potential, and the rapidly activating delayed rectifier K{sup +} current (I{sub Kr}) of guinea pigs' hearts, and hERG K{sup +} current expressed in Xenopus oocytes. PCB 126 shortened the corrected QT interval (QTc) of ECG and decreased the action potential duration at 90% (APD{sub 90}), and 50% of repolarization (APD{sub 50}) (P < 0.05) without changing the action potential duration at 20% (APD{submore » 20}). PCB 77 decreased APD{sub 20} (P < 0.05) without affecting QTc, APD{sub 90}, and APD{sub 50}. The PCB 126 increased the I{sub Kr} in guinea-pig ventricular myocytes held at 36 °C and hERG K{sup +} current amplitude at the end of the voltage steps in voltage-dependent mode (P < 0.05); however, PCB 77 did not change the hERG K{sup +} current amplitude. The PCB 77 increased the diastolic Ca{sup 2+} and decreased Ca{sup 2+} transient amplitude (P < 0.05), however PCB 126 did not change. The results suggest that PCB 126 shortened the QTc and decreased the APD{sub 90} possibly by increasing I{sub Kr}, while PCB 77 decreased the APD{sub 20} possibly by other modulation related with intracellular Ca{sup 2+}. The present data indicate that the environmental toxicants, PCBs, can acutely affect cardiac electrophysiology including ECG, action potential, intracellular Ca{sup 2+}, and channel activity, resulting in toxic effects on the cardiac function in view of the possible accumulation of the PCBs in human body. -- Highlights: ► PCBs are known as serious environmental pollutants and developmental disruptors. ► PCB 126 shortened QT interval of ECG and action potential duration. ► PCB 126 increased human ether-a-go-go-related K{sup +} current and I{sub Kr}. ► PCB 77 decreased action potential duration and increased intracellular Ca{sup 2+} content. ► PCBs acutely change cardiac electrophysiology and rhythmicity.« less

Dynamic Action Potential Restitution Contributes to Mechanical Restitution in Right Ventricular Myocytes From Pulmonary Hypertensive Rats.

PubMed

Hardy, Matthew E L; Pervolaraki, Eleftheria; Bernus, Olivier; White, Ed

2018-01-01

We investigated the steepened dynamic action potential duration (APD) restitution of rats with pulmonary artery hypertension (PAH) and right ventricular (RV) failure and tested whether the observed APD restitution properties were responsible for negative mechanical restitution in these myocytes. PAH and RV failure were provoked in male Wistar rats by a single injection of monocrotaline (MCT) and compared with saline-injected animals (CON). Action potentials were recorded from isolated RV myocytes at stimulation frequencies between 1 and 9 Hz. Action potential waveforms recorded at 1 Hz were used as voltage clamp profiles (action potential clamp) at stimulation frequencies between 1 and 7 Hz to evoke rate-dependent currents. Voltage clamp profiles mimicking typical CON and MCT APD restitution were applied and cell shortening simultaneously monitored. Compared with CON myocytes, MCT myocytes were hypertrophied; had less polarized diastolic membrane potentials; had action potentials that were triggered by decreased positive current density and shortened by decreased negative current density; APD was longer and APD restitution steeper. APD90 restitution was unchanged by exposure to the late Na + -channel blocker (5 μM) ranolazine or the intracellular Ca 2+ buffer BAPTA. Under AP clamp, stimulation frequency-dependent inward currents were smaller in MCT myocytes and were abolished by BAPTA. In MCT myocytes, increasing stimulation frequency decreased contraction amplitude when depolarization duration was shortened, to mimic APD restitution, but not when depolarization duration was maintained. We present new evidence that the membrane potential of PAH myocytes is less stable than normal myocytes, being more easily perturbed by external currents. These observations can explain increased susceptibility to arrhythmias. We also present novel evidence that negative APD restitution is at least in part responsible for the negative mechanical restitution in PAH myocytes. Thus, our study links electrical restitution remodeling to a defining mechanical characteristic of heart failure, the reduced ability to respond to an increase in demand.

NVP-QBE170: an inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia

PubMed Central

Coote, K J; Paisley, D; Czarnecki, S; Tweed, M; Watson, H; Young, A; Sugar, R; Vyas, M; Smith, N J; Baettig, U; Groot-Kormelink, P J; Gosling, M; Lock, R; Ethell, B; Williams, G; Schumacher, A; Harris, J; Abraham, W M; Sabater, J; Poll, C T; Faller, T; Collingwood, S P; Danahay, H

2015-01-01

Background and Purpose Inhaled amiloride, a blocker of the epithelial sodium channel (ENaC), enhances mucociliary clearance (MCC) in cystic fibrosis (CF) patients. However, the dose of amiloride is limited by the mechanism-based side effect of hyperkalaemia resulting from renal ENaC blockade. Inhaled ENaC blockers with a reduced potential to induce hyperkalaemia provide a therapeutic strategy to improve mucosal hydration and MCC in the lungs of CF patients. The present study describes the preclinical profile of a novel ENaC blocker, NVP-QBE170, designed for inhaled delivery, with a reduced potential to induce hyperkalaemia. Experimental Approach The in vitro potency and duration of action of NVP-QBE170 were compared with amiloride and a newer ENaC blocker, P552-02, in primary human bronchial epithelial cells (HBECs) by short-circuit current. In vivo efficacy and safety were assessed in guinea pig (tracheal potential difference/hyperkalaemia), rat (hyperkalaemia) and sheep (MCC). Key Results In vitro, NVP-QBE170 potently inhibited ENaC function in HBEC and showed a longer duration of action to comparator molecules. In vivo, intratracheal (i.t.) instillation of NVP-QBE170 attenuated ENaC activity in the guinea pig airways with greater potency and duration of action than that of amiloride without inducing hyperkalaemia in either guinea pig or rat. Dry powder inhalation of NVP-QBE170 by conscious sheep increased MCC and was better than inhaled hypertonic saline in terms of efficacy and duration of action. Conclusions and Implications NVP-QBE170 highlights the potential for inhaled ENaC blockers to exhibit efficacy in the airways with a reduced risk of hyperkalaemia, relative to existing compounds. PMID:25573195

NVP-QBE170: an inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia.

PubMed

Coote, K J; Paisley, D; Czarnecki, S; Tweed, M; Watson, H; Young, A; Sugar, R; Vyas, M; Smith, N J; Baettig, U; Groot-Kormelink, P J; Gosling, M; Lock, R; Ethell, B; Williams, G; Schumacher, A; Harris, J; Abraham, W M; Sabater, J; Poll, C T; Faller, T; Collingwood, S P; Danahay, H

2015-06-01

Inhaled amiloride, a blocker of the epithelial sodium channel (ENaC), enhances mucociliary clearance (MCC) in cystic fibrosis (CF) patients. However, the dose of amiloride is limited by the mechanism-based side effect of hyperkalaemia resulting from renal ENaC blockade. Inhaled ENaC blockers with a reduced potential to induce hyperkalaemia provide a therapeutic strategy to improve mucosal hydration and MCC in the lungs of CF patients. The present study describes the preclinical profile of a novel ENaC blocker, NVP-QBE170, designed for inhaled delivery, with a reduced potential to induce hyperkalaemia. The in vitro potency and duration of action of NVP-QBE170 were compared with amiloride and a newer ENaC blocker, P552-02, in primary human bronchial epithelial cells (HBECs) by short-circuit current. In vivo efficacy and safety were assessed in guinea pig (tracheal potential difference/hyperkalaemia), rat (hyperkalaemia) and sheep (MCC). In vitro, NVP-QBE170 potently inhibited ENaC function in HBEC and showed a longer duration of action to comparator molecules. In vivo, intratracheal (i.t.) instillation of NVP-QBE170 attenuated ENaC activity in the guinea pig airways with greater potency and duration of action than that of amiloride without inducing hyperkalaemia in either guinea pig or rat. Dry powder inhalation of NVP-QBE170 by conscious sheep increased MCC and was better than inhaled hypertonic saline in terms of efficacy and duration of action. NVP-QBE170 highlights the potential for inhaled ENaC blockers to exhibit efficacy in the airways with a reduced risk of hyperkalaemia, relative to existing compounds. © 2015 The British Pharmacological Society.

Ventricular filling slows epicardial conduction and increases action potential duration in an optical mapping study of the isolated rabbit heart.

PubMed

Sung, Derrick; Mills, Robert W; Schettler, Jan; Narayan, Sanjiv M; Omens, Jeffrey H; McCulloch, Andrew D

2003-07-01

Mechanical stimulation can induce electrophysiologic changes in cardiac myocytes, but how mechanoelectric feedback in the intact heart affects action potential propagation remains unclear. Changes in action potential propagation and repolarization with increased left ventricular end-diastolic pressure from 0 to 30 mmHg were investigated using optical mapping in isolated perfused rabbit hearts. With respect to 0 mmHg, epicardial strain at 30 mmHg in the anterior left ventricle averaged 0.040 +/- 0.004 in the muscle fiber direction and 0.032 +/- 0.006 in the cross-fiber direction. An increase in ventricular loading increased average epicardial activation time by 25%+/- 3% (P < 0.0001) and correspondingly decreased average apparent surface conduction velocity by 16%+/- 7% (P = 0.007). Ventricular loading did not significantly alter action potential duration at 20% repolarization (APD20) but did at 80% repolarization (APD80), from 179 +/- 7 msec to 207 +/- 5 msec (P < 0.0001). The dispersion of APD20 was decreased with loading from 19 +/- 2 msec to 13 +/- 2 msec (P = 0.024), whereas the dispersion of APD80 was not significantly changed. These electrophysiologic changes with ventricular loading were not affected by the nonspecific stretch-activated channel blocker streptomycin (200 microM) and were not attributable to changes in myocardial perfusion or the presence of an electromechanical decoupling agent (butanedione monoxime) during optical mapping. Acute loading of the left ventricle of the isolated rabbit heart decreased apparent epicardial conduction velocity and increased action potential duration by a load-dependent mechanism that may not involve stretch-activated channels.

Overexpression of the Large-Conductance, Ca2+-Activated K+ (BK) Channel Shortens Action Potential Duration in HL-1 Cardiomyocytes.

PubMed

Stimers, Joseph R; Song, Li; Rusch, Nancy J; Rhee, Sung W

2015-01-01

Long QT syndrome is characterized by a prolongation of the interval between the Q wave and the T wave on the electrocardiogram. This abnormality reflects a prolongation of the ventricular action potential caused by a number of genetic mutations or a variety of drugs. Since effective treatments are unavailable, we explored the possibility of using cardiac expression of the large-conductance, Ca2+-activated K+ (BK) channel to shorten action potential duration (APD). We hypothesized that expression of the pore-forming α subunit of human BK channels (hBKα) in HL-1 cells would shorten action potential duration in this mouse atrial cell line. Expression of hBKα had minimal effects on expression levels of other ion channels with the exception of a small but significant reduction in Kv11.1. Patch-clamped hBKα expressing HL-1 cells exhibited an outward voltage- and Ca2+-sensitive K+ current, which was inhibited by the BK channel blocker iberiotoxin (100 nM). This BK current phenotype was not detected in untransfected HL-1 cells or in HL-1 null cells sham-transfected with an empty vector. Importantly, APD in hBKα-expressing HL-1 cells averaged 14.3 ± 2.8 ms (n = 10), which represented a 53% reduction in APD compared to HL-1 null cells lacking BKα expression. APD in the latter cells averaged 31.0 ± 5.1 ms (n = 13). The shortened APD in hBKα-expressing cells was restored to normal duration by 100 nM iberiotoxin, suggesting that a repolarizing K+ current attributed to BK channels accounted for action potential shortening. These findings provide initial proof-of-concept that the introduction of hBKα channels into a cardiac cell line can shorten APD, and raise the possibility that gene-based interventions to increase hBKα channels in cardiac cells may hold promise as a therapeutic strategy for long QT syndrome.

Compound muscle action potential duration in critical illness neuromyopathy.

PubMed

Kramer, Christopher L; Boon, Andrea J; Harper, C Michel; Goodman, Brent P

2018-03-01

We sought to determine the specificity of compound muscle action potential (CMAP) durations and amplitudes in a large critical illness neuromyopathy (CINM) cohort relative to controls with other neuromuscular conditions. Fifty-eight patients with CINM who had been seen over a 17-year period were retrospectively studied. Electrodiagnostic findings of the CINM cohort were compared with patients with axonal peripheral neuropathy and myopathy due to other causes. Mean CMAP durations were prolonged, and mean CMAP amplitudes were severely reduced both proximally and distally in all nerves studied in the CINM cohort relative to the control groups. The specificity of prolonged CMAP durations for CINM approached 100% if they were encountered in more than 1 nerve. Prolonged, low-amplitude CMAPs occur more frequently and with greater severity in CINM patients than in neuromuscular controls with myopathy and axonal neuropathy and are highly specific for the diagnosis of CINM. Muscle Nerve 57: 395-400, 2018. © 2017 Wiley Periodicals, Inc.

Simulation of action potentials from metabolically impaired cardiac myocytes. Role of ATP-sensitive K+ current.

PubMed

Ferrero, J M; Sáiz, J; Ferrero, J M; Thakor, N V

1996-08-01

The role of the ATP-sensitive K+ current (IK-ATP) and its contribution to electrophysiological changes that occur during metabolic impairment in cardiac ventricular myocytes is still being discussed. The aim of this work was to quantitatively study this issue by using computer modeling. A model of IK-ATP is formulated and incorporated into the Luo-Rudy ionic model of the ventricular action potential. Action potentials under different degrees of activation of IK-ATP are simulated. Our results show that in normal ionic concentrations, only approximately 0.6% of the KATP channels, when open, should account for a 50% reduction in action potential duration. However, increased levels of intracellular Mg2+ counteract this shortening. Under conditions of high [K+]0, such as those found in early ischemia, the activation of only approximately 0.4% of the KATP channels could account for a 50% reduction in action potential duration. Thus, our results suggest that opening of IK-ATP channels should play a significant role in action potential shortening during hypoxic/ischemic episodes, with the fraction of open channels involved being very low ( < 1%). However, the results of the model suggest that activation of IK-ATP alone does not quantitatively account for the observed K+ efflux in metabolically impaired cardiac myocytes. Mechanisms other than KATP channel activation should be responsible for a significant part of the K+ efflux measured in hypoxic/ischemic situations.

Peripheral nerve recruitment curve using near-infrared stimulation

NASA Astrophysics Data System (ADS)

Dautrebande, Marie; Doguet, Pascal; Gorza, Simon-Pierre; Delbeke, Jean; Nonclercq, Antoine

2018-02-01

In the context of near-infrared neurostimulation, we report on an experimental hybrid electrode allowing for simultaneous photonic or electrical neurostimulation and for electrical recording of evoked action potentials. The electrode includes three contacts and one optrode. The optrode is an opening in the cuff through which the tip of an optical fibre is held close to the epineurium. Two contacts provide action potential recording. The remaining contact, together with a remote subcutaneous electrode, is used for electric stimulation which allows periodical assessment of the viability of the nerve during the experiment. A 1470 nm light source was used to stimulate a mouse sciatic nerve. Neural action potentials were not successfully recorded because of the electrical noise so muscular activity was used to reflect the motor fibres stimulation. A recruitment curve was obtained by stimulating with photonic pulses of same power and increasing duration and recording the evoked muscular action potentials. Motor fibres can be recruited with radiant exposures between 0.05 and 0.23 J/cm2 for pulses in the 100 to 500 μs range. Successful stimulation at short duration and at a commercial wavelength is encouraging in the prospect of miniaturisation and practical applications. Motor fibres recruitment curve is a first step in an ongoing research work. Neural action potential acquisition will be improved, with aim to shed light on the mechanism of action potential initiation under photonic stimulation.

[Patterns of action potential firing in cortical neurons of neonatal mice and their electrophysiological property].

PubMed

Furong, Liu; Shengtian, L I

2016-05-25

To investigate patterns of action potential firing in cortical heurons of neonatal mice and their electrophysiological properties. The passive and active membrane properties of cortical neurons from 3-d neonatal mice were observed by whole-cell patch clamp with different voltage and current mode. Three patterns of action potential firing were identified in response to depolarized current injection. The effects of action potential firing patterns on voltage-dependent inward and outward current were found. Neurons with three different firing patterns had different thresholds of depolarized current. In the morphology analysis of action potential, the three type neurons were different in rise time, duration, amplitude and threshold of the first action potential evoked by 80 pA current injection. The passive properties were similar in three patterns of action potential firing. These results indicate that newborn cortical neurons exhibit different patterns of action potential firing with different action potential parameters such as shape and threshold.

A Quantitative Comparison of the Behavior of Human Ventricular Cardiac Electrophysiology Models in Tissue

PubMed Central

Elshrif, Mohamed M.; Cherry, Elizabeth M.

2014-01-01

Numerical integration of mathematical models of heart cell electrophysiology provides an important computational tool for studying cardiac arrhythmias, but the abundance of available models complicates selecting an appropriate model. We study the behavior of two recently published models of human ventricular action potentials, the Grandi-Pasqualini-Bers (GPB) and the O'Hara-Virág-Varró-Rudy (OVVR) models, and compare the results with four previously published models and with available experimental and clinical data. We find the shapes and durations of action potentials and calcium transients differ between the GPB and OVVR models, as do the magnitudes and rate-dependent properties of transmembrane currents and the calcium transient. Differences also occur in the steady-state and S1–S2 action potential duration and conduction velocity restitution curves, including a maximum conduction velocity for the OVVR model roughly half that of the GPB model and well below clinical values. Between single cells and tissue, both models exhibit differences in properties, including maximum upstroke velocity, action potential amplitude, and minimum diastolic interval. Compared to experimental data, action potential durations for the GPB and OVVR models agree fairly well (although OVVR epicardial action potentials are shorter), but maximum slopes of steady-state restitution curves are smaller. Although studies show alternans in normal hearts, it occurs only in the OVVR model, and only for a narrow range of cycle lengths. We find initiated spiral waves do not progress to sustained breakup for either model. The dominant spiral wave period of the GPB model falls within clinically relevant values for ventricular tachycardia (VT), but for the OVVR model, the dominant period is longer than periods associated with VT. Our results should facilitate choosing a model to match properties of interest in human cardiac tissue and to replicate arrhythmia behavior more closely. Furthermore, by indicating areas where existing models disagree, our findings suggest avenues for further experimental work. PMID:24416228

Ventricular filling slows epicardial conduction and increases action potential duration in an optical mapping study of the isolated rabbit heart

NASA Technical Reports Server (NTRS)

Sung, Derrick; Mills, Robert W.; Schettler, Jan; Narayan, Sanjiv M.; Omens, Jeffrey H.; McCulloch, Andrew D.; McCullough, A. D. (Principal Investigator)

2003-01-01

INTRODUCTION: Mechanical stimulation can induce electrophysiologic changes in cardiac myocytes, but how mechanoelectric feedback in the intact heart affects action potential propagation remains unclear. METHODS AND RESULTS: Changes in action potential propagation and repolarization with increased left ventricular end-diastolic pressure from 0 to 30 mmHg were investigated using optical mapping in isolated perfused rabbit hearts. With respect to 0 mmHg, epicardial strain at 30 mmHg in the anterior left ventricle averaged 0.040 +/- 0.004 in the muscle fiber direction and 0.032 +/- 0.006 in the cross-fiber direction. An increase in ventricular loading increased average epicardial activation time by 25%+/- 3% (P < 0.0001) and correspondingly decreased average apparent surface conduction velocity by 16%+/- 7% (P = 0.007). Ventricular loading did not significantly alter action potential duration at 20% repolarization (APD20) but did at 80% repolarization (APD80), from 179 +/- 7 msec to 207 +/- 5 msec (P < 0.0001). The dispersion of APD20 was decreased with loading from 19 +/- 2 msec to 13 +/- 2 msec (P = 0.024), whereas the dispersion of APD80 was not significantly changed. These electrophysiologic changes with ventricular loading were not affected by the nonspecific stretch-activated channel blocker streptomycin (200 microM) and were not attributable to changes in myocardial perfusion or the presence of an electromechanical decoupling agent (butanedione monoxime) during optical mapping. CONCLUSION: Acute loading of the left ventricle of the isolated rabbit heart decreased apparent epicardial conduction velocity and increased action potential duration by a load-dependent mechanism that may not involve stretch-activated channels.

Sleep and metabolic control: waking to a problem?

PubMed

Trenell, Michael I; Marshall, Nathaniel S; Rogers, Naomi L

2007-01-01

1. The aim of the present review is to outline: (i) the association between sleep and metabolism; (ii) how sleep duration influences the development of disease; and (iii) how sex differences, ageing and obesity may potentially influence the relationship between sleep, metabolic control and subsequent disease. 2. Sleep is associated with a number of endocrine changes, including a change in insulin action in healthy young individuals. Sleep duration shows a prospective U-shaped relationship with all-cause mortality, cardiovascular disease and Type 2 diabetes. 3. Chronic sleep restriction is becoming more common. Experimental sleep restriction impedes daytime glucose control and increases appetite. 4. The sex hormones oestrogen and testosterone influence sleep duration and quality and may account for sex differences in the prevalence of sleep-related disorders. 5. Ageing is associated with a decreased sleep duration, decreased muscle mass and impaired insulin action. 6. Obesity impairs insulin action and is associated with the incidence and severity of obstructive sleep apnoea. 7. Sleep plays an integral role in metabolic control. Consequently, insufficient sleep may represent a modifiable risk factor for the development of Type 2 diabetes. The challenge ahead is to identify how sex differences, ageing and obesity could potentially influence the relationship between sleep and metabolism.

The influence of passband limitation on the waveform of extracellular action potential.

PubMed

Mizuhiki, Takashi; Inaba, Kiyonori; Setogawa, Tsuyoshi; Toda, Koji; Ozaki, Shigeru; Shidara, Muneteka

2012-03-01

The duration of the extracellular action potential (EAP) in single neuronal recording has often been used as a clue to infer biochemical, physiological or functional substrate of the recorded neurons, e.g. neurochemical type. However, when recording a neuronal activity, the high-pass filter is routinely used to achieve higher signal-to-noise ratio. Signal processing theory predicts that passband limitation stretches the waveform of discrete brief impulse. To examine whether the duration of filtered EAP could be the reliable measure, we investigated the influence of high-pass filter both by simulation and unfiltered unit recording data from monkey dorsal raphe. Consistent with the findings in recent theoretical study, the unfiltered EAPs displayed the sharp wave without following bumps. The duration of unfiltered EAP was not correlated with that of filtered EAP. Thus the duration of original EAP cannot be estimated from filtered EAP. It is needed to reexamine the EAP duration measured for classifying the neurons whose activities were recorded under the passband limitation in the related studies. Copyright © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Median and ulnar muscle and sensory evoked potentials.

PubMed

Felsenthal, G

1978-08-01

The medical literature was reviewed to find suggested clinical applications of the study of the amplitude of evoked muscle action potentials (MAP) and sensory action potentials (SAP). In addition, the literature was reviewed to ascertain the normal amplitude and duration of the evoked MAP and SAP as well as the factors affecting the amplitude: age, sex, temperature, ischemia. The present study determined the normal amplitude and duration of the median and ulnar MAP and SAP in fifty normal subjects. The amplitude of evoked muscle or sensory action potentials depends on multiple factors. Increased skin resistance, capacitance, and impedance at the surface of the recording electrode diminishes the amplitude. Similarly, increased distance from the source of the action potential diminishes its amplitude. Increased interelectrode distance increases the amplitude of the bipolarly recorded sensory action potential until a certain interelectrode distance is exceeded and the diphasic response becomes tri- or tetraphasic. Artifact or poor technique may reduce the potential difference between the recording electrodes or obscure the late positive phase of the action potential and thus diminish the peak to peak amplitude measurement. Intraindividual comparison indicated a marked difference of amplitude in opposite hands. The range of the MAP of the abductor pollicis brevis in one hand was 40.0--100% of the response in the opposite hand. For the abductor digiti minimi, the MAP was 58.5--100% of the response of the opposite hand. The median and ulnar SAP was between 50--100% of the opposite SAP. Consequent to these findings the effect of hand dominance on the amplitude of median and ulnar evoked muscle and sensory action potentials was studied in 41 right handed volunteers. The amplitudes of the median muscle action potential (p less than 0.02) and the median and ulnar sensory action potentials (p less than 0.001) were significantly less in the dominant hand. There was no significant difference between the ulnar muscle action potentials or for the median and ulnar distal motor and sensory latencies in the right and left hands of this group of volunteers.

The pacemaker activity generating the intrinsic myogenic contraction of the dorsal vessel of Tenebrio molitor (Coleoptera).

PubMed

Markou, T; Theophilidis, G

2000-11-01

Combined intracellular and extracellular recordings from various parts of the isolated dorsal vessel of Tenebrio molitor revealed some of the following electrophysiological properties of the heart and the aorta. (i) The wave of depolarization causing forward pulsation of the dorsal vessel was always transmitted from posterior to anterior, with a conduction velocity of 0.014 m s(-1) in the heart and 0.001 m s(-1) in the aorta when the heart rate was 60 beats min(-1). (ii) There was no pacemaker activity in the aorta. (iii) The duration of the compound action potential in the aortic muscle depended on the duration of the pacemaker action potential generated in the heart. (iv) Isolated parts of the heart continued to contract rhythmically for hours, indicating powerful pacemaker activity in individual cardiac segments. (v) There was a direct relationship between action potential duration and the length of the preceding diastolic interval. (vi) The rhythmic wave of depolarization was dependent on the influx of Ca(2+). (vii) The recovery of the electrical properties of myocardial cells that had been disrupted by sectioning was rapid. (viii) In hearts sectioned into two halves, the rhythmic pacemaker action potentials recorded simultaneously from the two isolated halves eventually drifted out of phase, but they had the same intrinsic frequency. In the light of these data, we discuss two alternative models for the generation of spontaneous rhythmic pumping movements of the heart and aorta.

TRPM4 non-selective cation channels influence action potentials in rabbit Purkinje fibres.

PubMed

Hof, Thomas; Sallé, Laurent; Coulbault, Laurent; Richer, Romain; Alexandre, Joachim; Rouet, René; Manrique, Alain; Guinamard, Romain

2016-01-15

The transient receptor potential melastatin 4 (TRPM4) inhibitor 9-phenanthrol reduces action potential duration in rabbit Purkinje fibres but not in ventricle. TRPM4-like single channel activity is observed in isolated rabbit Purkinje cells but not in ventricular cells. The TRPM4-like current develops during the notch and early repolarization phases of the action potential in Purkinje cells. Transient receptor potential melastatin 4 (TRPM4) Ca(2+)-activated non-selective cation channel activity has been recorded in cardiomyocytes and sinus node cells from mammals. In addition, TRPM4 gene mutations are associated with human diseases of cardiac conduction, suggesting that TRPM4 plays a role in this aspect of cardiac function. Here we evaluate the TRPM4 contribution to cardiac electrophysiology of Purkinje fibres. Ventricular strips with Purkinje fibres were isolated from rabbit hearts. Intracellular microelectrodes recorded Purkinje fibre activity and the TRPM4 inhibitor 9-phenanthrol was applied to unmask potential TRPM4 contributions to the action potential. 9-Phenanthrol reduced action potential duration measured at the point of 50 and 90% repolarization with an EC50 of 32.8 and 36.1×10(-6) mol l(-1), respectively, but did not modulate ventricular action potentials. Inside-out patch-clamp recordings were used to monitor TRPM4 activity in isolated Purkinje cells. TRPM4-like single channel activity (conductance = 23.8 pS; equal permeability for Na(+) and K(+); sensitivity to voltage, Ca(2+) and 9-phenanthrol) was observed in 43% of patches from Purkinje cells but not from ventricular cells (0/16). Action potential clamp experiments performed in the whole-cell configuration revealed a transient inward 9-phenanthrol-sensitive current (peak density = -0.65 ± 0.15 pA pF(-1); n = 5) during the plateau phases of the Purkinje fibre action potential. These results show that TRPM4 influences action potential characteristics in rabbit Purkinje fibres and thus could modulate cardiac conduction and be involved in triggering arrhythmias. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids

PubMed Central

Covey, Dan P.; Bunner, Kendra D.; Schuweiler, Douglas R.; Cheer, Joseph F.; Garris, Paul A.

2018-01-01

The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement. PMID:27038339

Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids.

PubMed

Covey, Dan P; Bunner, Kendra D; Schuweiler, Douglas R; Cheer, Joseph F; Garris, Paul A

2016-06-01

The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Effects of acetylcholine and noradrenalin on action potentials of isolated rabbit sinoatrial and atrial myocytes.

PubMed

Verkerk, Arie O; Geuzebroek, Guillaume S C; Veldkamp, Marieke W; Wilders, Ronald

2012-01-01

The autonomic nervous system controls heart rate and contractility through sympathetic and parasympathetic inputs to the cardiac tissue, with acetylcholine (ACh) and noradrenalin (NA) as the chemical transmitters. In recent years, it has become clear that specific Regulators of G protein Signaling proteins (RGS proteins) suppress muscarinic sensitivity and parasympathetic tone, identifying RGS proteins as intriguing potential therapeutic targets. In the present study, we have identified the effects of 1 μM ACh and 1 μM NA on the intrinsic action potentials of sinoatrial (SA) nodal and atrial myocytes. Single cells were enzymatically isolated from the SA node or from the left atrium of rabbit hearts. Action potentials were recorded using the amphotericin-perforated patch-clamp technique in the absence and presence of ACh, NA, or a combination of both. In SA nodal myocytes, ACh increased cycle length and decreased diastolic depolarization rate, whereas NA decreased cycle length and increased diastolic depolarization rate. Both ACh and NA increased maximum upstroke velocity. Furthermore, ACh hyperpolarized the maximum diastolic potential. In atrial myocytes stimulated at 2 Hz, both ACh and NA hyperpolarized the maximum diastolic potential, increased the action potential amplitude, and increased the maximum upstroke velocity. Action potential duration at 50 and 90% repolarization was decreased by ACh, but increased by NA. The effects of both ACh and NA on action potential duration showed a dose dependence in the range of 1-1000 nM, while a clear-cut frequency dependence in the range of 1-4 Hz was absent. Intermediate results were obtained in the combined presence of ACh and NA in both SA nodal and atrial myocytes. Our data uncover the extent to which SA nodal and atrial action potentials are intrinsically dependent on ACh, NA, or a combination of both and may thus guide further experiments with RGS proteins.

Effects of Acetylcholine and Noradrenalin on Action Potentials of Isolated Rabbit Sinoatrial and Atrial Myocytes

PubMed Central

Verkerk, Arie O.; Geuzebroek, Guillaume S. C.; Veldkamp, Marieke W.; Wilders, Ronald

2012-01-01

The autonomic nervous system controls heart rate and contractility through sympathetic and parasympathetic inputs to the cardiac tissue, with acetylcholine (ACh) and noradrenalin (NA) as the chemical transmitters. In recent years, it has become clear that specific Regulators of G protein Signaling proteins (RGS proteins) suppress muscarinic sensitivity and parasympathetic tone, identifying RGS proteins as intriguing potential therapeutic targets. In the present study, we have identified the effects of 1 μM ACh and 1 μM NA on the intrinsic action potentials of sinoatrial (SA) nodal and atrial myocytes. Single cells were enzymatically isolated from the SA node or from the left atrium of rabbit hearts. Action potentials were recorded using the amphotericin-perforated patch-clamp technique in the absence and presence of ACh, NA, or a combination of both. In SA nodal myocytes, ACh increased cycle length and decreased diastolic depolarization rate, whereas NA decreased cycle length and increased diastolic depolarization rate. Both ACh and NA increased maximum upstroke velocity. Furthermore, ACh hyperpolarized the maximum diastolic potential. In atrial myocytes stimulated at 2 Hz, both ACh and NA hyperpolarized the maximum diastolic potential, increased the action potential amplitude, and increased the maximum upstroke velocity. Action potential duration at 50 and 90% repolarization was decreased by ACh, but increased by NA. The effects of both ACh and NA on action potential duration showed a dose dependence in the range of 1–1000 nM, while a clear-cut frequency dependence in the range of 1–4 Hz was absent. Intermediate results were obtained in the combined presence of ACh and NA in both SA nodal and atrial myocytes. Our data uncover the extent to which SA nodal and atrial action potentials are intrinsically dependent on ACh, NA, or a combination of both and may thus guide further experiments with RGS proteins. PMID:22754533

Inhibition of the reverse mode of the Na+/Ca2+ exchange by KB-R7943 augments arrhythmogenicity in the canine heart during rapid heart rates.

PubMed

Shinada, Takuro; Hirayama, Yoshiyuki; Maruyama, Mitsunori; Ohara, Toshihiko; Yashima, Masaaki; Kobayashi, Yoshinori; Atarashi, Hirotsugu; Takano, Teruo

2005-07-01

To test the hypothesis that the reverse mode of the Na+/Ca2+ exchange augmented by a rapid heart rate has an antiarrhythmic effect by shortening the action potential duration, we examined the effects of KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl] isothiourea methanesulfonate), a selective inhibitor of the reverse mode of the Na+/Ca2+ exchange, to attenuate this effect. We recorded the electrocardiogram, monophasic action potential (MAP), and left ventricular pressure in canine beating hearts. In comparison to the control, KB-R7943 significantly increased the QTc value and MAP duration. MAP alternans and left ventricular pressure alternans were observed after changing the cycle length to 300 milliseconds in the control studies. KB-R7943 magnified both types of alternans and produced spatially discordant alternans between right and left ventricles. Early after-depolarizations and nonsustained ventricular tachycardia occurred in the presence of KB-R7943. Our data suggest that the reverse mode of the Na+/Ca2+ exchange may contribute to suppression of arrhythmias by abbreviating action potential duration under pathophysiological conditions. This conclusion is based on further confirmation by future studies of the specificity of KB-R7943 for block of the reverse mode of the Na+/Ca2+ exchange.

[Effects of dauricine on action potentials and slow inward currents of guinea pig ventricular papillary muscles].

PubMed

Li, S N; Zhang, K Y

1992-11-01

Effects of dauricine (Dau) on the action potentials (AP), the slow action potentials (SAP), and the slow inward currents (Isi) of guinea pig ventricular papillary muscles were observed by means of intracellular microelectrode and single sucrose gap voltage clamp technique. In the early stage, Dau shortened action potential duration 100 (APD100) and effective refractory period (ERP) (ERP/APD < 1; P < 0.01), but did not affect APD20 and other parameters. In the late stage, Dau prolonged APD100, ERP, and APD20, significantly decreased action potential amplitude (APA), maximum velocity (Vmax), and overshot (OS) (ERP/APD > 1; P < 0.01), greatly diminished APA and OS of SAP induced by isoprenaline (P < 0.01), and remarkably inhibited Isi (P < 0.01). The results suggested that Dau exerted an inhibitory effect on Na+, Ca2+, and K+ channels.

Effects of redox and sulfhydryl reagents on the bioelectric properties of the giant axon of the squid.

PubMed

Huneeus-Cox, F; Fernandez, H L; Smith, B H

1966-09-01

The effects of internally and externally applied sulfhydryl reagents on the bioelectric properties of the giant axon of the squid Loligo pealeii and Dosidicus gigas were studied. Cysteine-HCl (400 mM, pH 7.3) was used to remove axoplasm from the perfusion channel. Oxidizing agents (1 to 60 mM) tended to increase the duration of the action potential and had a slow, irreversible blocking effect when perfused internally; the membrane potential was little affected. Reducing agents applied internally caused a decrease in the spike duration without affecting its height or the membrane potential, although at high concentrations there was reversible deterioration of the action potential. Both external and internal perfusion of mercaptide-forming reagents caused deterioration in the action and membrane potentials with conduction block occurring in 5 to 45 min. 2-mercaptoethanol reversed the effects. Thiol alkylating reagents, iodoacetate and iodoacetamide, were without effect. N-ethylmaleimide did, however, block. Tests with chelating agents for nonheme iron in the membrane brought about no change in the electrical parameters. The implications of the present findings with regard to the macromolecular mechanism of excitation are discussed.

Effects of Redox and Sulfhydryl Reagents on the Bioelectric Properties of the Giant Axon of the Squid

PubMed Central

Huneeus-Cox, F.; Fernandez, H. L.; Smith, B. H.

1966-01-01

The effects of internally and externally applied sulfhydryl reagents on the bioelectric properties of the giant axon of the squid Loligo pealeii and Dosidicus gigas were studied. Cysteine-HCl (400 mM, pH 7.3) was used to remove axoplasm from the perfusion channel. Oxidizing agents (1 to 60 mM) tended to increase the duration of the action potential and had a slow, irreversible blocking effect when perfused internally; the membrane potential was little affected. Reducing agents applied internally caused a decrease in the spike duration without affecting its height or the membrane potential, although at high concentrations there was reversible deterioration of the action potential. Both external and internal perfusion of mercaptide-forming reagents caused deterioration in the action and membrane potentials with conduction block occurring in 5 to 45 min. 2-mercaptoethanol reversed the effects. Thiol alkylating reagents, iodoacetate and iodoacetamide, were without effect. N-ethylmaleimide did, however, block. Tests with chelating agents for nonheme iron in the membrane brought about no change in the electrical parameters. The implications of the present findings with regard to the macromolecular mechanism of excitation are discussed. ImagesFigure 1 PMID:5970570

Effects of ethyl chloride spray on pain and parameters of needle electromyography in the upper extremity.

PubMed

Moon, Young-Eun; Kim, Sang-Hyun

2014-10-01

The aim of this study was to compare the effects of ethyl chloride and placebo sprays for reducing pain induced by needle electromyography and changes in parameters of the motor unit action potential during needle electromyography of the upper extremity. Sixty patients were randomized into the ethyl chloride or placebo spray groups. In both groups, spray was applied just before needle electromyography of the flexor carpi radialis, and a visual analog scale to evaluate the pain of needle electromyography and a five-point Likert scale for patient satisfaction and preference for reexamination were compared between the two groups. Then, changes in the amplitude, phases, turns, and duration of the motor unit action potential during needle electromyography of the biceps brachii were compared before and after spraying in each group. The visual analog scale was significantly lower, and patient satisfaction and preference for reexamination were significantly higher in the ethyl chloride spray group. Among the parameters of the motor unit action potential, there were no significant changes except for an increased duration after spraying with ethyl chloride. Ethyl chloride spray can effectively reduce pain, but it must be used with caution because it may affect parameters of the motor unit action potential during needle electromyography.

Warm Body Temperature Facilitates Energy Efficient Cortical Action Potentials

PubMed Central

Yu, Yuguo; Hill, Adam P.; McCormick, David A.

2012-01-01

The energy efficiency of neural signal transmission is important not only as a limiting factor in brain architecture, but it also influences the interpretation of functional brain imaging signals. Action potential generation in mammalian, versus invertebrate, axons is remarkably energy efficient. Here we demonstrate that this increase in energy efficiency is due largely to a warmer body temperature. Increases in temperature result in an exponential increase in energy efficiency for single action potentials by increasing the rate of Na+ channel inactivation, resulting in a marked reduction in overlap of the inward Na+, and outward K+, currents and a shortening of action potential duration. This increase in single spike efficiency is, however, counterbalanced by a temperature-dependent decrease in the amplitude and duration of the spike afterhyperpolarization, resulting in a nonlinear increase in the spike firing rate, particularly at temperatures above approximately 35°C. Interestingly, the total energy cost, as measured by the multiplication of total Na+ entry per spike and average firing rate in response to a constant input, reaches a global minimum between 37–42°C. Our results indicate that increases in temperature result in an unexpected increase in energy efficiency, especially near normal body temperature, thus allowing the brain to utilize an energy efficient neural code. PMID:22511855

Spatial variability in T-tubule and electrical remodeling of left ventricular epicardium in mouse hearts with transgenic Gαq overexpression-induced pathological hypertrophy

PubMed Central

Tao, Wen; Shi, Jianjian; Dorn, Gerald W.; Wei, Lei; Rubart, Michael

2012-01-01

Pathological left ventricular hypertrophy (LVH) is consistently associated with prolongation of the ventricular action potentials. A number of previous studies, employing various experimental models of hypertrophy, have revealed marked differences in the effects of hypertrophy on action potential duration (APD) between myocytes from endocardial and epicardial layers of the LV free wall. It is not known, however, whether pathological LVH is also accompanied by redistribution of APD among myocytes from the same layer in the LV free wall. In the experiments here, LV epicardial action potential remodeling was examined in a mouse model of decompensated LVH, produced by cardiac-restricted transgenic Gαq overexpression. Confocal linescanning-based optical recordings of propagated action potentials from individual in situ cardiomyocytes across the outer layer of the anterior LV epicardium demonstrated spatially non-uniform action potential prolongation in transgenic hearts, giving rise to alterations in spatial dispersion of epicardial repolarization. Local density and distribution of anti-Cx43 mmune reactivity in Gαq hearts were unchanged compared to wild-type hearts, suggesting preservation of intercellular coupling. Confocal microscopy also revealed heterogeneous disorganization of T-tubules in epicardial cardiomyocytes in situ. These data provide evidence of the existence of significant electrical and structural heterogeneity within the LV epicardial layer of hearts with transgenic Gαq overexpression-induced hypertrophy, and further support the notion that a small portion of electrically well connected LV tissue can maintain dispersion of action potential duration through heterogeneity in the activities of sarcolemmal ionic currents that control repolarization. It remains to be examined whether other experimental models of pathological LVH, including pressure overload LVH, similarly exhibit alterations in T-tubule organization and/or dispersion of repolarization within distinct layers of LV myocardium. PMID:22728217

Crataegus extract blocks potassium currents in guinea pig ventricular cardiac myocytes.

PubMed

Müller, A; Linke, W; Klaus, W

1999-05-01

Crataegus extract is used in cardiology for the treatment of mild to moderate heart failure (NYHA II) in Germany. However, little is known about the electrophysiological actions of Crataegus extract in the heart. Recently, it was shown that Crataegus extract prolongs the refractory period in isolated perfused hearts and increases action potential duration in guinea pig papillary muscle. It was the aim of this study to find out the mechanism of the increase in action potential duration caused by Crataegus extract. Using the patch-clamp technique, we measured the effects of Crataegus extract (10 mg/l; flavonoid content: 2.25%, total procyanidin content: 11.3 +/- 0.4%) on the inward rectifier and the delayed rectifier potassium current in isolated guinea pig ventricular myocytes. To get some insight into the mechanism underlying the positive inotropic effect of Crataegus extract, we also looked for effects on the L-type calcium current. Crataegus extract slightly blocked both the delayed and the inward rectifier potassium current. The inhibition amounted to 25% and about 15%, respectively. This amount of inhibition of these repolarising currents is sufficient to explain the prolongation of action potential duration caused by Crataegus extract. To our surprise we could not detect any influence of Crataegus extract on the L-type calcium current. In summary, our results show that Crataegus extract blocks repolarising potassium currents in ventricular myocytes. This effect is similar to the action of class III antiarrhythmic drugs and might be the basis of the antiarrhythmic effects described for Crataegus extract. Our measurements of the L-type calcium current indicate that Crataegus extract's positive inotropic effect is not caused by phosphodiesterase inhibition or a beta-sympathomimetic effect.

Pb2+ Modulates Ca2+ Membrane Permeability In Paramecium

NASA Astrophysics Data System (ADS)

Bernal-Martínez, Juan; Ortega Soto, Arturo

2004-09-01

Intracellular recording experiments in current clamp configuration were done to evaluate whether Pb2+ modulates ionic membrane permeability in the fresh water Paramecium tetraurelia. It was found that Pb2+ triggers in a dose-dependent manner, a burst of spontaneous action potentials followed by a robust and sustained after hyper-polarization. In addition, Pb2+ increased the frequency of firing the spontaneous Ca2+-Action Potential and also, the duration of Ca2+-Action Potential, in a dose and reversibly-dependent manner. These results suggest that Pb2+ increases calcium membrane permeability of Paramecium and probably activates a calcium-dependent-potassium conductance in the ciliate.

Monophasic action potentials of right atrium and electrophysiological properties of AV conducting system in patients with hypothyroidism.

PubMed Central

Gavrilescu, S; Luca, C; Streian, C; Lungu, G; Deutsch, G

1976-01-01

In 12 patients with manifest hypothyroidism right atrial monophasic action potentials showed a significant prolongation in comparison with data from normal or euthyroid patients. Atrial effective refractory periods were also significantly prolonged. After thyroid treatment the monophasic action potential duration and the effective refractory period of the right atrium were within normal ranges. In 6 hypothyroid patients studies of AV conduction with the aid of His bundle electrography and atrial pacing showed a supraHisian conduction delay which was manifest in one case and latent in another two. InfraHisian conduction delay was encountered in 2 cases. PMID:1008978

Electrophysiological characteristics of hamster dorsal root ganglion cells and their response to axotomy.

PubMed

Gurtu, S; Smith, P A

1988-02-01

1. The active and passive membrane properties of neurons in the lower lumbar (L6, L7) or sacral (S1) dorsal root ganglia from golden hamsters were examined in vitro by means of conventional intracellular recording techniques. Data were collected from neurons exhibiting action potentials (AP) of 70 mV or more in amplitude. 2. Cells with axonal conduction velocities (CV) greater than 20 m/s were termed fast-A-cells, those with CVs between 2.5 and 20 m/s were termed A-delta-cells, and those with CVs less than 1 m/s were termed C-cells. 3. Fast-A-cells usually exhibited short-duration APs (2.51 +/- 0.41 ms, n = 19) followed by short (less than 50 ms) afterhyperpolarizations (AHPs). C-cells usually exhibited long-duration APs (10.5 +/- 0.69 ms, n = 18) followed by long-duration AHPs (much greater than 50 ms). The characteristics of APs in A-delta-cells (AP mean duration 3.34 +/- 0.42 ms, n = 32) were intermediate between those of fast-A- and C-cells. Long AHPs (duration much greater than 50 ms) were manifest in 43.8% of A-delta-cells. 4. A time-dependent sag in hyperpolarizing electrotonic potentials (rectification) was found in 68.8% of fast-A-cells, 45.5% of A-delta-cells, and 62.5% of C-cells. 5. To examine neuronal properties 1-6 wk after transection of the sciatic nerve (axotomy), cells were reclassified as SAP (short action potential) cells and LAP (long action potential) cells. Cells in the SAP category had AP durations less than 5 ms and included all fast-A-cells and the majority of A-delta-cells. The LAP category included cells with AP durations greater than 8 ms contained only C-cells. 6. Axotomy failed to decrease the CV of LAP cells or A-delta-cells in the SAP group. The CV of LAP cells may have increased (P less than 0.05), whereas that of SAP cells was unchanged. 7. The duration of the AP and AHP of SAP cells were slightly increased (0.1 greater than P greater than 0.05), whereas AP and AHP duration of LAP cells were unchanged after axotomy. AHP amplitudes of all cell types tended to be smaller (0.1 greater than P greater than 0.05). Axotomy did not alter the resting membrane potential or reduce the incidence of rectification in any cell type. 8. Invasion of the soma by axonally evoked APs was impeded in all cell types after axotomy even though a decrease (P less than 0.05) in rheobase of SAP cells occurred.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of recording site on extracted features of motor unit action potential.

PubMed

Artuğ, N Tuğrul; Goker, Imran; Bolat, Bülent; Osman, Onur; Kocasoy Orhan, Elif; Baslo, M Baris

2016-06-01

Motor unit action potential (MUAP), which consists of individual muscle fiber action potentials (MFAPs), represents the electrical activity of the motor unit. The values of the MUAP features are changed by denervation and reinnervation in neurogenic involvement as well as muscle fiber loss with increased diameter variability in myopathic diseases. The present study is designed to investigate how increased muscle fiber diameter variability affects MUAP parameters in simulated motor units. In order to detect this variation, simulated MUAPs were calculated both at the innervation zone where the MFAPs are more synchronized, and near the tendon, where they show increased temporal dispersion. Reinnervation in neurogenic state increases MUAP amplitude for the recordings at both the innervation zone and near the tendon. However, MUAP duration and the number of peaks significantly increased in a case of myopathy for recordings near the tendon. Furthermore, of the new features, "number of peaks×spike duration" was found as the strongest indicator of MFAP dispersion in myopathy. MUAPs were also recorded from healthy participants in order to investigate the biological counterpart of the simulation data. MUAPs which were recorded near to tendon revealed significantly prolonged duration and decreased amplitude. Although the number of peaks was increased by moving the needle near to tendon, this was not significant. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Optical mapping of optogenetically shaped cardiac action potentials.

PubMed

Park, Sarah A; Lee, Shin-Rong; Tung, Leslie; Yue, David T

2014-08-19

Light-mediated silencing and stimulation of cardiac excitability, an important complement to electrical stimulation, promises important discoveries and therapies. To date, cardiac optogenetics has been studied with patch-clamp, multielectrode arrays, video microscopy, and an all-optical system measuring calcium transients. The future lies in achieving simultaneous optical acquisition of excitability signals and optogenetic control, both with high spatio-temporal resolution. Here, we make progress by combining optical mapping of action potentials with concurrent activation of channelrhodopsin-2 (ChR2) or halorhodopsin (eNpHR3.0), via an all-optical system applied to monolayers of neonatal rat ventricular myocytes (NRVM). Additionally, we explore the capability of ChR2 and eNpHR3.0 to shape action-potential waveforms, potentially aiding the study of short/long QT syndromes that result from abnormal changes in action potential duration (APD). These results show the promise of an all-optical system to acquire action potentials with precise temporal optogenetics control, achieving a long-sought flexibility beyond the means of conventional electrical stimulation.

Optical mapping of optogenetically shaped cardiac action potentials

PubMed Central

Park, Sarah A.; Lee, Shin-Rong; Tung, Leslie; Yue, David T.

2014-01-01

Light-mediated silencing and stimulation of cardiac excitability, an important complement to electrical stimulation, promises important discoveries and therapies. To date, cardiac optogenetics has been studied with patch-clamp, multielectrode arrays, video microscopy, and an all-optical system measuring calcium transients. The future lies in achieving simultaneous optical acquisition of excitability signals and optogenetic control, both with high spatio-temporal resolution. Here, we make progress by combining optical mapping of action potentials with concurrent activation of channelrhodopsin-2 (ChR2) or halorhodopsin (eNpHR3.0), via an all-optical system applied to monolayers of neonatal rat ventricular myocytes (NRVM). Additionally, we explore the capability of ChR2 and eNpHR3.0 to shape action-potential waveforms, potentially aiding the study of short/long QT syndromes that result from abnormal changes in action potential duration (APD). These results show the promise of an all-optical system to acquire action potentials with precise temporal optogenetics control, achieving a long-sought flexibility beyond the means of conventional electrical stimulation. PMID:25135113

K(ATP) channel blocker HMR 1883 reduces monophasic action potential shortening during coronary ischemia in anesthetised pigs.

PubMed

Wirth, K J; Uhde, J; Rosenstein, B; Englert, H C; Gögelein, H; Schölkens, B A; Busch, A E

2000-02-01

ATP-sensitive potassium channels (KATP) open during myocardial ischemia. The ensuing repolarising potassium efflux shortens the action potential. Accumulation of extracellular potassium is able to partially depolarise the membrane, reducing the upstroke velocity of the action potential and thereby impairing impulse conduction. Both mechanisms are believed to be involved in the development of reentrant arrhythmias during cardiac ischemia. The sulfonylthiourea HMR 1883 (1-[[5-[2-(5-chloro-O-anisamido)ethyl]-methoxyphenyl]sulfonyl]-3-m ethylthiourea) was designed as a cardioselective KATP channel blocker for the prevention of arrhythmic sudden death in patients with ischemic heart disease. The aim of this study was to show that this compound, which has already shown antifibrillatory efficacy in dogs and rats, is able to inhibit ischemic changes of the action potential induced by coronary artery occlusion in anesthetised pigs. Action potentials were taken in situ with the technique of monophasic action potential (MAP) recording. In a control group (n=7), three consecutive occlusions of a small branch of the left circumflex coronary artery resulted in reproducible reductions in MAP duration and a decrease in upstroke velocity. In a separate group (n=7), HMR 1883 (3 mg/kg i.v.) significantly (P<0.05) reduced the ischemia-induced shortening of the MAP: during the first and second control occlusion of the coronary artery in the HMR 1883-group, MAP50 duration shortened from 218.5 +/- 3.0 ms to 166.7 +/- 3.3 ms and from 219.7 +/- 4.5 ms to 164.9 +/- 1.8 ms, respectively. After HMR 1883, during the third occlusion, MAP duration decreased from 226.9 +/- 3.6 ms to 205.3 +/- 4.3 ms only corresponding to 59% inhibition. HMR 1883 also improved the upstroke velocity of the MAP, which was depressed by ischemia: in the two preceding control occlusions ischemia prolonged the time to peak of the MAP, an index for upstroke velocity, from 10.83 +/- 0.43 ms to 39.42 +/- 1.60 ms and from 12.97 +/- 0.40 ms to 37.17 +/- 2.98 ms, respectively. With HMR 1883, time to peak during ischemia rose from 12.42 +/- 0.51 ms to 25.53+/-2.51 ms only, corresponding to an average inhibitory effect of 53.4%. The irregular repolarisation contour of the ischemic MAP was also improved. In conclusion, the present results indicate that HMR 1883 effectively blocks myocardial KATP channels during coronary ischemia in anesthetised pigs, preventing an excessive shortening of the action potential and improving excitation propagation.

Effects of nerve growth factor on the action potential duration and repolarizing currents in a rabbit model of myocardial infarction

PubMed Central

Lan, Yun-Feng; Zhang, Jian-Cheng; Gao, Jin-Lao; Wang, Xue-Ping; Fang, Zhou; Fu, Yi-Cheng; Chen, Mei-Yan; Lin, Min; Xue, Qiao; Li, Yang

2013-01-01

Objectives To investigate the effect of nerve growth factor (NGF) on the action potential and potassium currents of non-infarcted myocardium in the myocardial infarcted rabbit model. Methods Rabbits with occlusion of the left anterior descending coronary artery were prepared and allowed to recover for eight weeks (healed myocardial infarction, HMI). During ligation surgery of the left coronary artery, a polyethylene tube was placed near the left stellate ganglion in the subcutis of the neck for the purpose of administering NGF 400 U/d for eight weeks (HMI + NGF group). Cardiomyocytes were isolated from regions of the non-infarcted left ventricular wall and the action potentials and ion currents in these cells were recorded using whole-cell patch clamps. Results Compared with HMI and control cardiomyocytes, significant prolongation of APD50 or APD90 (Action potential duration (APD) measured at 50% and 90% of repolarization) in HMI + NGF cardiomyocytes was found. The results showed that the 4-aminopyridine sensitive transient outward potassium current (Ito), the rapidly activated omponent of delayed rectifier potassium current (IKr), the slowly activated component of delayed rectifier potassium current (IKs), and the L-type calcium current (ICaL) were significantly altered in NGF + HMI cardiomyocytes compared with HMI and control cells. Conclusions Our results suggest that NGF treatment significantly prolongs APD in HMI cardiomyocytes and that a decrease in outward potassium currents and an increase of inward Ca2+ current are likely the underlying mechanism of action. PMID:23610573

Effects of nerve growth factor on the action potential duration and repolarizing currents in a rabbit model of myocardial infarction.

PubMed

Lan, Yun-Feng; Zhang, Jian-Cheng; Gao, Jin-Lao; Wang, Xue-Ping; Fang, Zhou; Fu, Yi-Cheng; Chen, Mei-Yan; Lin, Min; Xue, Qiao; Li, Yang

2013-03-01

To investigate the effect of nerve growth factor (NGF) on the action potential and potassium currents of non-infarcted myocardium in the myocardial infarcted rabbit model. Rabbits with occlusion of the left anterior descending coronary artery were prepared and allowed to recover for eight weeks (healed myocardial infarction, HMI). During ligation surgery of the left coronary artery, a polyethylene tube was placed near the left stellate ganglion in the subcutis of the neck for the purpose of administering NGF 400 U/d for eight weeks (HMI + NGF group). Cardiomyocytes were isolated from regions of the non-infarcted left ventricular wall and the action potentials and ion currents in these cells were recorded using whole-cell patch clamps. Compared with HMI and control cardiomyocytes, significant prolongation of APD50 or APD90 (Action potential duration (APD) measured at 50% and 90% of repolarization) in HMI + NGF cardiomyocytes was found. The results showed that the 4-aminopyridine sensitive transient outward potassium current (I to), the rapidly activated omponent of delayed rectifier potassium current (I Kr), the slowly activated component of delayed rectifier potassium current (I Ks), and the L-type calcium current (I CaL) were significantly altered in NGF + HMI cardiomyocytes compared with HMI and control cells. Our results suggest that NGF treatment significantly prolongs APD in HMI cardiomyocytes and that a decrease in outward potassium currents and an increase of inward Ca(2+) current are likely the underlying mechanism of action.

Cardiac action potential repolarization revisited: early repolarization shows all-or-none behaviour.

PubMed

Trenor, Beatriz; Cardona, Karen; Saiz, Javier; Noble, Denis; Giles, Wayne

2017-11-01

In healthy mammalian hearts the action potential (AP) waveform initiates and modulates each contraction, or heartbeat. As a result, AP height and duration are key physiological variables. In addition, rate-dependent changes in ventricular AP duration (APD), and variations in APD at a fixed heart rate are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for safety pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence draws attention to the early repolarization phase of the action potential (and the J-wave of the ECG) as an additional important biomarker for arrhythmogenesis. Here we provide a mechanistic background to this early repolarization syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the cardiac action potential can exhibit distinct time- and voltage-dependent thresholds, and also demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of action potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as 'repolarization reserve'. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs). © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Effect of Purine Co-Transmitters on Automatic Activity Caused by Norepinephrine in Myocardial Sleeves of Pulmonary Veins.

PubMed

Karimova, V M; Pustovit, K B; Abramochkin, D V; Kuz'min, V S

2017-03-01

We studied the effect of extracellular purine nucleotides (NAD + and ATP) on spontaneous arrhythmogenic activity caused by norepinephrine in myocardial sleeves of pulmonary veins. In pulmonary veins, NAD + and ATP reduced the frequency of action potentials and their duration at regular type of spontaneous activity caused by norepinephrine. NAD + and ATP lengthened the intervals between spike bursts at periodic (burst) type of spontaneous activity. In addition, ATP shortened the duration of spike bursts and the number of action potentials in the "bursts" caused by norepinephrine in the pulmonary veins. It was hypothesized that NAD + and ATP attenuate the effects of sympathetic stimulation and when released together with norepinephrine from sympathetic endings in vivo, probably, reduce arrhythmogenic activity in myocardial sleeves of pulmonary veins.

Upper stimulation threshold for retinal ganglion cell activation.

PubMed

Meng, Kevin; Fellner, Andreas; Rattay, Frank; Ghezzi, Diego; Meffin, Hamish; Ibbotson, Michael R; Kameneva, Tatiana

2018-08-01

The existence of an upper threshold in electrically stimulated retinal ganglion cells (RGCs) is of interest because of its relevance to the development of visual prosthetic devices, which are designed to restore partial sight to blind patients. The upper threshold is defined as the stimulation level above which no action potentials (direct spikes) can be elicited in electrically stimulated retina. We collected and analyzed in vitro recordings from rat RGCs in response to extracellular biphasic (anodic-cathodic) pulse stimulation of varying amplitudes and pulse durations. Such responses were also simulated using a multicompartment model. We identified the individual cell variability in response to stimulation and the phenomenon known as upper threshold in all but one of the recorded cells (n  =  20/21). We found that the latencies of spike responses relative to stimulus amplitude had a characteristic U-shape. In silico, we showed that the upper threshold phenomenon was observed only in the soma. For all tested biphasic pulse durations, electrode positions, and pulse amplitudes above lower threshold, a propagating action potential was observed in the distal axon. For amplitudes above the somatic upper threshold, the axonal action potential back-propagated in the direction of the soma, but the soma's low level of hyperpolarization prevented action potential generation in the soma itself. An upper threshold observed in the soma does not prevent spike conductance in the axon.

Excitability is increased in hippocampal CA1 pyramidal cells of Fmr1 knockout mice

PubMed Central

Luque, M. Angeles; Beltran-Matas, Pablo; Marin, M. Carmen; Torres, Blas

2017-01-01

Fragile X syndrome (FXS) is caused by a failure of neuronal cells to express the gene encoding the fragile mental retardation protein (FMRP). Clinical features of the syndrome include intellectual disability, learning impairment, hyperactivity, seizures and anxiety. Fmr1 knockout (KO) mice do not express FMRP and, as a result, reproduce some FXS behavioral abnormalities. While intrinsic and synaptic properties of excitatory cells in various part of the brain have been studied in Fmr1 KO mice, a thorough analysis of action potential characteristics and input-output function of CA1 pyramidal cells in this model is lacking. With a view to determining the effects of the absence of FMRP on cell excitability, we studied rheobase, action potential duration, firing frequency–current intensity relationship and action potential after-hyperpolarization (AHP) in CA1 pyramidal cells of the hippocampus of wild type (WT) and Fmr1 KO male mice. Brain slices were prepared from 8- to 12-week-old mice and the electrophysiological properties of cells recorded. Cells from both groups had similar resting membrane potentials. In the absence of FMRP expression, cells had a significantly higher input resistance, while voltage threshold and depolarization voltage were similar in WT and Fmr1 KO cell groups. No changes were observed in rheobase. The action potential duration was longer in the Fmr1 KO cell group, and the action potential firing frequency evoked by current steps of the same intensity was higher. Moreover, the gain (slope) of the relationship between firing frequency and injected current was 1.25-fold higher in the Fmr1 KO cell group. Finally, AHP amplitude was significantly reduced in the Fmr1 KO cell group. According to these data, FMRP absence increases excitability in hippocampal CA1 pyramidal cells. PMID:28931075

The Case for Durative Actions: A Commentary on PDDL2.1

NASA Technical Reports Server (NTRS)

Smith, David E.

2003-01-01

The addition of durative actions to PDDL2.1 sparked some controversy. Fox and Long argued that actions should be considered as instantaneous, but can start and stop processes. Ultimately, a limited notion of durative actions was incorporated into the language. I argue that this notion is impoverished, and that the underlying philosophical position of regarding durative actions as being a shorthand for a start action, process, and stop action ignores the realities of modelling and execution for complex systems.

Differential roles of two delayed rectifier potassium currents in regulation of ventricular action potential duration and arrhythmia susceptibility.

PubMed

Devenyi, Ryan A; Ortega, Francis A; Groenendaal, Willemijn; Krogh-Madsen, Trine; Christini, David J; Sobie, Eric A

2017-04-01

Arrhythmias result from disruptions to cardiac electrical activity, although the factors that control cellular action potentials are incompletely understood. We combined mathematical modelling with experiments in heart cells from guinea pigs to determine how cellular electrical activity is regulated. A mismatch between modelling predictions and the experimental results allowed us to construct an improved, more predictive mathematical model. The balance between two particular potassium currents dictates how heart cells respond to perturbations and their susceptibility to arrhythmias. Imbalances of ionic currents can destabilize the cardiac action potential and potentially trigger lethal cardiac arrhythmias. In the present study, we combined mathematical modelling with information-rich dynamic clamp experiments to determine the regulation of action potential morphology in guinea pig ventricular myocytes. Parameter sensitivity analysis was used to predict how changes in ionic currents alter action potential duration, and these were tested experimentally using dynamic clamp, a technique that allows for multiple perturbations to be tested in each cell. Surprisingly, we found that a leading mathematical model, developed with traditional approaches, systematically underestimated experimental responses to dynamic clamp perturbations. We then re-parameterized the model using a genetic algorithm, which allowed us to estimate ionic current levels in each of the cells studied. This unbiased model adjustment consistently predicted an increase in the rapid delayed rectifier K + current and a drastic decrease in the slow delayed rectifier K + current, and this prediction was validated experimentally. Subsequent simulations with the adjusted model generated the clinically relevant prediction that the slow delayed rectifier is better able to stabilize the action potential and suppress pro-arrhythmic events than the rapid delayed rectifier. In summary, iterative coupling of simulations and experiments enabled novel insight into how the balance between cardiac K + currents influences ventricular arrhythmia susceptibility. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Distinguishing mechanisms for alternans in cardiac cells using constant-diastolic-interval pacing

NASA Astrophysics Data System (ADS)

Cherry, Elizabeth M.

2017-09-01

Alternans, a proarrhythmic dynamical state in which cardiac action potentials alternate between long and short durations despite a constant pacing period, traditionally has been explained at the cellular level using nonlinear dynamics principles under the assumption that the action potential duration (APD) is determined solely by the time elapsed since the end of the previous action potential, called the diastolic interval (DI). In this scenario, APDs at a steady state should be the same provided that the preceding DIs are the same. Nevertheless, experiments attempting to eliminate alternans by dynamically adjusting the timing of pacing stimuli to keep the DI constant showed that alternans persisted, contradicting the traditional theory. It is now widely known that alternans also can arise from a different mechanism associated with intracellular calcium cycling. Our goal is to determine whether intracellular calcium dynamics can explain the experimental findings regarding the persistence of alternans despite a constant DI. For this, we use mathematical models capable of producing alternans through both voltage- and calcium-mediated mechanisms. We show that for voltage-driven alternans, action potentials elicited from a constant-DI protocol are always the same. However, in the case of calcium-driven alternans, the constant-DI protocol can result in alternans. Reducing the strength of the calcium instability progressively reduces and finally eliminates constant-DI alternans. Our findings suggest that screening for the presence of alternans using a constant-DI protocol has the potential for differentiating between voltage-driven and calcium-driven alternans.

Coding rate and duration of vocalizations of the frog, Xenopus laevis.

PubMed

Zornik, Erik; Yamaguchi, Ayako

2012-08-29

Vocalizations involve complex rhythmic motor patterns, but the underlying temporal coding mechanisms in the nervous system are poorly understood. Using a recently developed whole-brain preparation from which "fictive" vocalizations are readily elicited in vitro, we investigated the cellular basis of temporal complexity of African clawed frogs (Xenopus laevis). Male advertisement calls contain two alternating components--fast trills (∼300 ms) and slow trills (∼700 ms) that contain clicks repeated at ∼60 and ∼30 Hz, respectively. We found that males can alter the duration of fast trills without changing click rates. This finding led us to hypothesize that call rate and duration are regulated by independent mechanisms. We tested this by obtaining whole-cell patch-clamp recordings in the "fictively" calling isolated brain. We discovered a single type of premotor neuron with activity patterns correlated with both the rate and duration of fast trills. These "fast-trill neurons" (FTNs) exhibited long-lasting depolarizations (LLDs) correlated with each fast trill and action potentials that were phase-locked with motor output-neural correlates of call duration and rate, respectively. When depolarized without central pattern generator activation, FTNs produced subthreshold oscillations and action potentials at fast-trill rates, indicating FTN resonance properties are tuned to, and may dictate, the fast-trill rhythm. NMDA receptor (NMDAR) blockade eliminated LLDs in FTNs, and NMDAR activation in synaptically isolated FTNs induced repetitive LLDs. These results suggest FTNs contain an NMDAR-dependent mechanism that may regulate fast-trill duration. We conclude that a single premotor neuron population employs distinct mechanisms to regulate call rate and duration.

A Parametric Computational Model of the Action Potential of Pacemaker Cells.

PubMed

Ai, Weiwei; Patel, Nitish D; Roop, Partha S; Malik, Avinash; Andalam, Sidharta; Yip, Eugene; Allen, Nathan; Trew, Mark L

2018-01-01

A flexible, efficient, and verifiable pacemaker cell model is essential to the design of real-time virtual hearts that can be used for closed-loop validation of cardiac devices. A new parametric model of pacemaker action potential is developed to address this need. The action potential phases are modeled using hybrid automaton with one piecewise-linear continuous variable. The model can capture rate-dependent dynamics, such as action potential duration restitution, conduction velocity restitution, and overdrive suppression by incorporating nonlinear update functions. Simulated dynamics of the model compared well with previous models and clinical data. The results show that the parametric model can reproduce the electrophysiological dynamics of a variety of pacemaker cells, such as sinoatrial node, atrioventricular node, and the His-Purkinje system, under varying cardiac conditions. This is an important contribution toward closed-loop validation of cardiac devices using real-time heart models.

Enhanced functional expression of transient outward current in hypertrophied feline myocytes.

PubMed

Ten Eick, R E; Zhang, K; Harvey, R D; Bassett, A L

1993-08-01

Cardiac hypertrophy can decrease myocardial contractility and alter the electrophysiological activity of the heart. It is well documented that action potentials recorded from hypertrophied feline ventricular cells can exhibit depressed plateau voltages and prolonged durations. Similar findings have been made by others in rabbit, rat, guinea pig, and human heart. Whole-cell patch voltage-clamp studies designed to explain these changes in the action potential suggest that the only component of the membrane current recorded from feline right ventricular (RV) myocytes found to be substantially different from normal is the 4-amino-pyridine-sensitive transient outward current (I(to)). However, it was not clear if the change in I(to) could explain the changes in the action potential of hypertrophied cardiocytes, nor was it clear if these changes reflect an alteration in the electrophysiological character of the channels underlying I(to). A kinetic comparison of I(to) elicited by hypertrophied RV myocytes with that elicited by comparable normal RV myocytes previously revealed no differences, suggesting that the increased magnitude of the peak I(to) recorded from hypertrophied myocytes arises because the current density increases and not because of any alteration in the kinetic parameters governing the current. This finding suggests that in hypertrophy additional normal channels are expressed rather than a kinetically different channel subtype emerging. Investigations designed to determine if enhancement of I(to) could explain the hypertrophy-induced changes in plateau voltage and action potential duration suggest that a change in I(to) density can indeed explain the entire effect of hypertrophy on RV action potentials. If this notion is correct, the likelihood of "sudden death" in patients with myocardial hypertrophy might be decreased by a blocker selective for cardiac I(to).

Human stem cell-derived cardiomyocytes detect drug-mediated changes in action potentials and ion currents.

PubMed

Gibson, John K; Yue, Yimei; Bronson, Jared; Palmer, Cassie; Numann, Randy

2014-01-01

It has been proposed that proarrhythmia assessment for safety pharmacology testing includes the use of human pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) to detect drug-induced changes in cardiac electrophysiology. This study measured the actions of diverse agents on action potentials (AP) and ion currents recorded from hiPSC-CM. During AP experiments, the hiPSC-CM were paced at 1Hz during a baseline period, and when increasing concentrations of test compound were administered at 4-minute intervals. AP parameters, including duration (APD60 and APD90), resting membrane potential, rate of rise, and amplitude, were measured throughout the entire experiment. Voltage clamp experiments with E-4031 and nifedipine were similarly conducted. E-4031 produced a dose-dependent prolongation of cardiac action potential and blocked the hERG/IKr current with an IC50 of 17nM. At 3nM, dofetilide significantly increased APD90. Astemizole significantly increased APD60 and APD90 at 30nM. Terfenadine significantly increased APD90 at concentrations greater than 10nM. Fexofenadine, a metabolite of terfenadine, did not produce any electrophysiologic changes in cardiac action potentials. Flecainide produced a dose-dependent prolongation of the cardiac action potential at 1 and 3μM. Acute exposure to nifedipine significantly decreased APD60 and APD90 and produced a dose-dependent block of calcium current with an IC50 of 0.039μM. Verapamil first shortened APD60 and APD90 in a dose-dependent manner, until a compensating increase in APD90, presumably via hERG blockade, was observed at 1 and 3μM. Following a chronic exposure (20-24h) to clinically relevant levels of pentamidine, a significant increase in action potential duration was accompanied by early afterdepolarizations (EADs). These experiments show the ability of AP measured from hiPSC-CM to record the interactions of various ion channels via AP recording and avoid the limitations of using several single ion channel assays in a noncardiac tissue. Copyright © 2014 Elsevier Inc. All rights reserved.

Slow [Na+]i dynamics impacts arrhythmogenesis and spiral wave reentry in cardiac myocyte ionic model.

PubMed

Krogh-Madsen, Trine; Christini, David J

2017-09-01

Accumulation of intracellular Na + is gaining recognition as an important regulator of cardiac myocyte electrophysiology. The intracellular Na + concentration can be an important determinant of the cardiac action potential duration, can modulate the tissue-level conduction of excitation waves, and can alter vulnerability to arrhythmias. Mathematical models of cardiac electrophysiology often incorporate a dynamic intracellular Na + concentration, which changes much more slowly than the remaining variables. We investigated the dependence of several arrhythmogenesis-related factors on [Na + ] i in a mathematical model of the human atrial action potential. In cell simulations, we found that [Na + ] i accumulation stabilizes the action potential duration to variations in several conductances and that the slow dynamics of [Na + ] i impacts bifurcations to pro-arrhythmic afterdepolarizations, causing intermittency between different rhythms. In long-lasting tissue simulations of spiral wave reentry, [Na + ] i becomes spatially heterogeneous with a decreased area around the spiral wave rotation center. This heterogeneous region forms a functional anchor, resulting in diminished meandering of the spiral wave. Our findings suggest that slow, physiological, rate-dependent variations in [Na + ] i may play complex roles in cellular and tissue-level cardiac dynamics.

Slow [Na+]i dynamics impacts arrhythmogenesis and spiral wave reentry in cardiac myocyte ionic model

NASA Astrophysics Data System (ADS)

Krogh-Madsen, Trine; Christini, David J.

2017-09-01

Accumulation of intracellular Na+ is gaining recognition as an important regulator of cardiac myocyte electrophysiology. The intracellular Na+ concentration can be an important determinant of the cardiac action potential duration, can modulate the tissue-level conduction of excitation waves, and can alter vulnerability to arrhythmias. Mathematical models of cardiac electrophysiology often incorporate a dynamic intracellular Na+ concentration, which changes much more slowly than the remaining variables. We investigated the dependence of several arrhythmogenesis-related factors on [Na+]i in a mathematical model of the human atrial action potential. In cell simulations, we found that [Na+]i accumulation stabilizes the action potential duration to variations in several conductances and that the slow dynamics of [Na+]i impacts bifurcations to pro-arrhythmic afterdepolarizations, causing intermittency between different rhythms. In long-lasting tissue simulations of spiral wave reentry, [Na+]i becomes spatially heterogeneous with a decreased area around the spiral wave rotation center. This heterogeneous region forms a functional anchor, resulting in diminished meandering of the spiral wave. Our findings suggest that slow, physiological, rate-dependent variations in [Na+]i may play complex roles in cellular and tissue-level cardiac dynamics.

Neural hijacking: action of high-frequency electrical stimulation on cortical circuits.

PubMed

Cheney, P D; Griffin, D M; Van Acker, G M

2013-10-01

Electrical stimulation of the brain was one of the first experimental methods applied to understanding brain organization and function and it continues as a highly useful method both in research and clinical applications. Intracortical microstimulation (ICMS) involves applying electrical stimuli through a microelectrode suitable for recording the action potentials of single neurons. ICMS can be categorized into single-pulse stimulation; high-frequency, short-duration stimulation; and high-frequency, long-duration stimulation. For clinical and experimental reasons, considerable interest focuses on the mechanism of neural activation by electrical stimuli. In this article, we discuss recent results suggesting that action potentials evoked in cortical neurons by high-frequency electrical stimulation do not sum with the natural, behaviorally related background activity; rather, high-frequency stimulation eliminates and replaces natural activity. We refer to this as neural hijacking. We propose that a major component of the mechanism underlying neural hijacking is excitation of axons by ICMS and elimination of natural spikes by antidromic collision with stimulus-driven spikes evoked at high frequency. Evidence also supports neural hijacking as an important mechanism underlying the action of deep brain stimulation in the subthalamic nucleus and its therapeutic effect in treating Parkinson's disease.

Zinc-induced protection against cadmium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Early, J.L.; Schnell, R.C.

Pretreatment of male rats with cadmium acetate potentiates the duration of hexobarbital hypnosis and inhibits the rate of hepatic microsomal drug metabolism. Pretreatment of rats with zinc acetate protects against these alterations in drug action elicited by cadmium.

Brain electromagnetic activity and lightning: potentially congruent scale-invariant quantitative properties

PubMed Central

Persinger, Michael A.

2012-01-01

The space-time characteristics of the axonal action potential are remarkably similar to the scaled equivalents of lightning. The energy and current densities from these transients within their respective volumes or cross-sectional areas are the same order of magnitude. Length–velocity ratios and temporal durations are nearly identical. There are similar chemical consequences such as the production of nitric oxide. Careful, quantitative examination of the characteristics of lightning may reveal analogous features of the action potential that could lead to a more accurate understanding of these powerful correlates of neurocognitive processes. PMID:22615688

Heterogeneous memory in restitution of action potential duration in pig ventricles.

PubMed

Jing, Linyuan; Chourasia, Sonam; Patwardhan, Abhijit

2010-01-01

Restitution of action potential duration and memory importantly affect electrical stability in ventricles. Studies have reported heterogeneous restitution among different regions of the ventricles. However, existence of heterogeneity in memory is not as well investigated. Transmembrane potentials were recorded in endocardial and epicardial tissues from both ventricles of farm pigs. Pacing protocols with sinusoidally changing diastolic intervals were used to reveal hysteresis in restitution, from which quantitative measures of memory were calculated. Larger measures of hysteresis were observed in the endocardium than the epicardium (P < .05): loop thickness (in milliseconds), 26.9 vs 16.2; overall tilt, 0.376 vs 0.249; and loop area (in square milliseconds), 7288 vs 4146. Except for overall tilt, no significant differences in these measures were observed between ventricles. Heterogeneity in memory exists in pig ventricles. Because regions with the steepest restitution may also have the largest memory, our results suggest that heterogeneity in memory should also be factored in when predicting electrical stability. Copyright 2010 Elsevier Inc. All rights reserved.

Microelectrode array measurement of potassium ion channel remodeling on the field action potential duration in rapid atrial pacing rabbits model.

PubMed

Sun, Juan; Yan, Huang; Wugeti, Najina; Guo, Yujun; Zhang, Ling; Ma, Mei; Guo, Xingui; Jiao, Changan; Xu, Wenli; Li, Tianqi

2015-01-01

Atrial fibrillation (AF) arises from abnormalities in atrial structure and electrical activity. Microelectrode arrays (MEA) is a real-time, nondestructive measurement of the resting and action potential signal, from myocardial cells, to the peripheral circuit of electrophysiological activity. This study examined the field action potential duration (fAPD) of the right atrial appendage (RAA) by MEA in rapid atrial pacing (RAP) in the right atrium of rabbits. In addition, this study also investigated the effect of potassium ion channel blockers on fAPD. 40 New Zealand white rabbits of either sex were randomly divided into 3 groups: 1) the control, 2) potassium ion channel blocker (TEA, 4-Ap and BaCl2), and 3) amiodarone groups. The hearts were quickly removed and right atrial appendage sectioned (slice thickness 500 μm). Each slice was perfused with Tyrode's solution and continuously stimulated for 30 minutes. Sections from the control group were superfused with Tyrode's solution for 10 minutes, while the blocker groups and amiodarone were both treated with their respective compounds for 10 minutes each. The fAPD of RAA and action field action potential morphology were measured using MEA. In non-pace (control) groups, fAPD was 188.33 ± 18.29 ms after Tyrode's solution superfusion, and 173.91 ± 6.83 ms after RAP. In pace/potassium ion channel groups, TEA and BaCl2 superfusion prolonged atrial field action potential (fAPD) (control vs blocker: 176.67 ± 8.66 ms vs 196.11 ± 10.76 ms, 182.22 ± 12.87 ms vs 191.11 ± 13.09 ms with TEA and BaCl2 superfusion, respectively, P < 0.05). 4-AP superfusion significantly prolonged FAPD. In pace/amiodarone groups, 4-Ap superfusion extended fAPD. MEA was a sensitive and stable reporter for the measurement of the tissue action potential in animal heart slices. After superfusing potassium ion channel blockers, fAPD was prolonged. These results suggest that Ito, IKur and IK1 remodel and mediate RAP-induced atrial electrical remodeling. Amiodarone alter potassium ion channel activity (Ito, IKur, IK1 and IKs), shortening fAPD.

Cardiac action potential imaging

NASA Astrophysics Data System (ADS)

Tian, Qinghai; Lipp, Peter; Kaestner, Lars

2013-06-01

Action potentials in cardiac myocytes have durations in the order of magnitude of 100 milliseconds. In biomedical investigations the documentation of the occurrence of action potentials is often not sufficient, but a recording of the shape of an action potential allows a functional estimation of several molecular players. Therefore a temporal resolution of around 500 images per second is compulsory. In the past such measurements have been performed with photometric approaches limiting the measurement to one cell at a time. In contrast, imaging allows reading out several cells at a time with additional spatial information. Recent developments in camera technologies allow the acquisition with the required speed and sensitivity. We performed action potential imaging on isolated adult cardiomyocytes of guinea pigs utilizing the fluorescent membrane potential sensor di-8-ANEPPS and latest electron-multiplication CCD as well as scientific CMOS cameras of several manufacturers. Furthermore, we characterized the signal to noise ratio of action potential signals of varying sets of cameras, dye concentrations and objective lenses. We ensured that di-8-ANEPPS itself did not alter action potentials by avoiding concentrations above 5 μM. Based on these results we can conclude that imaging is a reliable method to read out action potentials. Compared to conventional current-clamp experiments, this optical approach allows a much higher throughput and due to its contact free concept leaving the cell to a much higher degree undisturbed. Action potential imaging based on isolated adult cardiomyocytes can be utilized in pharmacological cardiac safety screens bearing numerous advantages over approaches based on heterologous expression of hERG channels in cell lines.

Restitution slope is principally determined by steady-state action potential duration.

PubMed

Shattock, Michael J; Park, Kyung Chan; Yang, Hsiang-Yu; Lee, Angela W C; Niederer, Steven; MacLeod, Kenneth T; Winter, James

2017-06-01

The steepness of the action potential duration (APD) restitution curve and local tissue refractoriness are both thought to play important roles in arrhythmogenesis. Despite this, there has been little recognition of the apparent association between steady-state APD and the slope of the restitution curve. The objective of this study was to test the hypothesis that restitution slope is determined by APD and to examine the relationship between restitution slope, refractoriness and susceptibility to VF. Experiments were conducted in isolated hearts and ventricular myocytes from adult guinea pigs and rabbits. Restitution curves were measured under control conditions and following intervention to prolong (clofilium, veratridine, bretylium, low [Ca]e, chronic transverse aortic constriction) or shorten (catecholamines, rapid pacing) ventricular APD. Despite markedly differing mechanisms of action, all interventions that prolonged the action potential led to a steepening of the restitution curve (and vice versa). Normalizing the restitution curve as a % of steady-state APD abolished the difference in restitution curves with all interventions. Effects on restitution were preserved when APD was modulated by current injection in myocytes pre-treated with the calcium chelator BAPTA-AM - to abolish the intracellular calcium transient. The non-linear relation between APD and the rate of repolarization of the action potential is shown to underpin the common influence of APD on the slope of the restitution curve. Susceptibility to VF was found to parallel changes in APD/refractoriness, rather than restitution slope. Steady-state APD is the principal determinant of the slope of the ventricular electrical restitution curve. In the absence of post-repolarization refractoriness, factors that prolong the action potential would be expected to steepen the restitution curve. However, concomitant changes in tissue refractoriness act to reduce susceptibility to sustained VF. Dependence on steady-state APD may contribute to the failure of restitution slope to predict sudden cardiac death. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology

Restitution slope is principally determined by steady-state action potential duration

PubMed Central

Shattock, Michael J.; Park, Kyung Chan; Yang, Hsiang-Yu; Lee, Angela W. C.; Niederer, Steven; MacLeod, Kenneth T.

2017-01-01

Aims The steepness of the action potential duration (APD) restitution curve and local tissue refractoriness are both thought to play important roles in arrhythmogenesis. Despite this, there has been little recognition of the apparent association between steady-state APD and the slope of the restitution curve. The objective of this study was to test the hypothesis that restitution slope is determined by APD and to examine the relationship between restitution slope, refractoriness and susceptibility to VF. Methods and results Experiments were conducted in isolated hearts and ventricular myocytes from adult guinea pigs and rabbits. Restitution curves were measured under control conditions and following intervention to prolong (clofilium, veratridine, bretylium, low [Ca]e, chronic transverse aortic constriction) or shorten (catecholamines, rapid pacing) ventricular APD. Despite markedly differing mechanisms of action, all interventions that prolonged the action potential led to a steepening of the restitution curve (and vice versa). Normalizing the restitution curve as a % of steady-state APD abolished the difference in restitution curves with all interventions. Effects on restitution were preserved when APD was modulated by current injection in myocytes pre-treated with the calcium chelator BAPTA-AM – to abolish the intracellular calcium transient. The non-linear relation between APD and the rate of repolarization of the action potential is shown to underpin the common influence of APD on the slope of the restitution curve. Susceptibility to VF was found to parallel changes in APD/refractoriness, rather than restitution slope. Conclusion(s) Steady-state APD is the principal determinant of the slope of the ventricular electrical restitution curve. In the absence of post-repolarization refractoriness, factors that prolong the action potential would be expected to steepen the restitution curve. However, concomitant changes in tissue refractoriness act to reduce susceptibility to sustained VF. Dependence on steady-state APD may contribute to the failure of restitution slope to predict sudden cardiac death. PMID:28371805

Long Duration Responses in Squid Giant Axons Injected with 134Cesium Sulfate Solutions

PubMed Central

Sjodin, R. A.

1966-01-01

Giant axons from the squid were injected with 1.5 M cesium sulfate solutions containing the radioactive isotopes 42K and 134Cs. These axons, when stimulated, gave characteristic long duration action potentials lasting between 5 and 45 msec. The effluxes of 42K and 134Cs were measured both under resting conditions and during periods of repetitive stimulation. During the lengthened responses there were considerable increases in potassium efflux but only small increases in cesium efflux. The selectivity of the delayed rectification process was about 9 times greater for potassium ions than for cesium ions. The data suggest that internal cesium ions inhibit the outward potassium movement occurring during an action potential. The extra potassium effluxes taking place during excitation appear to be reduced in the presence of cesium ions to values between 7 and 22% of those expected in the absence of cesium inhibition. PMID:11526828

Analgesic, diuretic, and anti-inflammatory principle from Scoparia dulcis.

PubMed

Ahmed, M; Shikha, H A; Sadhu, S K; Rahman, M T; Datta, B K

2001-08-01

Scoparinol, a diterpene, isolated from Scoparia dulcis showed significant analgesic (p < 0.001) and anti-inflammatory activity (p < 0.01) in animals. A sedative action of scoparinol was demonstrated by a marked potentiation of pentobarbital-induced sedation with a significant effect on both onset and duration of sleep (p < 0.05). Measurement of urine volume after administration of scoparinol indicated its significant diuretic action.

The influence of bat echolocation call duration and timing on auditory encoding of predator distance in noctuoid moths.

PubMed

Gordon, Shira D; Ter Hofstede, Hannah M

2018-03-22

Animals co-occur with multiple predators, making sensory systems that can encode information about diverse predators advantageous. Moths in the families Noctuidae and Erebidae have ears with two auditory receptor cells (A1 and A2) used to detect the echolocation calls of predatory bats. Bat communities contain species that vary in echolocation call duration, and the dynamic range of A1 is limited by the duration of sound, suggesting that A1 provides less information about bats with shorter echolocation calls. To test this hypothesis, we obtained intensity-response functions for both receptor cells across many moth species for sound pulse durations representing the range of echolocation call durations produced by bat species in northeastern North America. We found that the threshold and dynamic range of both cells varied with sound pulse duration. The number of A1 action potentials per sound pulse increases linearly with increasing amplitude for long-duration pulses, saturating near the A2 threshold. For short sound pulses, however, A1 saturates with only a few action potentials per pulse at amplitudes far lower than the A2 threshold for both single sound pulses and pulse sequences typical of searching or approaching bats. Neural adaptation was only evident in response to approaching bat sequences at high amplitudes, not search-phase sequences. These results show that, for short echolocation calls, a large range of sound levels cannot be coded by moth auditory receptor activity, resulting in no information about the distance of a bat, although differences in activity between ears might provide information about direction. © 2018. Published by The Company of Biologists Ltd.

Effects of K(+) channel openers on spontaneous action potentials in detrusor smooth muscle of the guinea-pig urinary bladder.

PubMed

Takagi, Hiroaki; Hashitani, Hikaru

2016-10-15

The modulation of spontaneous excitability in detrusor smooth muscle (DSM) upon the pharmacological activation of different populations of K(+) channels was investigated. Effects of distinct K(+) channel openers on spontaneous action potentials in DSM of the guinea-pig bladder were examined using intracellular microelectrode techniques. NS1619 (10μM), a large conductance Ca(2+)-activated K(+) (BK) channel opener, transiently increased action potential frequency and then prevented their generation without hyperpolarizing the membrane in a manner sensitive to iberiotoxin (IbTX, 100nM). A higher concentration of NS1619 (30μM) hyperpolarized the membrane and abolished action potential firing. NS309 (10μM) and SKA31 (100μM), small conductance Ca(2+)-activated K(+) (SK) channel openers, dramatically increased the duration of the after-hyperpolarization and then abolished action potential firing in an apamin (100nM)-sensitive manner. Flupirtine (10μM), a Kv7 channel opener, inhibited action potential firing without hyperpolarizing the membrane in a manner sensitive to XE991 (10μM), a Kv7 channel blocker. BRL37344 (10μM), a β3-adrenceptor agonist, or rolipram (10nM), a phosphodiesterase 4 inhibitor, also inhibited action potential firing. A higher concentration of rolipram (100nM) hyperpolarized the DSM and abolished the action potentials. IbTX (100nM) prevented the rolipram-induced blockade of action potentials but not the hyperpolarization. BK and Kv7 channels appear to predominantly contribute to the stabilization of DSM excitability. Spare SK channels could be pharmacologically activated to suppress DSM excitability. BK channels appear to be involved in the cyclic AMP-induced inhibition of action potentials but not the membrane hyperpolarization. Copyright © 2016 Elsevier B.V. All rights reserved.

The Effect of Rapacuronium or Succinylcholine on the Duration of Action of Rocuronium

DTIC Science & Technology

2001-10-01

23/Oct/2001 THESIS 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER THE EFFECT OF RAPACURONIUM OR SUCCINYLCHOLINE ON THE DURATION OF ACTION OF ROCURONIUM 5b... Rocuronium , an intermediate acting non-depolarizer, provides an alternative for intubation when succinylcholine is not recommended. Rapacuronium...approved in 1999, has a shorter onset and duration of action than rocuronium . The goal of this study was to determine whether the duration of action of

Consequences of converting graded to action potentials upon neural information coding and energy efficiency.

PubMed

Sengupta, Biswa; Laughlin, Simon Barry; Niven, Jeremy Edward

2014-01-01

Information is encoded in neural circuits using both graded and action potentials, converting between them within single neurons and successive processing layers. This conversion is accompanied by information loss and a drop in energy efficiency. We investigate the biophysical causes of this loss of information and efficiency by comparing spiking neuron models, containing stochastic voltage-gated Na(+) and K(+) channels, with generator potential and graded potential models lacking voltage-gated Na(+) channels. We identify three causes of information loss in the generator potential that are the by-product of action potential generation: (1) the voltage-gated Na(+) channels necessary for action potential generation increase intrinsic noise and (2) introduce non-linearities, and (3) the finite duration of the action potential creates a 'footprint' in the generator potential that obscures incoming signals. These three processes reduce information rates by ∼50% in generator potentials, to ∼3 times that of spike trains. Both generator potentials and graded potentials consume almost an order of magnitude less energy per second than spike trains. Because of the lower information rates of generator potentials they are substantially less energy efficient than graded potentials. However, both are an order of magnitude more efficient than spike trains due to the higher energy costs and low information content of spikes, emphasizing that there is a two-fold cost of converting analogue to digital; information loss and cost inflation.

Consequences of Converting Graded to Action Potentials upon Neural Information Coding and Energy Efficiency

PubMed Central

Sengupta, Biswa; Laughlin, Simon Barry; Niven, Jeremy Edward

2014-01-01

Information is encoded in neural circuits using both graded and action potentials, converting between them within single neurons and successive processing layers. This conversion is accompanied by information loss and a drop in energy efficiency. We investigate the biophysical causes of this loss of information and efficiency by comparing spiking neuron models, containing stochastic voltage-gated Na+ and K+ channels, with generator potential and graded potential models lacking voltage-gated Na+ channels. We identify three causes of information loss in the generator potential that are the by-product of action potential generation: (1) the voltage-gated Na+ channels necessary for action potential generation increase intrinsic noise and (2) introduce non-linearities, and (3) the finite duration of the action potential creates a ‘footprint’ in the generator potential that obscures incoming signals. These three processes reduce information rates by ∼50% in generator potentials, to ∼3 times that of spike trains. Both generator potentials and graded potentials consume almost an order of magnitude less energy per second than spike trains. Because of the lower information rates of generator potentials they are substantially less energy efficient than graded potentials. However, both are an order of magnitude more efficient than spike trains due to the higher energy costs and low information content of spikes, emphasizing that there is a two-fold cost of converting analogue to digital; information loss and cost inflation. PMID:24465197

Sprint training shortens prolonged action potential duration in postinfarction rat myocyte: mechanisms.

PubMed

Zhang, X Q; Zhang, L Q; Palmer, B M; Ng, Y C; Musch, T I; Moore, R L; Cheung, J Y

2001-05-01

Two electrophysiological manifestations of myocardial infarction (MI)-induced myocyte hypertrophy are prolongation of action potential duration (APD) and reduction of transient outward current (I(to)) density. Because high-intensity sprint training (HIST) ameliorated myocyte hypertrophy and improved myocyte Ca(2+) homeostasis and contractility after MI, the present study evaluated whether 6-8 wk of HIST would shorten the prolonged APD and improve the depressed I(to) in post-MI myocytes. There were no differences in resting membrane potential and action potential amplitude (APA) measured in myocytes isolated from sham-sedentary (Sed), MI-Sed, and MI-HIST groups. Times required for repolarization to 50 and 90% APA were significantly (P < 0.001) prolonged in MI-Sed myocytes. HIST reduced times required for repolarization to 50 and 90% APA to values observed in Sham-Sed myocytes. The fast and slow components of I(to) were significantly (P < 0.0001) reduced in MI-Sed myocytes. HIST significantly (P < 0.001) enhanced the fast and slow components of I(to) in MI myocytes, although not to levels observed in Sham-Sed myocytes. There were no significant differences in steady-state I(to) inactivation and activation parameters among Sham-Sed, MI-Sed, and MI-HIST myocytes. Likewise, recovery from time-dependent inactivation was also similar among the three groups. We suggest that normalization of APD after MI by HIST may be mediated by restoration of I(to) toward normal levels.

[Effects of 2-(p-dimethylaminostyryl) pyridine methycholide (DSPM-Ci) on ECG, left atrium contractivity and on papillary muscle action potentials].

PubMed

Jiang, X Y; Zhou, C M; Li, D M; Zhang, K J

1996-01-01

The effects of DSPM-Cl on ECG in rats, on the dose-effect curve in guinea pig left atria and on the fast action potential (AP), high-K+ depolarized slow action potential (SAP) in guinea pigs papillary muscle were examined electrophysiologically. DSPM-Cl (2 mg.kg-1) showed significant nagative frequency, negative conductivity effect, and prolonged the PP and PR interval. DSPM-CI (30-50 mumol.L-1) was shown to inhibit left atria contractility and shift the concentration-response curve of Iso and CaCl2 to the right with PD2' values of 4.60 and 4.13, respectively. In addition, DSPM-Cl was found to prolong the duration of action potential 90 (APD90) and effective refractory period (ERP), and decrease the maximal upstroke velocity (Vmax) in K(+)-depolarized guinea pigs papillary muscles. The results suggest that, like verpamil, DSPM-Cl might be a calcium antagonist.

GABAergic excitation of spider mechanoreceptors increases information capacity by increasing entropy rather than decreasing jitter.

PubMed

Pfeiffer, Keram; French, Andrew S

2009-09-02

Neurotransmitter chemicals excite or inhibit a range of sensory afferents and sensory pathways. These changes in firing rate or static sensitivity can also be associated with changes in dynamic sensitivity or membrane noise and thus action potential timing. We measured action potential firing produced by random mechanical stimulation of spider mechanoreceptor neurons during long-duration excitation by the GABAA agonist muscimol. Information capacity was estimated from signal-to-noise ratio by averaging responses to repeated identical stimulation sequences. Information capacity was also estimated from the coherence function between input and output signals. Entropy rate was estimated by a data compression algorithm and maximum entropy rate from the firing rate. Action potential timing variability, or jitter, was measured as normalized interspike interval distance. Muscimol increased firing rate, information capacity, and entropy rate, but jitter was unchanged. We compared these data with the effects of increasing firing rate by current injection. Our results indicate that the major increase in information capacity by neurotransmitter action arose from the increased entropy rate produced by increased firing rate, not from reduction in membrane noise and action potential jitter.

[Safety of new anti-arrhythmic drugs].

PubMed

Touboul, P

2005-04-01

The majority of new antiarrhythmic drugs are still undergoing clinical trials and are not yet available on the French market. The studies of efficacy are mainly targeted on the treatment of atrial fibrillation. Intravenous ibutilide prolongs the duration of the action potential by stimulating sodium exchange during phase 2 of the action potential. Used for terminating episodes of atrial flutter and fibrillation, ibutilide has been shown to have a low proarrhythmic effect. Dofetilide is a pure I(Kr) current antagonist and is given orally. The molecule prolongs the duration of the atrial and ventricular action potentials. The amplitude of this effect is inversely related to the heart rate. No effect has been observed on the mortality rate in the post-infarct period. Adjusting the dosage with respect to renal function has reduced the occurrence of torsades de pointe from 4.8 to 2.9%. Azimilide is an I(Kr) and I(Ks) current blocker and its efficacy decreases at rapid heart rates. After oral administration, azimilide does not appear to have a deleterious effect in patients with a history of myocardial infarction and left ventricular dysfunction. The risk of torsades de pointe is less than 1%. Cases of neutropaenia have been reported. Dronedarone is an amiodarone analogue without iodine. The molecule prolongs atrial and ventricular action potentials and its efficacy is maintained at high heart rates. This drug had deleterious effects when given to patients with coronary artery disease and left ventricular dysfunction. Gastrointestinal side effects may be observed at high dosage. The great advantages of dronedarone are the absence of thyroid complications and of pro-arrhythmic effects.

Application of optical action potentials in human induced pluripotent stem cells-derived cardiomyocytes to predict drug-induced cardiac arrhythmias.

PubMed

Lu, H R; Hortigon-Vinagre, M P; Zamora, V; Kopljar, I; De Bondt, A; Gallacher, D J; Smith, G

2017-09-01

Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are emerging as new and human-relevant source in vitro model for cardiac safety assessment that allow us to investigate a set of 20 reference drugs for predicting cardiac arrhythmogenic liability using optical action potential (oAP) assay. Here, we describe our examination of the oAP measurement using a voltage sensitive dye (Di-4-ANEPPS) to predict adverse compound effects using hiPS-CMs and 20 cardioactive reference compounds. Fluorescence signals were digitized at 10kHz and the records subsequently analyzed off-line. Cells were exposed to 30min incubation to vehicle or compound (n=5/dose, 4 doses/compound) that were blinded to the investigating laboratory. Action potential parameters were measured, including rise time (T rise ) of the optical action potential duration (oAPD). Significant effects on oAPD were sensitively detected with 11 QT-prolonging drugs, while oAPD shortening was observed with I Ca -antagonists, I Kr -activator or ATP-sensitive K + channel (K ATP )-opener. Additionally, the assay detected varied effects induced by 6 different sodium channel blockers. The detection threshold for these drug effects was at or below the published values of free effective therapeutic plasma levels or effective concentrations by other studies. The results of this blinded study indicate that OAP is a sensitive method to accurately detect drug-induced effects (i.e., duration/QT-prolongation, shortening, beat rate, and incidence of early after depolarizations) in hiPS-CMs; therefore, this technique will potentially be useful in predicting drug-induced arrhythmogenic liabilities in early de-risking within the drug discovery phase. Copyright © 2017 Elsevier Inc. All rights reserved.

Alternans promotion in cardiac electrophysiology models by delay differential equations.

PubMed

Gomes, Johnny M; Dos Santos, Rodrigo Weber; Cherry, Elizabeth M

2017-09-01

Cardiac electrical alternans is a state of alternation between long and short action potentials and is frequently associated with harmful cardiac conditions. Different dynamic mechanisms can give rise to alternans; however, many cardiac models based on ordinary differential equations are not able to reproduce this phenomenon. A previous study showed that alternans can be induced by the introduction of delay differential equations (DDEs) in the formulations of the ion channel gating variables of a canine myocyte model. The present work demonstrates that this technique is not model-specific by successfully promoting alternans using DDEs for five cardiac electrophysiology models that describe different types of myocytes, with varying degrees of complexity. By analyzing results across the different models, we observe two potential requirements for alternans promotion via DDEs for ionic gates: (i) the gate must have a significant influence on the action potential duration and (ii) a delay must significantly impair the gate's recovery between consecutive action potentials.

Intermittent blood pressure control: potential consequences for outcome.

PubMed

Leenen, F H

1999-05-01

Although both blood pressure (BP) and left ventricular (LV) mass at initial evaluation predict future cardiovascular risk, the actual BP and LV mass achieved over years of treatment more clearly relate to cardiovascular event rates. Intermittent compliance or noncompliance is the major reason for uncontrolled hypertension and presumably persistent LV hypertrophy. In general, drugs with rapid onset and short duration of action are not desirable because this profile may lead to large variations in BP lowering effect during actual drug intake and rapid disappearance of the antihypertensive effect with missed doses. In addition, intermittent compliance per se introduces the potential for adverse events. For drugs requiring several dose-titrations (e.g., alpha1-blockers), restarting at full doses may lead to excessive drug action and symptomatic hypotension. For other drugs (e.g., short acting beta-blockers or clonidine-like drugs), sudden discontinuation with intermittent compliance may lead to rebound-enhanced sympathetic responsiveness after one to two days, resulting not only in side effects, but also in adverse events, particularly in patients with (silent) coronary artery disease. The rapid onset, short acting dihydropyridines cause intermittent BP control at each dosing, particularly at higher doses. This intermittent control of BP is even more apparent at dosing intervals that are long relative to the duration of action. Thus, sympathetic activation and potential for adverse events can be anticipated at each dosing unless these drugs are being taken frequently at relatively low doses. For diuretics, angiotensin-converting enzyme inhibitors and angiotensin I receptor blockers, no adverse effects have been identified with intermittent compliance. Intermittent BP control is, in general, not an appropriate approach to the management of hypertension and introduces additional risks depending on the type of antihypertensive drug. In contrast, drugs with slow onset and long duration of action provide a more consistent effect during actual drug intake and a more persistent effect during short periods of noncompliance.

Neural and receptor cochlear potentials obtained by transtympanic electrocochleography in auditory neuropathy.

PubMed

Santarelli, Rosamaria; Starr, Arnold; Michalewski, Henry J; Arslan, Edoardo

2008-05-01

Transtympanic electrocochleography (ECochG) was recorded bilaterally in children and adults with auditory neuropathy (AN) to evaluate receptor and neural generators. Test stimuli were clicks from 60 to 120dB p.e. SPL. Measures obtained from eight AN subjects were compared to 16 normally hearing children. Receptor cochlear microphonics (CMs) in AN were of normal or enhanced amplitude. Neural compound action potentials (CAPs) and receptor summating potentials (SPs) were identified in five AN ears. ECochG potentials in those ears without CAPs were of negative polarity and of normal or prolonged duration. We used adaptation to rapid stimulus rates to distinguish whether the generators of the negative potentials were of neural or receptor origin. Adaptation in controls resulted in amplitude reduction of CAP twice that of SP without affecting the duration of ECochG potentials. In seven AN ears without CAP and with prolonged negative potential, adaptation was accompanied by reduction of both amplitude and duration of the negative potential to control values consistent with neural generation. In four ears without CAP and with normal duration potentials, adaptation was without effect consistent with receptor generation. In five AN ears with CAP, there was reduction in amplitude of CAP and SP as controls but with a significant decrease in response duration. Three patterns of cochlear potentials were identified in AN: (1) presence of receptor SP without CAP consistent with pre-synaptic disorder of inner hair cells; (2) presence of both SP and CAP consistent with post-synaptic disorder of proximal auditory nerve; (3) presence of prolonged neural potentials without a CAP consistent with post-synaptic disorder of nerve terminals. Cochlear potential measures may identify pre- and post-synaptic disorders of inner hair cells and auditory nerves in AN.

Channel sialic acids limit hERG channel activity during the ventricular action potential.

PubMed

Norring, Sarah A; Ednie, Andrew R; Schwetz, Tara A; Du, Dongping; Yang, Hui; Bennett, Eric S

2013-02-01

Activity of human ether-a-go-go-related gene (hERG) 1 voltage-gated K(+) channels is responsible for portions of phase 2 and phase 3 repolarization of the human ventricular action potential. Here, we questioned whether and how physiologically and pathophysiologically relevant changes in surface N-glycosylation modified hERG channel function. Voltage-dependent hERG channel gating and activity were evaluated as expressed in a set of Chinese hamster ovary (CHO) cell lines under conditions of full glycosylation, no sialylation, no complex N-glycans, and following enzymatic deglycosylation of surface N-glycans. For each condition of reduced glycosylation, hERG channel steady-state activation and inactivation relationships were shifted linearly by significant depolarizing ∼9 and ∼18 mV, respectively. The hERG window current increased significantly by 50-150%, and the peak shifted by a depolarizing ∼10 mV. There was no significant change in maximum hERG current density. Deglycosylated channels were significantly more active (20-80%) than glycosylated controls during phases 2 and 3 of action potential clamp protocols. Simulations of hERG current and ventricular action potentials corroborated experimental data and predicted reduced sialylation leads to a 50-70-ms decrease in action potential duration. The data describe a novel mechanism by which hERG channel gating is modulated through physiologically and pathophysiologically relevant changes in N-glycosylation; reduced channel sialylation increases hERG channel activity during the action potential, thereby increasing the rate of action potential repolarization.

Effect of mental challenge induced by movie clips on action potential duration in normal human subjects independent of heart rate

PubMed Central

Child, Nicholas; Hanson, Ben; Bishop, Martin; Rinaldi, Christopher A; Bostock, Julian; Western, David; Cooklin, Michael; O’Neil, Mark; Wright, Matthew; Razavi, Reza; Gill, Jaswinder; Taggart, Peter

2014-01-01

Background Mental stress and emotion have long been associated with ventricular arrhythmias and sudden death in animal models and humans. The effect of mental challenge on ventricular action potential duration (APD) in conscious healthy humans has not been reported. Methods and Results Activation recovery intervals (ARI) measured from unipolar electrograms as a surrogate for APD (n=19) were recorded from right and left ventricular endocardium during steady state pacing while subjects watched an emotionally charged film clip. To assess the possible modulating role of altered respiration on APD, the subjects then repeated the same breathing pattern they had during the stress, but without the movie clip. Haemodynamic parameters (mean, systolic, and diastolic blood pressure, and rate of pressure increase) and respiration rate increased during the stressful part of the film clip (p=0.001). APD decreased during the stressful parts of the film clip, eg for global RV ARI at end of film clip 193.8ms (SD 14) vs 198.0ms (SD13) during the matched breathing control (end film LV 199.8ms (SD16) vs control 201.6ms (SD15), p=0.004. Respiration rate increased during the stressful part of the film clip (by 2 breaths/minute), and was well matched in the respective control period without any haemodynamic or ARI changes. Conclusions Our results document for the first time direct recordings of the effect of a mental challenge protocol on ventricular action potential duration in conscious humans. The effect of mental challenge on APD was not secondary to emotionally-induced altered respiration or heart rate. PMID:24833641

Induction of temporally dissociated morphological and physiological differentiation of N1E-115 cells.

PubMed

Cosgrove, C; Cobbett, P

1991-07-01

Clonal cells derived from neural tumors have been widely used to study the processes of neuronal differentiation in vitro. The murine neuroblastoma clone N1E-115 has recently been shown to differentiate morphologically in response to removal of serum from the culture medium. In the present study, the nature and time course of electrophysiological differentiation of N1E-115 cells maintained in serum-free medium was examined. Differentiated cells had a higher resting potential and lower input conductance than nondifferentiated cells. Differentiated but not nondifferentiated cells generated current evoked action potentials, and differentiated cells fired spontaneous, repetitive action potentials after 13 days in serum-free medium. The rate of potential change during the depolarizing and repolarizing phases of the action potential became faster as the duration of maintenance of cells in serum-free medium increased. Remarkably, morphological differentiation appeared to be complete after exposure to serum-free medium for 5 days but electrophysiological differentiation was not complete until 13 days in this medium.

NeuroGrid: recording action potentials from the surface of the brain.

PubMed

Khodagholy, Dion; Gelinas, Jennifer N; Thesen, Thomas; Doyle, Werner; Devinsky, Orrin; Malliaras, George G; Buzsáki, György

2015-02-01

Recording from neural networks at the resolution of action potentials is critical for understanding how information is processed in the brain. Here, we address this challenge by developing an organic material-based, ultraconformable, biocompatible and scalable neural interface array (the 'NeuroGrid') that can record both local field potentials(LFPs) and action potentials from superficial cortical neurons without penetrating the brain surface. Spikes with features of interneurons and pyramidal cells were simultaneously acquired by multiple neighboring electrodes of the NeuroGrid, allowing for the isolation of putative single neurons in rats. Spiking activity demonstrated consistent phase modulation by ongoing brain oscillations and was stable in recordings exceeding 1 week's duration. We also recorded LFP-modulated spiking activity intraoperatively in patients undergoing epilepsy surgery. The NeuroGrid constitutes an effective method for large-scale, stable recording of neuronal spikes in concert with local population synaptic activity, enhancing comprehension of neural processes across spatiotemporal scales and potentially facilitating diagnosis and therapy for brain disorders.

Oxidative shift in tissue redox potential increases beat-to-beat variability of action potential duration.

PubMed

Kistamás, Kornél; Hegyi, Bence; Váczi, Krisztina; Horváth, Balázs; Bányász, Tamás; Magyar, János; Szentandrássy, Norbert; Nánási, Péter P

2015-07-01

Profound changes in tissue redox potential occur in the heart under conditions of oxidative stress frequently associated with cardiac arrhythmias. Since beat-to-beat variability (short term variability, SV) of action potential duration (APD) is a good indicator of arrhythmia incidence, the aim of this work was to study the influence of redox changes on SV in isolated canine ventricular cardiomyocytes using a conventional microelectrode technique. The redox potential was shifted toward a reduced state using a reductive cocktail (containing dithiothreitol, glutathione, and ascorbic acid) while oxidative changes were initiated by superfusion with H2O2. Redox effects were evaluated as changes in "relative SV" determined by comparing SV changes with the concomitant APD changes. Exposure of myocytes to the reductive cocktail decreased SV significantly without any detectable effect on APD. Application of H2O2 increased both SV and APD, but the enhancement of SV was the greater, so relative SV increased. Longer exposure to H2O2 resulted in the development of early afterdepolarizations accompanied by tremendously increased SV. Pretreatment with the reductive cocktail prevented both elevation in relative SV and the development of afterdepolarizations. The results suggest that the increased beat-to-beat variability during an oxidative stress contributes to the generation of cardiac arrhythmias.

Electrical and Mechanical Responses in Deep Abdominal Extensor Muscles of Crayfish and Lobster

PubMed Central

Abbott, Bernard C.; Parnas, I.

1965-01-01

Electrical and mechanical studies have been made of the deep abdominal extensor muscles, medial (DEAM) and lateral (DEAL), of crayfish and lobster. The medial muscle responds to direct (intracellular) and indirect stimulation with a transient membrane depolarization which exhibits the properties of a propagated non-decremental action potential but does not overshoot the zero level. The amplitude is about 30 mv in crayfish and 50 mv in lobster. It is followed by a fast all-or-none twitch whose duration at 20°C is 30 to 50 msec. and whose developed tension is 500 gm/cm2 or about half the tetanic value. Membrane potential is K+-dependent and immersion in high K+ induces a brief transient tension rise as in other twitch-type muscles. The action potential and twitch are normal even if all external Na+ is replaced with sucrose but vary with external Ca++, the action potential increasing 8 to 10 mv for a twofold increase in Ca++. The lateral muscle (DEAL) is much slower and responds to intracellular stimulation only with an electrotonic or a local response. Mechanical responses and relaxation speeds are slow with minimal duration of contraction of 0.5 to 2 seconds. Immersion in high K solutions induces large maintained tensions. Sarcomere length in the fast DEAM is uniform and about 2 µ at rest, but in the DEAL speed is less and sarcomere length is greater averaging about 4.5 µ but with a mixed population of fibers. PMID:14324996

Extracellular NAD+ Suppresses Adrenergic Effects in the Atrial Myocardium of Rats during the Early Postnatal Ontogeny.

PubMed

Pustovit, K B; Ivanova, A D; Kuz'min, V S

2018-05-01

The effects of sympathetic cotransmitter NAD+ (10 μM) on bioelectric activity of the heart under conditions of adrenergic stimulation were studied on isolated spontaneously contracting preparations (without stimulation) of the right atrium from 2-7-day-old rats. Action potentials were recorded in the working myocardium using standard microelectrode technique. Perfusion of the right atrium with norepinephrine solution (1 μM) altered the configuration and significantly lengthened the action potentials. NAD + against the background of norepinephrine stimulation significantly decreased the duration of action potentials, in particular, at 25% repolarization. The effect of purine compounds NAD + , ATP, and adenosine on bioelectrical activity of the heart of newborn rats was studied under basal conditions (without norepinephrine stimulation). The effect of NAD + against the background of adrenergic stimulation was more pronounced than under basal conditions and was probably determined by suppression of I CaL , which can be the main mechanism of NAD + action on rat heart.

Simulation of axonal excitability using a Spreadsheet template created in Microsoft Excel.

PubMed

Brown, A M

2000-08-01

The objective of this present study was to implement an established simulation protocol (A.M. Brown, A methodology for simulating biological systems using Microsoft Excel, Comp. Methods Prog. Biomed. 58 (1999) 181-90) to model axonal excitability. The simulation protocol involves the use of in-cell formulas directly typed into a spreadsheet and does not require any programming skills or use of the macro language. Once the initial spreadsheet template has been set up the simulations described in this paper can be executed with a few simple keystrokes. The model axon contained voltage-gated ion channels that were modeled using Hodgkin Huxley style kinetics. The basic properties of axonal excitability modeled were: (1) threshold of action potential firing, demonstrating that not only are the stimulus amplitude and duration critical in the generation of an action potential, but also the resting membrane potential; (2) refractoriness, the phenomenon of reduced excitability immediately following an action potential. The difference between the absolute refractory period, when no amount of stimulus will elicit an action potential, and relative refractory period, when an action potential may be generated by applying increased stimulus, was demonstrated with regard to the underlying state of the Na(+) and K(+) channels; (3) temporal summation, a process by which two sub-threshold stimuli can unite to elicit an action potential was shown to be due to conductance changes outlasting the first stimulus and summing with the second stimulus-induced conductance changes to drive the membrane potential past threshold; (4) anode break excitation, where membrane hyperpolarization was shown to produce an action potential by removing Na(+) channel inactivation that is present at resting membrane potential. The simulations described in this paper provide insights into mechanisms of axonal excitation that can be carried out by following an easily understood protocol.

The Application of a Massively Parallel Computer to the Simulation of Electrical Wave Propagation Phenomena in the Heart Muscle Using Simplified Models

NASA Technical Reports Server (NTRS)

Karpoukhin, Mikhii G.; Kogan, Boris Y.; Karplus, Walter J.

1995-01-01

The simulation of heart arrhythmia and fibrillation are very important and challenging tasks. The solution of these problems using sophisticated mathematical models is beyond the capabilities of modern super computers. To overcome these difficulties it is proposed to break the whole simulation problem into two tightly coupled stages: generation of the action potential using sophisticated models. and propagation of the action potential using simplified models. The well known simplified models are compared and modified to bring the rate of depolarization and action potential duration restitution closer to reality. The modified method of lines is used to parallelize the computational process. The conditions for the appearance of 2D spiral waves after the application of a premature beat and the subsequent traveling of the spiral wave inside the simulated tissue are studied.

An automated system using spatial oversampling for optical mapping in murine atria. Development and validation with monophasic and transmembrane action potentials.

PubMed

Yu, Ting Yue; Syeda, Fahima; Holmes, Andrew P; Osborne, Benjamin; Dehghani, Hamid; Brain, Keith L; Kirchhof, Paulus; Fabritz, Larissa

2014-08-01

We developed and validated a new optical mapping system for quantification of electrical activation and repolarisation in murine atria. The system makes use of a novel 2nd generation complementary metal-oxide-semiconductor (CMOS) camera with deliberate oversampling to allow both assessment of electrical activation with high spatial and temporal resolution (128 × 2048 pixels) and reliable assessment of atrial murine repolarisation using post-processing of signals. Optical recordings were taken from isolated, superfused and electrically stimulated murine left atria. The system reliably describes activation sequences, identifies areas of functional block, and allows quantification of conduction velocities and vectors. Furthermore, the system records murine atrial action potentials with comparable duration to both monophasic and transmembrane action potentials in murine atria. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

cAMP modulates multiple K+ currents, increasing spike duration and excitability in Aplysia sensory neurons.

PubMed

Goldsmith, B A; Abrams, T W

1992-12-01

Enhancement of the defensive withdrawal reflex of Aplysia involves a prolongation of the action potentials of mechanosensory neurons, which contributes to facilitation of transmitter release from these cells. Recent reports have suggested that whereas cAMP-dependent modulation of K+ current increases sensory neuron excitability, a cAMP-independent decrease in K+ current may increase the action potential duration and, thus, facilitate transmitter release. We have tested this proposal using Walsh cAMP-dependent protein kinase inhibitor or activators of the cAMP cascade and found that cAMP plays a major role in the spike-broadening effects of facilitatory transmitter; however, broadening requires higher levels of activation of the cAMP-dependent kinase than does increasing excitability. A steeply voltage-dependent transient K+ current, termed IKV,early, and the slowly activating S-type K+ (S-K+) current are both reduced by activation of the cAMP cascade, although with different sensitivities to the second messenger, enabling excitability and spike duration to be regulated independently. Differences in cAMP sensitivity also suggested that the originally described S-K+ current actually consists of two independent components, a slowly activating component and a time-independent, "steady-state" current that is activated at rest.

Protective effects of isorhynchophylline on cardiac arrhythmias in rats and guinea pigs.

PubMed

Gan, Runtao; Dong, Guo; Yu, Jiangbo; Wang, Xu; Fu, Songbin; Yang, Shusen

2011-09-01

As one important constituent extracted from a traditional Chinese medicine, Uncaria Rhynchophylla Miq Jacks, isorhynchophylline has been used to treat hypertension, epilepsy, headache, and other illnesses. Whether isorhynchophylline protects hearts against cardiac arrhythmias is still incompletely investigated. This study was therefore aimed to examine the preventive effects of isorhynchophylline on heart arrhythmias in guinea pigs and rats and then explore their electrophysiological mechanisms. In vivo, ouabain and calcium chloride were used to establish experimental arrhythmic models in guinea pigs and rats. In vitro, the whole-cell patch-lamp technique was used to study the effect of isorhynchophylline on action potential duration and calcium channels in acutely isolated guinea pig and rat cardiomyocytes. The dose of ouabain required to induce cardiac arrhythmias was much larger in guinea pigs administered with isorhynchophylline. Additionally, the onset time of cardiac arrhythmias induced by calcium chloride was prolonged, and the duration was shortened in rats pretreated with isorhynchophylline. The further study showed that isorhynchophylline could significantly decrease action potential duration and inhibit calcium currents in isolated guinea pig and rat cardiomyocytes in a dose-dependent manner. In summary, isorhynchophylline played a remarkably preventive role in cardiac arrhythmias through the inhibition of calcium currents in rats and guinea pigs. © Georg Thieme Verlag KG Stuttgart · New York.

Reconstruction of the action potential of ventricular myocardial fibres

PubMed Central

Beeler, G. W.; Reuter, H.

1977-01-01

1. A mathematical model of membrane action potentials of mammalian ventricular myocardial fibres is described. The reconstruction model is based as closely as possible on ionic currents which have been measured by the voltage-clamp method. 2. Four individual components of ionic current were formulated mathematically in terms of Hodgkin—Huxley type equations. The model incorporates two voltage- and time-dependent inward currents, the excitatory inward sodium current, iNa, and a secondary or slow inward current, is, primarily carried by calcium ions. A time-independent outward potassium current, iK1, exhibiting inward-going rectification, and a voltage- and time-dependent outward current, ix1, primarily carried by potassium ions, are further elements of the model. 3. The iNa is primarily responsible for the rapid upstroke of the action potential, while the other current components determine the configuration of the plateau of the action potential and the re-polarization phase. The relative importance of inactivation of is and of activation of ix1 for termination of the plateau is evaluated by the model. 4. Experimental phenomena like slow recovery of the sodium system from inactivation, frequency dependence of the action potential duration, all-or-nothing re-polarization, membrane oscillations are adequately described by the model. 5. Possible inadequacies and shortcomings of the model are discussed. PMID:874889

The assessment of electrophysiological activity in human-induced pluripotent stem cell-derived cardiomyocytes exposed to dimethyl sulfoxide and ethanol by manual patch clamp and multi-electrode array system.

PubMed

Hyun, Soo-Wang; Kim, Bo-Ram; Hyun, Sung-Ae; Seo, Joung-Wook

2017-09-01

Recently, electrophysiological activity has been effectively measured in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to predict drug-induced arrhythmia. Dimethyl sulfoxide (DMSO) and ethanol have been used as diluting agents in many experiments. However, the maximum DMSO and ethanol concentrations that can be effectively used in the measurement of electrophysiological parameters in hiPSC-CMs-based patch clamp and multi-electrode array (MEA) have not been fully elucidated. We investigated the effects of varying concentrations of DMSO and ethanol used as diluting agents on several electrophysiological parameters in hiPSC-CMs using patch clamp and MEA. Both DMSO and ethanol at concentrations>1% in external solution resulted in osmolality >400mOsmol/kg, but pH was not affected by either agent. Neither DMSO nor ethanol led to cell death at the concentrations examined. However, resting membrane potential, action potential amplitude, action potential duration at 90% and 40%, and corrected field potential duration were decreased significantly at 1% ethanol concentration. DMSO at 1% also significantly decreased the sodium spike amplitude. In addition, the waveform of action potential and field potential was recorded as irregular at 3% concentrations of both DMSO and ethanol. Concentrations of up to 0.3% of either agent did not affect osmolality, pH, cell death, or electrophysiological parameters in hiPSC-CMs. Our findings suggest that 0.3% is the maximum concentration at which DMSO or ethanol should be used for dilution purposes in hiPSC-CMs-based patch clamp and MEA. Copyright © 2017 Elsevier Inc. All rights reserved.

The effects of bilastine compared with cetirizine, fexofenadine, and placebo on allergen-induced nasal and ocular symptoms in patients exposed to aeroallergen in the Vienna Challenge Chamber.

PubMed

Horak, Friedrich; Zieglmayer, Petra; Zieglmayer, René; Lemell, Patrick

2010-05-01

This double-blind cross-over study compared the potential of bilastine, cetirizine, and fexofenadine to relieve the symptoms of allergic rhinitis. Seventy-five allergic volunteers were challenged with grass pollen in the Vienna Challenge Chamber (VCC) on two consecutive days of allergen provocation; 6 h on day 1 and 4 h day 2. Bilastine 20 mg, cetirizine 10 mg, fexofenadine 120 mg, or placebo were taken orally 2 h after the start of provocation on day 1 only. Total nasal symptom scores, the global symptom scores, nasal secretions, and eye symptoms were assessed on both day 1 and day 2. Bilastine had a rapid onset of action, within 1 h, and a long duration of action, greater than 26 h. Cetirizine was similar. Fexofenadine was similar on day 1 but less effective on day 2, indicating a shorter duration of action. Bilastine, like cetirizine and fexofenadine, was safe and well tolerated in this study.

Botulism in 2 urban dogs

PubMed Central

Uriarte, Ane; Thibaud, Jean-Laurent; Blot, Stéphane

2010-01-01

Two dogs from the same owner were referred for ascending weakness and paresis of 2 to 3 days duration. Electromyography and electroneurography determined that there were normal F-waves, decreased compound action potential, and decreased activity on repetitive nerve stimulation. These findings were valuable in diagnosing botulism in the dogs. PMID:21197207

Physiological properties of anatomically identified basket and bistratified cells in the CA1 area of the rat hippocampus in vitro.

PubMed

Buhl, E H; Szilágyi, T; Halasy, K; Somogyi, P

1996-01-01

Basket and bistratified cells form two anatomically distinct classes of GABAergic local-circuit neurons in the CA1 region of the rat hippocampus. A physiological comparison was made of intracellularly recorded basket (n = 13) and bistratified neurons (n = 6), all of which had been anatomically defined by their efferent target profile (Halasy et al., 1996). Basket cells had an average resting membrane potential of -64.2 +/- 7.2 vs. -69.2 +/- 4.6 mV in bistratified cells. The latter had considerably higher mean input resistances (60.2 +/- 42.1 vs. 31.3 +/- 10.9 M Ohms) and longer membrane time constants (18.6 +/- 8.1 vs. 9.8 +/- 4.5 ms) than basket cells. Differences were also apparent in the duration of action potentials, those of basket cells being 364 +/- 77 and those of bistratified cells being 527 +/- 138 microseconds at half-amplitude. Action potentials were generally followed by prominent, fast after-hyperpolarizing potentials which in basket cells were 13.5 +/- 6.7 mV in amplitude vs. 10.5 +/- 5.1 in bistratified cells. The differences in membrane time constant, resting membrane potential, and action potential duration reached statistical significance (P < 0.05). Extracellular stimulation of Schaffer collateral/commissural afferents elicited short-latency excitatory postsynaptic potentials (EPSPs) in both cell types. The average 10-90% rise time and duration (at half-amplitude) of subthreshold EPSPs in basket cells were 1.9 +/- 0.5 and 10.7 +/- 5.6 ms, compared to 3.3 +/- 1.3 and 20.1 +/- 9.7 ms in bistratified cells, the difference in EPSP rise times being statistically significant. Basket and bistratified EPSPs were highly sensitive to a bath applied antagonist of non-N-methyl-D-aspartate (NMDA) receptors, whereas the remaining slow-rise EPSP could be abolished by an NMDA receptor antagonist. Increasing stimulation intensity elicited biphasic inhibitory postsynaptic potentials (IPSPs) in both basket and bistratified cells. In conclusion, basket and bistratified cells in the CA1 area show prominent differences in several of their membrane and firing properties. Both cell classes are activated by Schaffer collateral/commissural axons in a feedforward manner and receive inhibitory input from other, as yet unidentified, local-circuit neurons.

Factors predictive of the onset and duration of action of local anesthesia in mandibular third-molar surgery: a prospective study.

PubMed

Al-Shayyab, Mohammad H; Baqain, Zaid H

2018-04-01

The aim of this study was to assess the influence of patients' and surgical variables on the onset and duration of action of local anesthesia (LA) in mandibular third-molar (M3) surgery. Patients scheduled for mandibular M3 surgery were considered for inclusion in this prospective cohort study. Patients' and surgical variables were recorded. Two per cent (2%) lidocaine with 1:100,000 epinephrine was used to block the nerves for extraction of mandibular M3. Then, the onset of action and duration of LA were monitored. Univariate analysis and multivariate regression analysis were used to analyze the data. The final cohort included 88 subjects (32 men and 56 women; mean age ± SD = 29.3 ± 12.3 yr). With univariate analysis, age, gender, body mass index (BMI), smoking quantity and duration, operation time, and 'volume of local anesthetic needed' significantly influenced the onset of action and duration of LA. Multivariate regression revealed that age and smoking quantity were the only statistically significant predictors of the onset of action of LA, whereas age, smoking quantity, and 'volume of local anesthetic needed' were the only statistically significant predictors of duration of LA. Further studies are recommended to uncover other predictors of the onset of action and duration of LA. © 2018 Eur J Oral Sci.

Chemical and pharmacological properties of diflunisal.

PubMed

Shen, T Y

1983-01-01

Diflunisal, 5-(2',4'-difluorophenyl) salicylic acid, was discovered as a potent antiinflammatory analgesic agent after an extensive investigation of more than 500 salicylic acid analogs. The addition of a difluorophenyl substituent at the C5 position of salicylic acid yielded a new molecule with much improved lipophilicity, a longer duration of action, and a molecular configuration that is optimal for greater antiinflammatory and analgesic activities. The difluorophenyl group is metabolically stable; the acyl and phenolic glucuronides of the intact diflunisal are major urinary metabolites. The absence of an O-acetyl group in this novel salicylate analog circumvents the well-known in vivo acylation potential of aspirin and renders diflunisal a reversible cyclooxygenase inhibitor with a secondary oxygen radical scavenging effect. In a variety of analgesic, acute, and chronic antiinflammatory models, diflunisal is active at 10 mg/kg, approximately 5 to 10 times more potent than aspirin. It has a relatively low potential to cause gastrointestinal irritation as indicated by the lack of acute effect on the integrity of gastric mucosa barrier, no change of intragastric potential, and no disturbance of prostaglandin production by the gastric tissue. Diflunisal holds promise as a new clinically useful analgesic and antiinflammatory drug with good tolerance and a long duration of action.

Rosewood oil induces sedation and inhibits compound action potential in rodents.

PubMed

de Almeida, Reinaldo Nóbrega; Araújo, Demétrius Antonio Machado; Gonçalves, Juan Carlos Ramos; Montenegro, Fabrícia Costa; de Sousa, Damião Pergentino; Leite, José Roberto; Mattei, Rita; Benedito, Marco Antonio Campana; de Carvalho, José Gilberto Barbosa; Cruz, Jader Santos; Maia, José Guilherme Soares

2009-07-30

Aniba rosaeodora is an aromatic plant which has been used in Brazil folk medicine due to its sedative effect. Therefore, the purpose of the present study was to evaluate the sedative effect of linalool-rich rosewood oil in mice. In addition we sought to investigate the linalool-rich oil effects on the isolated nerve using the single sucrose-gap technique. Sedative effect was determined by measuring the potentiation of the pentobarbital-induced sleeping time. The compound action potential amplitude was evaluated as a way to detect changes in excitability of the isolated nerve. The results showed that administration of rosewood oil at the doses of 200 and 300 mg/kg significantly decreased latency and increased the duration of sleeping time. On the other hand, the dose of 100 mg/kg potentiated significantly the pentobarbital action decreasing pentobarbital latency time and increasing pentobarbital sleeping time. In addition, the effect of linalool-rich rosewood oil on the isolated nerve of the rat was also investigated through the single sucrose-gap technique. The amplitude of the action potential decreased almost 100% when it was incubated for 30 min at 100 microg/ml. From this study, it is suggested a sedative effect of linalool-rich rosewood oil that could, at least in part, be explained by the reduction in action potential amplitude that provokes a decrease in neuronal excitability.

Physiological properties of anatomically identified axo-axonic cells in the rat hippocampus.

PubMed

Buhl, E H; Han, Z S; Lörinczi, Z; Stezhka, V V; Karnup, S V; Somogyi, P

1994-04-01

1. The properties of a well-defined type of GABAergic local circuit neuron, the axo-axonic cell (n = 17), were investigated in rat hippocampal slice preparations. During intracellular recording we injected axo-axonic cells with biocytin and subsequently identified them with correlated light and electron microscopy. Employing an immunogold-silver intensification technique we showed that one of the physiologically characterized cells was immunoreactive for gamma-aminobutyric acid (GABA). 2. Axo-axonic cells were encountered in the dentate gyrus (n = 5) as well as subfields CA3 (n = 2) and CA1 (n = 10). They generally had smooth, beaded dendrites that extended throughout all hippocampal layers. Their axons ramified densely in the cell body layers and in the subjacent stratum oriens or hilus, respectively. Tested with electron microscopy, labeled terminals (n = 53) established synapses exclusively with the axon initial segment of principal cells in strata oriens and pyramidale and rarely in lower radiatum. Within a 400-microns slice a single CA1 axo-axonic cell was estimated to be in synaptic contact with 686 pyramidal cells. 3. Axo-axonic cells (n = 14) had a mean resting membrane potential of -65.1 mV, an average input resistance of 73.9 M omega, and a mean time constant of 7.7 ms. Action potentials were of short duration (389-microseconds width at half-amplitude) and had a mean amplitude of 64.1 mV. 4. Nine of 10 tested cells showed a varying degree of spike frequency adaptation in response to depolarizing current injection. Current-evoked action potentials were usually curtailed by a deep (10.2 mV) short-latency afterhyperpolarization (AHP) with a mean duration of 28.1 ms. 5. Cells with strong spike frequency accommodation (n = 5) had a characteristic firing pattern with numerous spike doublets. These appeared to be triggered by an underlying depolarizing afterpotential. In the same cells, prolonged bursts of action potentials were followed by a prominent long-duration AHP with a mean time constant of 1.15 s. 6. Axo-axonic cells responded to the stimulation of afferent pathways with short-latency excitatory postsynaptic potentials (EPSPs) or at higher stimulation intensity with up to three action potentials. Axo-axonic cells in the dentate gyrus could be activated by stimulating the CA3 area as well as the perforant path, whereas in the CA1 area responses were elicited after shocks to the perforant path, Schaffer collaterals, and the stratum oriens-alveus border. 7. In the CA1 area the EPSP amplitude increased in response to membrane hyperpolarization.(ABSTRACT TRUNCATED AT 400 WORDS)

[Brain Mechanisms for Measuring Time: Population Coding of Durations].

PubMed

Hayashi, Masamichi J

2016-11-01

Temporal processing is crucial in many aspects of our perception and action. While there is mounting evidence for the encoding mechanisms of spatial ("where") and identity ("what") information, those of temporal information ("when") remain largely unknown. Recent studies suggested that, similarly to the basic visual stimulus features such as orientation, motion direction, and numerical quantity, event durations are also represented by a population of neurons that are tuned for specific, preferred durations. This paper first reviews recent psychophysical studies on duration aftereffect. Changes in the three parameters (response gain, shift, and width of tuning curves) are then discussed that may need to be taken into account in the putative duration-channel model. Next, the potential neural basis of the duration channels is examined by overviewing recent neuroimaging and electrophysiological studies on time perception. Finally, this paper proposes a general neural basis of timing that commonly represents time-differences independent of stimulus types (e.g., a single duration v.s. multiple brief events). This extends the idea of the "when pathway" from the perception of temporal order to the general timing mechanisms for the perception of duration, temporal frequency, and synchrony.

Effects of pioglitazone on cardiac ion currents and action potential morphology in canine ventricular myocytes.

PubMed

Kistamás, Kornél; Szentandrássy, Norbert; Hegyi, Bence; Ruzsnavszky, Ferenc; Váczi, Krisztina; Bárándi, László; Horváth, Balázs; Szebeni, Andrea; Magyar, János; Bányász, Tamás; Kecskeméti, Valéria; Nánási, Péter P

2013-06-15

Despite its widespread therapeutical use there is little information on the cellular cardiac effects of the antidiabetic drug pioglitazone in larger mammals. In the present study, therefore, the concentration-dependent effects of pioglitazone on ion currents and action potential configuration were studied in isolated canine ventricular myocytes using standard microelectrode, conventional whole cell patch clamp, and action potential voltage clamp techniques. Pioglitazone decreased the maximum velocity of depolarization and the amplitude of phase-1 repolarization at concentrations ≥3 μM. Action potentials were shortened by pioglitazone at concentrations ≥10 μM, which effect was accompanied with significant reduction of beat-to-beat variability of action potential duration. Several transmembrane ion currents, including the transient outward K(+) current (Ito), the L-type Ca(2+) current (ICa), the rapid and slow components of the delayed rectifier K(+) current (IKr and IKs, respectively), and the inward rectifier K(+) current (IK1) were inhibited by pioglitazone under conventional voltage clamp conditions. Ito was blocked significantly at concentrations ≥3 μM, ICa, IKr, IKs at concentrations ≥10 μM, while IK1 at concentrations ≥30 μM. Suppression of Ito, ICa, IKr, and IK1 has been confirmed also under action potential voltage clamp conditions. ATP-sensitive K(+) current, when activated by lemakalim, was effectively blocked by pioglitazone. Accordingly, action potentials were prolonged by 10 μM pioglitazone when the drug was applied in the presence of lemakalim. All these effects developed rapidly and were readily reversible upon washout. In conclusion, pioglitazone seems to be a harmless agent at usual therapeutic concentrations. Copyright © 2013 Elsevier B.V. All rights reserved.

Effect of action potential duration on Tpeak-Tend interval, T-wave area and T-wave amplitude as indices of dispersion of repolarization: Theoretical and simulation study in the rabbit heart.

PubMed

Arteyeva, Natalia V; Azarov, Jan E

The aim of the study was to differentiate the effect of dispersion of repolarization (DOR) and action potential duration (APD) on T-wave parameters being considered as indices of DOR, namely, Tpeak-Tend interval, T-wave amplitude and T-wave area. T-wave was simulated in a wide physiological range of DOR and APD using a realistic rabbit model based on experimental data. A simplified mathematical formulation of T-wave formation was conducted. Both the simulations and the mathematical formulation showed that Tpeak-Tend interval and T-wave area are linearly proportional to DOR irrespectively of APD range, while T-wave amplitude is non-linearly proportional to DOR and inversely proportional to the minimal repolarization time, or minimal APD value. Tpeak-Tend interval and T-wave area are the most accurate DOR indices independent of APD. T-wave amplitude can be considered as an index of DOR when the level of APD is taken into account. Copyright © 2017 Elsevier Inc. All rights reserved.

Multi-electrode array technologies for neuroscience and cardiology

NASA Astrophysics Data System (ADS)

Spira, Micha E.; Hai, Aviad

2013-02-01

At present, the prime methodology for studying neuronal circuit-connectivity, physiology and pathology under in vitro or in vivo conditions is by using substrate-integrated microelectrode arrays. Although this methodology permits simultaneous, cell-non-invasive, long-term recordings of extracellular field potentials generated by action potentials, it is 'blind' to subthreshold synaptic potentials generated by single cells. On the other hand, intracellular recordings of the full electrophysiological repertoire (subthreshold synaptic potentials, membrane oscillations and action potentials) are, at present, obtained only by sharp or patch microelectrodes. These, however, are limited to single cells at a time and for short durations. Recently a number of laboratories began to merge the advantages of extracellular microelectrode arrays and intracellular microelectrodes. This Review describes the novel approaches, identifying their strengths and limitations from the point of view of the end users -- with the intention to help steer the bioengineering efforts towards the needs of brain-circuit research.

Multi-electrode array technologies for neuroscience and cardiology.

PubMed

Spira, Micha E; Hai, Aviad

2013-02-01

At present, the prime methodology for studying neuronal circuit-connectivity, physiology and pathology under in vitro or in vivo conditions is by using substrate-integrated microelectrode arrays. Although this methodology permits simultaneous, cell-non-invasive, long-term recordings of extracellular field potentials generated by action potentials, it is 'blind' to subthreshold synaptic potentials generated by single cells. On the other hand, intracellular recordings of the full electrophysiological repertoire (subthreshold synaptic potentials, membrane oscillations and action potentials) are, at present, obtained only by sharp or patch microelectrodes. These, however, are limited to single cells at a time and for short durations. Recently a number of laboratories began to merge the advantages of extracellular microelectrode arrays and intracellular microelectrodes. This Review describes the novel approaches, identifying their strengths and limitations from the point of view of the end users--with the intention to help steer the bioengineering efforts towards the needs of brain-circuit research.

Motor Unit Activity during Fatiguing Isometric Muscle Contraction in Hemispheric Stroke Survivors

PubMed Central

McManus, Lara; Hu, Xiaogang; Rymer, William Z.; Suresh, Nina L.; Lowery, Madeleine M.

2017-01-01

Enhanced muscle weakness is commonly experienced following stroke and may be accompanied by increased susceptibility to fatigue. To examine the contributions of central and peripheral factors to isometric muscle fatigue in stroke survivors, this study investigates changes in motor unit (MU) mean firing rate, and action potential duration during, and directly following, a sustained submaximal fatiguing contraction at 30% maximum voluntary contraction (MVC). A series of short contractions of the first dorsal interosseous muscle were performed pre- and post-fatigue at 20% MVC, and again following a 10-min recovery period, by 12 chronic stroke survivors. Individual MU firing times were extracted using surface EMG decomposition and used to obtain the spike-triggered average MU action potential waveforms. During the sustained fatiguing contraction, the mean rate of change in firing rate across all detected MUs was greater on the affected side (-0.02 ± 0.03 Hz/s) than on the less-affected side (-0.004 ± 0.003 Hz/s, p = 0.045). The change in firing rate immediately post-fatigue was also greater on the affected side than less-affected side (-13.5 ± 20 and 0.1 ± 19%, p = 0.04). Mean MU firing rates increased following the recovery period on the less-affected side when compared to the affected side (19.3 ± 17 and 0.5 ± 20%, respectively, p = 0.03). MU action potential duration increased post-fatigue on both sides (10.3 ± 1.2 to 11.2 ± 1.3 ms on the affected side and 9.9 ± 1.7 to 11.2 ± 1.9 ms on the less-affected side, p = 0.001 and p = 0.02, respectively), and changes in action potential duration tended to be smaller in subjects with greater impairment (p = 0.04). This study presents evidence of both central and peripheral fatigue at the MU level during isometric fatiguing contraction for the first time in stroke survivors. Together, these preliminary observations indicate that the response to an isometric fatiguing contraction differs between the affected and less-affected side post-stroke, and may suggest that central mechanisms observed here as changes in firing rate are the dominant processes leading to task failure on the affected side. PMID:29225574

Effects of Trichothecenes on Cardiac Cell Electrical Function

DTIC Science & Technology

1985-12-13

Figure 8 illustrate the typical effects of trichothecene mycotoxins in canine ventricular cells. T-2 tetraol, for example, reduced the total duration of...potentials from false tendon cells and ventricular muscle cells (shown in Figure 8) illustrate the typical effects of trichothecene mycotoxins in canine...the plateau (arrow) from 14 my to 4 my. Table 6 summarizes the effects of T-2 mycotoxin on the action potential parameters of false tendon cells and

Rate dependency of delayed rectifier currents during the guinea-pig ventricular action potential

PubMed Central

Rocchetti, Marcella; Besana, Alessandra; Gurrola, Georgina B; Possani, Lourival D; Zaza, Antonio

2001-01-01

The action potential clamp technique was exploited to evaluate the rate dependency of delayed rectifier currents (IKr and IKs) during physiological electrical activity. IKr and IKs were measured in guinea-pig ventricular myocytes at pacing cycle lengths (CL) of 1000 and 250 ms.A shorter CL, with the attendant changes in action potential shape, was associated with earlier activation and increased magnitude of both IKr and IKs. Nonetheless, the relative contributions of IKr and IKs to total transmembrane current were independent of CL.Shortening of diastolic interval only (constant action potential shape) enhanced IKs, but not IKr.IKr was increased by a change in the action potential shape only (constant diastolic interval).In ramp clamp experiments, IKr amplitude was directly proportional to repolarization rate at values within the low physiological range (< 1.0 V s−1); at higher repolarization rates proportionality became shallower and finally reversed.When action potential duration (APD) was modulated by constant current injection (I-clamp), repolarization rates > 1.0 V s−1 were associated with a reduced effect of IKr block on APD. The effect of changes in repolarization rate was independent of CL and occurred in the presence of IKs blockade.In spite of its complexity, the behaviour of IKr was accurately predicted by a numerical model based entirely on known kinetic properties of the current.Both IKr and IKs may be increased at fast heart rates, but this may occur through completely different mechanisms. The mechanisms identified are such as to contribute to abnormal rate dependency of repolarization in prolonged repolarization syndromes. PMID:11483703

Electrophysiological, vasoactive, and gastromodulatory effects of stevia in healthy Wistar rats.

PubMed

Yesmine, Saquiba; Connolly, Kylie; Hill, Nicholas; Coulson, Fiona R; Fenning, Andrew S

2013-07-01

Antihypertensive and antidiabetic effects of stevia, Stevia rebaudiana (Asteraceae), have been demonstrated in several human and animal models. The current study aims to define stevia's role in modifying the electrophysiological and mechanical properties of cardiomyocytes, blood vessels, and gastrointestinal smooth muscle. Tissues from thoracic aorta, mesenteric arteries, ileum, and left ventricular papillary muscles were excised from 8-week-old healthy Wistar rats. The effects of stevia (1 × 10-9 M to 1 × 10-4 M) were measured on these tissues. Stevia's effects in the presence of verapamil, 4-AP, and L-NAME were also assessed. In cardiomyocytes, stevia attenuated the force of contraction, decreased the average peak amplitude, and shortened the repolarisation phase of action potential - repolarisation phase of action potential20 by 25 %, repolarisation phase of action potential50 by 34 %, and repolarisation phase of action potential90 by 36 %. Stevia caused relaxation of aortic tissues which was significantly potentiated in the presence of verapamil. In mesenteric arteries, incubation with L-NAME failed to block stevia-induced relaxation indicating the mechanism of action may not be fully via nitric oxide-dependent pathways. Stevia concentration-dependently reduced electrical field stimulated and carbachol-induced contractions in the isolated ileum. This study is the first to show the effectiveness of stevia in reducing cardiac action potential duration at 20 %, 50 %, and 90 % of repolarisation. Stevia also showed beneficial modulatory effects on cardiovascular and gastrointestinal tissues via calcium channel antagonism, activation of the M2 muscarinic receptor function, and enhanced nitric oxide release. Georg Thieme Verlag KG Stuttgart · New York.

Electrodiagnosis of reversible conduction failure in Guillain-Barré syndrome.

PubMed

Chan, Yee-Cheun; Punzalan-Sotelo, Aubrey M; Kannan, Therimadasamy A; Shahrizaila, Nortina; Umapathi, Thirugnanam; Goh, Eunice J H; Fukami, Yuki; Wilder-Smith, Einar; Yuki, Nobuhiro

2017-11-01

In this study we propose electrodiagnostic criteria for early reversible conduction failure (ERCF) in axonal Guillain-Barré syndrome (GBS) and apply them to a cohort of GBS patients. Serial nerve conduction studies (NCS) were retrospectively analyzed in 82 GBS patients from 3 centers. The criteria for the presence of ERCF in a nerve were: (i) a 50% increase in amplitude of distal compound muscle action potentials or sensory nerve action potentials; or (ii) resolution of proximal motor conduction block with an accompanying decrease in distal latencies or compound muscle action potential duration or increase in conduction velocities. Of 82 patients from 3 centers, 37 (45%) had ERCF, 21 (26%) had a contrasting evolution pattern, and 8 (10%) had both. Sixteen patients did not show an amplitude increase of at least 50%. Our proposed criteria identified a group of patients with a characteristic evolution of NCS abnormality that is consistent with ERCF. Muscle Nerve 56: 919-924, 2017. © 2017 Wiley Periodicals, Inc.

Anodal sensory nerve action potentials: From physiological understanding to potential clinical applicability.

PubMed

Leote, Joao; Pereira, Pedro; Cabib, Christopher; Cipullo, Federica; Valls-Sole, Josep

2016-06-01

Low-intensity electrical stimuli of digital nerves may generate a double peak potential (DPp), composed of a cathodal (caAP) and an anodal (anAP) potential in orthodromic recordings. We studied the effects on caAP and anAP of stimuli of variable intensity, duration, and frequency. We also applied a conditioning stimulus to study potential differences in recovery time. The anAP was obtained in 33 of 40 healthy subjects (82.5%) and 4 of 20 patients with various types of sensory neuropathies (20%). Changes in stimulus duration and intensity had reciprocal effects on the amplitude of the anAP and the caAP. There were significant differences in recovery time between caAP and anAP after a conditioning stimulus. The caAP and anAP are 2 interdependent waveforms generated by different effects of the same stimulus over axons at the verge of depolarization. Muscle Nerve 53: 897-905, 2016. © 2015 Wiley Periodicals, Inc.

Twenty-four-hour duration of effect of intranasal corticosteroids for seasonal allergic rhinitis symptoms: clinical evidence and relevance.

PubMed

DuBuske, Lawrence M

2012-01-01

Seasonal allergic rhinitis (SAR) symptoms are often most severe and/or disruptive during overnight and morning hours, resulting in cognitive/performance impairments and reduced quality of life throughout the following day. Surveys of allergy patients and health care practitioners reveal a common perception that intranasal steroids (INSs), many of which are dosed q.d., fail to adequately relieve symptoms for a full 24 hours. This review assessed whether perceptions of the 24-hour duration of action of INSs correspond with duration of action documented in clinical literature. SAR clinical trial literature of the last 5 years was reviewed to identify studies of INSs incorporating morning instantaneous (A.M. NOW) or instantaneous assessments of 24-hour duration of action. In numerous placebo-controlled trials of INSs in patients with SAR, treatment was associated with significantly greater improvements in A.M. NOW symptoms from baseline versus placebo. For congestion, this is noteworthy, because patients often cite this symptom, especially in the morning, as the most bothersome symptom. Comparison of A.M. NOW and daily scores suggests minimal drop in efficacy at 24 hours postdose. In several studies, INS treatment was found superior to intranasal or oral antihistamines in A.M. NOW symptom improvement. Once-daily INSs have potential for effective 24-hour symptom relief; however, there is an apparent disconnect between these findings and patient/physician perceptions. This discrepancy may be explained, in part, by less-than-ideal treatment adherence among "real-world" patients versus subjects treated in clinical trials. Proactive counseling can encourage proper INS use and help maximize treatment benefits.

Easy Method to Examine Single Nerve Fiber Excitability and Conduction Parameters Using Intact Nonanesthetized Earthworms

ERIC Educational Resources Information Center

Bähring, Robert; Bauer, Christiane K.

2014-01-01

The generation and conduction of neuronal action potentials (APs) were the subjects of a cell physiology exercise for first-year medical students. In this activity, students demonstrated the all-or-none nature of AP generation, measured conduction velocity, and examined the dependence of the threshold stimulus amplitude on stimulus duration. For…

Chemical and Pharmacological Properties of Diflunisal.

PubMed

Shen, T Y

1983-03-01

Diflunisal, 5-(2',4'-difluorophenyl) salicylic acid, was discovered as a potent antiinflammatory analgesic agent after an extensive investigation of more than 500 salicylic acid analogs. The addition of a difluorophenyl substituent at the C 5 position of salicylic acid yielded a new molecule with much improved lipophilicity, a longer duration of action, and a molecular configuration that is optimal for greater antiinflammatory and analgesic activities. The difluorophenyl group is metabolically stable; the acyl and phenolic glucuronides of the intact diflunisal are major urinary metabolites. The absence of an O-acetyl group in this novel salicylate analog circumvents the well-known in vivo acylation potential of aspirin and renders diflunisal a reversible cyclooxygenase inhibitor with a secondary oxygen radical scavenging effect. In a variety of analgesic, acute, and chronic antiinflammatory models, diflunisal is active at 10 mg/kg, approximately 5 to 10 times more potent than aspirin. It has a relatively low potential to cause gastrointestinal irritation as indicated by the lack of acute effect on the integrity of gastric mucosal barrier, no change of intragastric potential, and no disturbance of prostaglandin production by the gastric tissue. Diflunisal holds promise as a new clinically useful analgesic and antiinflammatory drug with good tolerance and a long duration of action. 1983 Pharmacotherapy Publications Inc.

Seasonal acclimatization of the cardiac action potential in the Arctic navaga cod (Eleginus navaga, Gadidae).

PubMed

Hassinen, Minna; Abramochkin, Denis V; Vornanen, Matti

2014-04-01

Freshwater fishes of north-temperate latitudes adjust electrical excitability of the heart to seasonal temperature changes by changing expression levels of ion channel isoforms. However, little is known about thermal responses of action potential (AP) in the hearts of marine polar fishes. To this end, we examined cardiac AP in the atrial myocardium of the Arctic navaga cod (Eleginus navaga) from the White Sea (Russia) acclimatized to winter (March) and summer (September) seasons. Acute increases in temperature from 4 to 10 °C were associated with increases in heart rate, maximum velocity of AP upstroke and negative resting membrane potential, while duration of AP was shortened in both winter-acclimatized and summer-acclimatized navaga hearts. In winter, there was a compensatory shortening (41.1%) of atrial AP duration and this was associated with a strong increase in transcript expression of Erg K(+) channels, known to produce the rapid component of the delayed rectifier K(+) current, I(Kr). Smaller increases were found in the expression of Kir2.1 channels that produce the inward rectifier K(+) current, I(K1). These findings indicate that the heart of navaga cod has a good acclimatory capacity in electrical excitation of cardiac myocytes, which enables cardiac function in the cold-eurythermal waters of the subarctic White Sea.

A mathematical model of the electrophysiological alterations in rat ventricular myocytes in type-I diabetes.

PubMed

Pandit, Sandeep V; Giles, Wayne R; Demir, Semahat S

2003-02-01

Our mathematical model of the rat ventricular myocyte (Pandit et al., 2001) was utilized to explore the ionic mechanism(s) that underlie the altered electrophysiological characteristics associated with the short-term model of streptozotocin-induced, type-I diabetes. The simulations show that the observed reductions in the Ca(2+)-independent transient outward K(+) current (I(t)) and the steady-state outward K(+) current (I(ss)), along with slowed inactivation of the L-type Ca(2+) current (I(CaL)), can result in the prolongation of the action potential duration, a well-known experimental finding. In addition, the model demonstrates that the slowed reactivation kinetics of I(t) in diabetic myocytes can account for the more pronounced rate-dependent action potential duration prolongation in diabetes, and that a decrease in the electrogenic Na(+)-K(+) pump current (I(NaK)) results in a small depolarization in the resting membrane potential (V(rest)). This depolarization reduces the availability of the Na(+) channels (I(Na)), thereby resulting in a slower upstroke (dV/dt(max)) of the diabetic action potential. Additional simulations suggest that a reduction in the magnitude of I(CaL), in combination with impaired sarcoplasmic reticulum uptake can lead to a decreased sarcoplasmic reticulum Ca(2+) load. These factors contribute to characteristic abnormal [Ca(2+)](i) homeostasis (reduced peak systolic value and rate of decay) in myocytes from diabetic animals. In combination, these simulation results provide novel information and integrative insights concerning plausible ionic mechanisms for the observed changes in cardiac repolarization and excitation-contraction coupling in rat ventricular myocytes in the setting of streptozotocin-induced, type-I diabetes.

Acute Tryptophan Depletion Increases Translational Indices of Anxiety but not Fear: Serotonergic Modulation of the Bed Nucleus of the Stria Terminalis?

PubMed Central

Robinson, Oliver J; Overstreet, Cassie; Allen, Phillip S; Pine, Daniel S; Grillon, Christian

2012-01-01

Serotonin is strongly implicated in the mammalian stress response, but surprisingly little is known about its mode of action. Recent data suggest that serotonin can inhibit aversive responding in humans, but this remains underspecified. In particular, data in rodents suggest that global serotonin depletion may specifically increase long-duration bed nucleus of the stria terminalis (BNST)-mediated aversive responses (ie, anxiety), but not short-duration BNST-independent responses (ie, fear). Here, we extend these findings to humans. In a balanced, placebo-controlled crossover design, healthy volunteers (n=20) received a controlled diet with and without the serotonin precursor tryptophan (acute tryptophan depletion; ATD). Aversive states were indexed by translational acoustic startle measures. Fear and anxiety were operationally defined as the increase in startle reactivity during short- and long-duration threat periods evoked by predictable shock (fear-potentiated startle) and by the context in which the shocks were administered (anxiety-potentiated startle), respectively. ATD significantly increased long-duration anxiety-potentiated startle but had no effect on short-duration fear-potentiated startle. These results suggest that serotonin depletion in humans selectively increases anxiety but not fear. Current translational frameworks support the proposition that ATD thus disinhibits dorsal raphé-originating serotonergic control of corticotropin-releasing hormone-mediated excitation of the BNST. This generates a candidate neuropharmacological mechanism by which depleted serotonin may increase response to sustained threats, alongside clear implications for our understanding of the manifestation and treatment of mood and anxiety disorders. PMID:22491355

What makes a reach movement effortful? Physical effort discounting supports common minimization principles in decision making and motor control

PubMed Central

Ulbrich, Philipp; Gail, Alexander

2017-01-01

When deciding between alternative options, a rational agent chooses on the basis of the desirability of each outcome, including associated costs. As different options typically result in different actions, the effort associated with each action is an essential cost parameter. How do humans discount physical effort when deciding between movements? We used an action-selection task to characterize how subjective effort depends on the parameters of arm transport movements and controlled for potential confounding factors such as delay discounting and performance. First, by repeatedly asking subjects to choose between 2 arm movements of different amplitudes or durations, performed against different levels of force, we identified parameter combinations that subjects experienced as identical in effort (isoeffort curves). Movements with a long duration were judged more effortful than short-duration movements against the same force, while movement amplitudes did not influence effort. Biomechanics of the movements also affected effort, as movements towards the body midline were preferred to movements away from it. Second, by introducing movement repetitions, we further determined that the cost function for choosing between effortful movements had a quadratic relationship with force, while choices were made on the basis of the logarithm of these costs. Our results show that effort-based action selection during reaching cannot easily be explained by metabolic costs. Instead, force-loaded reaches, a widely occurring natural behavior, imposed an effort cost for decision making similar to cost functions in motor control. Our results thereby support the idea that motor control and economic choice are governed by partly overlapping optimization principles. PMID:28586347

β1-Adrenoceptor autoantibodies affect action potential duration and delayed rectifier potassium currents in guinea pigs.

PubMed

Zhao, Yuhui; Huang, Haixia; Du, Yunhui; Li, Xiao; Lv, Tingting; Zhang, Suli; Wei, Hua; Shang, Jianyu; Liu, Ping; Liu, Huirong

2015-01-01

β1-Adrenoceptor autoantibodies (β1-AAs) affect the action potential duration (APD) in cardiomyocytes and are related to ventricular arrhythmias. The delayed rectifier potassium current (I K) plays a crucial role in APD, but the effects of β1-AAs on I K have not been completely illuminated. This work aimed to observe the effects of β1-AAs on I K and APD and further explore the mechanisms of β1-AA-mediated ventricular arrhythmias. β1-AAs were obtained from sera of patients with coronary heart disease (CHD) and nonsustained ventricular tachycardia. With whole-cell patch clamp technique, action potentials and I K were recorded. The results illustrated 0.1 μmol/L β1-AAs shortened APD at 50 % (APD50) and 90 % (APD90) of the repolarization. However, at 0.01 μmol/L, β1-AAs had no effects on either APD90 or APD50 (P > 0.05). At 0.001 μmol/L, β1-AAs significantly prolonged APD90 and APD50. Moreover, β1-AAs (0.001, 0.01, 0.1 μmol/L) dose-dependently increased the rapidly activating delayed rectifier potassium current (I Kr), but similarly decreased the slowly activating delayed rectifier potassium current (I Ks) and increased L-type calcium currents at the different concentrations. Taken together, the IKr increase induced by high β1-AA concentrations is responsible for a significant APD reduction which would contribute to repolarization changes and trigger the malignant ventricular arrhythmias in CHD patients.

The effect of topical benzamil and amiloride on nasal potential difference in cystic fibrosis.

PubMed

Rodgers, H C; Knox, A J

1999-09-01

The electrochemical defect in the bronchial epithelium in cystic fibrosis (CF) consists of defective chloride secretion and excessive sodium reabsorption. The sodium channel blocker, amiloride, has been shown to reversibly correct the sodium reabsorption in CF subjects, but long term studies of amiloride have been disappointing due to its short duration of action. Benzamil, a benzyl substituted amiloride analogue, has a longer duration of action than amiloride in cultured human nasal epithelium. The results of the first randomized, placebo controlled, double blind, crossover study are reported here comparing the effects of benzamil and amiloride on nasal potential difference (nasal PD) in CF. Ten adults with CF attended on three occasions. At each visit baseline nasal PD was recorded, the drug (amiloride 1 x 10(-3) M, benzamil 1.7 x 10(-3) M, or 0.9% sodium chloride) was administered topically via a nasal spray, and nasal PD was measured at 15, 30 min, 1, 2, 4 and 8 h. Results were expressed as maximum change in nasal PD from baseline (PDmax), time for PDmax to return to 50% of baseline (t0.5), and the area under the curve (AUC). PDmax values for benzamil (20.6+/-0.9 mV) and amiloride (20.3+/-1.6 mV), were similar. The duration of effect was much longer for benzamil as measured as either AUC or t0.5 AUC values were 11.8+/-1.6 mV for benzamil, 2.8+/-0.4 mV for amiloride and 0.6+/-0.4 mV for placebo. The AUC value for benzamil was significantly greater than amiloride (95% confidence interval (CI) for the difference 5.3-12.7 mV, p<0.0001). t0.5 values were 4.3+/-0.7 h for benzamil and 0.6+/-0.1 h for amiloride (95% CI for the difference 2.0-5.3 h, p<0.001). It is concluded that benzamil has a similar maximal effect to amiloride but a more prolonged duration of action on nasal potential difference in cystic fibrosis. Benzamil may be a useful sodium channel blocker for the long-term treatment of the biochemical defect in the lungs of patients with cystic fibrosis.

Construction and use of a zebrafish heart voltage and calcium optical mapping system, with integrated electrocardiogram and programmable electrical stimulation

PubMed Central

Lin, Eric; Craig, Calvin; Lamothe, Marcel; Sarunic, Marinko V.; Beg, Mirza Faisal

2015-01-01

Zebrafish are increasingly being used as a model of vertebrate cardiology due to mammalian-like cardiac properties in many respects. The size and fecundity of zebrafish make them suitable for large-scale genetic and pharmacological screening. In larger mammalian hearts, optical mapping is often used to investigate the interplay between voltage and calcium dynamics and to investigate their respective roles in arrhythmogenesis. This report outlines the construction of an optical mapping system for use with zebrafish hearts, using the voltage-sensitive dye RH 237 and the calcium indicator dye Rhod-2 using two industrial-level CCD cameras. With the use of economical cameras and a common 532-nm diode laser for excitation, the rate dependence of voltage and calcium dynamics within the atrial and ventricular compartments can be simultaneously determined. At 140 beats/min, the atrial action potential duration was 36 ms and the transient duration was 53 ms. With the use of a programmable electrical stimulator, a shallow rate dependence of 3 and 4 ms per 100 beats/min was observed, respectively. In the ventricle the action potential duration was 109 ms and the transient duration was 124 ms, with a steeper rate dependence of 12 and 16 ms per 100 beats/min. Synchronous electrocardiograms and optical mapping recordings were recorded, in which the P-wave aligns with the atrial voltage peak and R-wave aligns with the ventricular peak. A simple optical pathway and imaging chamber are detailed along with schematics for the in-house construction of the electrocardiogram amplifier and electrical stimulator. Laboratory procedures necessary for zebrafish heart isolation, cannulation, and loading are also presented. PMID:25740339

Block of voltage-gated potassium channels by Pacific ciguatoxin-1 contributes to increased neuronal excitability in rat sensory neurons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Birinyi-Strachan, Liesl C.; Gunning, Simon J.; Lewis, Richard J.

2005-04-15

The present study investigated the actions of the polyether marine toxin Pacific ciguatoxin-1 (P-CTX-1) on neuronal excitability in rat dorsal root ganglion (DRG) neurons using patch-clamp recording techniques. Under current-clamp conditions, bath application of 2-20 nM P-CTX-1 caused a rapid, concentration-dependent depolarization of the resting membrane potential in neurons expressing tetrodotoxin (TTX)-sensitive voltage-gated sodium (Na{sub v}) channels. This action was completely suppressed by the addition of 200 nM TTX to the external solution, indicating that this effect was mediated through TTX-sensitive Na{sub v} channels. In addition, P-CTX-1 also prolonged action potential and afterhyperpolarization (AHP) duration. In a subpopulation of neurons,more » P-CTX-1 also produced tonic action potential firing, an effect that was not accompanied by significant oscillation of the resting membrane potential. Conversely, in neurons expressing TTX-resistant Na{sub v} currents, P-CTX-1 failed to alter any parameter of neuronal excitability examined in this study. Under voltage-clamp conditions in rat DRG neurons, P-CTX-1 inhibited both delayed-rectifier and 'A-type' potassium currents in a dose-dependent manner, actions that occurred in the absence of alterations to the voltage dependence of activation. These actions appear to underlie the prolongation of the action potential and AHP, and contribute to repetitive firing. These data indicate that a block of potassium channels contributes to the increase in neuronal excitability, associated with a modulation of Na{sub v} channel gating, observed clinically in response to ciguatera poisoning.« less

Isosteviol prevents the prolongation of action potential in hypertrophied cardiomyoctyes by regulating transient outward potassium and L-type calcium channels.

PubMed

Fan, Zhuo; Lv, Nanying; Luo, Xiao; Tan, Wen

2017-10-01

Cardiac hypertrophy is a thickening of the heart muscle that is associated with cardiovascular diseases such as hypertension and myocardial infarction. It occurs initially as an adaptive process against increased workloads and often leads to sudden arrhythmic deaths. Studies suggest that the lethal arrhythmia is attributed to hypertrophy-induced destabilization of cardiac electrical activity, especially the prolongation of the action potential. The reduced activity of I to is demonstrated to be responsible for the ionic mechanism of prolonged action potential duration and arrhythmogeneity. Isosteviol (STV), a derivative of stevioside, plays a protective role in a variety of stress-induced cardiac diseases. Here we report effects of STV on rat ISO-induced hypertrophic cardiomyocytes. STV alleviated ISO-induced hypertrophy of cardiomyocytes by decreasing cell area of hypertrophied cardiomyocytes. STV application prevented the prolongation of action potential which was prominent in hypertrophied cells. The decrease and increase of current densities for I to and I CaL observed in hypertrophied myocytes were both prevented by STV application. In addition, the results of qRT-PCR suggested that the changes of electrophysiological activity of I to and I CaL are correlated to the alterations of the mRNA transcription level. Copyright © 2017. Published by Elsevier B.V.

Crayfish neuromuscular facilitation activated by constant presynaptic action potentials and depolarizing pulses

PubMed Central

Zucker, Robert S.

1974-01-01

1. Experiments were conducted to test the hypothesis that facilitation of transmitter release in response to repetitive stimulation of the exciter motor axon to the crayfish claw opener muscle is due to an increase in the amplitude or duration of the action potential in presynaptic terminals. No consistent changes were found in the nerve terminal potential (n.t.p.) recorded extracellularly at synaptic sites on the surface of muscle fibres. 2. Apparent changes in n.t.p. are attributed to three causes. (i) Some recordings are shown to be contaminated by non-specific muscle responses which grow during facilitation. (ii) Some averaged n.t.p.s exhibit opposite changes in amplitude and duration which suggest a change in the synchrony of presynaptic nerve impulses at different frequencies. (iii) Some changes in n.t.p. are blocked by γ-methyl glutamate, an antagonist of the post-synaptic receptor, which suggests that these changes are caused by small muscle movements. 3. The only change in n.t.p. believed to represent an actual change in the intracellular signal is a reduction in n.t.p. amplitude to the second of two stimuli separated by a brief interval. 4. Tetra-ethyl ammonium ions increase synaptic transmission about 20% and prolong the n.t.p. about 15%. This result suggests that an increase in n.t.p. large enough to increase transmission by the several hundred per cent occurring during facilitation would be detected. 5. The nerve terminals are electrically excitable, and most synaptic sites have a diphasic or triphasic n.t.p., which suggests that the motor neurone terminals are actively invaded by nerve impulses. 6. When nerve impulses are blocked in tetrodotoxin, depolarization of nerve terminals increases the frequency of miniature excitatory junctional potentials (e.j.p.s), and a phasic e.j.p. can be evoked by large, brief depolarizing pulses. Responses to repetitive or paired depolarizations of constant amplitude and duration exhibit a facilitation similar to that of e.j.p.s evoked by nerve impulses. 7. It is concluded that facilitation in the crayfish claw opener is not due to a change in the presynaptic action potential, but is due to some change at a later step in the depolarization—secretion process. PMID:4153766

Crayfish neuromuscular facilitation activated by constant presynaptic action potentials and depolarizing pulses.

PubMed

Zucker, R S

1974-08-01

1. Experiments were conducted to test the hypothesis that facilitation of transmitter release in response to repetitive stimulation of the exciter motor axon to the crayfish claw opener muscle is due to an increase in the amplitude or duration of the action potential in presynaptic terminals. No consistent changes were found in the nerve terminal potential (n.t.p.) recorded extracellularly at synaptic sites on the surface of muscle fibres.2. Apparent changes in n.t.p. are attributed to three causes.(i) Some recordings are shown to be contaminated by non-specific muscle responses which grow during facilitation.(ii) Some averaged n.t.p.s exhibit opposite changes in amplitude and duration which suggest a change in the synchrony of presynaptic nerve impulses at different frequencies.(iii) Some changes in n.t.p. are blocked by gamma-methyl glutamate, an antagonist of the post-synaptic receptor, which suggests that these changes are caused by small muscle movements.3. The only change in n.t.p. believed to represent an actual change in the intracellular signal is a reduction in n.t.p. amplitude to the second of two stimuli separated by a brief interval.4. Tetra-ethyl ammonium ions increase synaptic transmission about 20% and prolong the n.t.p. about 15%. This result suggests that an increase in n.t.p. large enough to increase transmission by the several hundred per cent occurring during facilitation would be detected.5. The nerve terminals are electrically excitable, and most synaptic sites have a diphasic or triphasic n.t.p., which suggests that the motor neurone terminals are actively invaded by nerve impulses.6. When nerve impulses are blocked in tetrodotoxin, depolarization of nerve terminals increases the frequency of miniature excitatory junctional potentials (e.j.p.s), and a phasic e.j.p. can be evoked by large, brief depolarizing pulses. Responses to repetitive or paired depolarizations of constant amplitude and duration exhibit a facilitation similar to that of e.j.p.s evoked by nerve impulses.7. It is concluded that facilitation in the crayfish claw opener is not due to a change in the presynaptic action potential, but is due to some change at a later step in the depolarization-secretion process.

Mechanoelectric feedback in a model of the passively inflated left ventricle.

PubMed

Vetter, F J; McCulloch, A D

2001-05-01

Mechanoelectric feedback has been described in isolated cells and intact ventricular myocardium, but the mechanical stimulus that governs mechanosensitive channel activity in intact tissue is unknown. To study the interaction of myocardial mechanics and electrophysiology in multiple dimensions, we used a finite element model of the rabbit ventricles to simulate electrical propagation through passively loaded myocardium. Electrical propagation was simulated using the collocation-Galerkin finite element method. A stretch-dependent current was added in parallel to the ionic currents in the Beeler-Reuter ventricular action potential model. We investigated different mechanical coupling parameters to simulate stretch-dependent conductance modulated by either fiber strain, cross-fiber strain, or a combination of the two. In response to pressure loading, the conductance model governed by fiber strain alone reproduced the epicardial decrease in action potential amplitude as observed in experimental preparations of the passively loaded rabbit heart. The model governed by only cross-fiber strain reproduced the transmural gradient in action potential amplitude as observed in working canine heart experiments, but failed to predict a sufficient decrease in amplitude at the epicardium. Only the model governed by both fiber and cross-fiber strain reproduced the epicardial and transmural changes in action potential amplitude similar to experimental observations. In addition, dispersion of action potential duration nearly doubled with the same model. These results suggest that changes in action potential characteristics may be due not only to length changes along the long axis direction of the myofiber, but also due to deformation in the plane transverse to the fiber axis. The model provides a framework for investigating how cellular biophysics affect the function of the intact ventricles.

Effects of phloretin and phloridzin on Ca2+ handling, the action potential, and ion currents in rat ventricular myocytes.

PubMed

Olson, Marnie L; Kargacin, Margaret E; Ward, Christopher A; Kargacin, Gary J

2007-06-01

The effects of the phytoestrogens phloretin and phloridzin on Ca(2+) handling, cell shortening, the action potential, and Ca(2+) and K(+) currents in freshly isolated cardiac myocytes from rat ventricle were examined. Phloretin increased the amplitude and area and decreased the rate of decline of electrically evoked Ca(2+) transients in the myocytes. These effects were accompanied by an increase in the Ca(2+) load of the sarcoplasmic reticulum, as determined by the area of caffeine-evoked Ca(2+) transients. An increase in the extent of shortening of the myocytes in response to electrically evoked action potentials was also observed in the presence of phloretin. To further examine possible mechanisms contributing to the observed changes in Ca(2+) handling and contractility, the effects of phloretin on the cardiac action potential and plasma membrane Ca(2+) and K(+) currents were examined. Phloretin markedly increased the action potential duration in the myocytes, and it inhibited the Ca(2+)-independent transient outward K(+) current (I(to)). The inwardly rectifying K(+) current, the sustained outward delayed rectifier K(+) current, and L-type Ca(2+) currents were not significantly different in the presence and absence of phloretin, nor was there any evidence that the Na(+)/Ca(2+) exchanger was affected. The effects of phloretin on Ca(2+) handling in the myocytes are consistent with its effects on I(to). Phloridzin did not significantly alter the amplitude or area of electrically evoked Ca(2+) transients in the myocytes, nor did it have detectable effects on the sarcoplasmic reticulum Ca(2+) load, cell shortening, or the action potential.

Cardiovascular Safety Pharmacology of Sibutramine.

PubMed

Yun, Jaesuk; Chung, Eunyong; Choi, Ki Hwan; Cho, Dae Hyun; Song, Yun Jeong; Han, Kyoung Moon; Cha, Hey Jin; Shin, Ji Soon; Seong, Won-Keun; Kim, Young-Hoon; Kim, Hyung Soo

2015-07-01

Sibutramine is an anorectic that has been banned since 2010 due to cardiovascular safety issues. However, counterfeit drugs or slimming products that include sibutramine are still available in the market. It has been reported that illegal sibutramine-contained pharmaceutical products induce cardiovascular crisis. However, the mechanism underlying sibutramine-induced cardiovascular adverse effect has not been fully evaluated yet. In this study, we performed cardiovascular safety pharmacology studies of sibutramine systemically using by hERG channel inhibition, action potential duration, and telemetry assays. Sibutramine inhibited hERG channel current of HEK293 cells with an IC50 of 3.92 μM in patch clamp assay and increased the heart rate and blood pressure (76 Δbpm in heart rate and 51 ΔmmHg in blood pressure) in beagle dogs at a dose of 30 mg/kg (per oral), while it shortened action potential duration (at 10 μM and 30 μM, resulted in 15% and 29% decreases in APD50, and 9% and 17% decreases in APD90, respectively) in the Purkinje fibers of rabbits and had no effects on the QTc interval in beagle dogs. These results suggest that sibutramine has a considerable adverse effect on the cardiovascular system and may contribute to accurate drug safety regulation.

Quantitative motor unit action potential analysis of supraspinatus, infraspinatus, deltoideus and biceps femoris muscles in adult Royal Dutch sport horses.

PubMed

Jose-Cunilleras, E; Wijnberg, I D

2016-03-01

Reference values for quantitative electromyography (QEMG) in shoulder and hindlimb muscles of horses are limited. To determine normative data on QEMG analysis of supraspinatus (SS), infraspinatus (IS), deltoideus (DT) and biceps femoris (BF) muscles. Experimental observational study and retrospective case series. Seven adult healthy Royal Dutch sport horses underwent quantitative motor unit action potential analysis of each muscle using commercial electromyography equipment. Measurements were made according to published methods. One-way ANOVA was used to compare quantitative motor unit action potential variables between muscles, with post hoc testing according to Bonferroni, with significance set at P<0.05. The QEMG and clinical information from horses with lower motor neuron disorders (n = 7) or myopathy (n = 4) were summarised retrospectively. The 95% confidence intervals of duration, amplitude, phases, turns, area and size index of quantitative motor unit action potential were 8.7-10.4 ms, 651-867 μV, 3.2-3.7, 3.7-4.7, 1054-1457 μV·ms and 1.1-1.5 for SS, 9.6-11.0 ms, 779-1082 μV, 3.3-3.7, 3.8-4.7, 1349-2204 μV·ms and 1.4-1.9 for IS, 6.0-9.1 ms, 370-691 μV, 2.9-3.7, 2.8-4.5, 380-1374 μV·ms and 0.3-1.3 for DT and 5.7-7.8 ms, 265-385 μV, 2.7-3.2, 2.6-3.1, 296-484 μV·ms and 0.2-0.5 for BF, respectively. Mean duration, amplitude, number of phases and turns, area and size index were significantly (P<0.01) higher in SS and IS than in DT and BF muscles. In addition, 4 of 7 normal horses had >15% polyphasic motor unit action potentials in SS and IS muscles. Differences between muscles should be taken into account when performing QEMG in order to be able to distinguish normal horses from horses with suspected neurogenic or myogenic disorders. These normal data provide the basis for objective QEMG assessment of shoulder and hindlimb muscles. Quantitative electromyography appears to be helpful in diagnosing neuropathies and discriminating these from myopathies. © 2015 EVJ Ltd.

[Effect of pazufloxacin mesilate, a new quinolone antibacterial agent, for intravenous use on QT interval].

PubMed

Fukuda, Hitoshi; Morita, Yukie; Shiotani, Norio; Mizuo, Midori; Komae, Norihisa

2004-08-01

The potential for QT interval prolongation of pazufloxacin mesilate (PZFX mesilate), a new quinolone antibacterial agent for intravenous use, was investigated by in vitro and in vivo electrophysiology studies. Following results were obtained. In vitro electrophysiology study using guinea pig papillary muscles: PZFX mesilate (30-300 microM) had no effects on resting membrane potential (RMP), action potential amplitude (APA) and action potential duration (APD). Reference quinolones, sparfloxacin (3-30 microM) and moxifloxacin (10-100 microM), had no effects on RMP and APA, but significantly prolonged APD at more than 3 and 10 microM, respectively, while ciprofloxacin (10-100 microM) had no effect on each parameter. In vivo electrophysiology study using anesthetized dogs: PZFX mesilate had no effects on electrocardiograph parameter (PR interval, QRS interval, QT interval and QTc) after intravenous administration of 3-30 mg/kg. These results suggest that PZFX mesilate has low potential for QT interval prolongation.

Real time estimation of generation, extinction and flow of muscle fibre action potentials in high density surface EMG.

PubMed

Mesin, Luca

2015-02-01

Developing a real time method to estimate generation, extinction and propagation of muscle fibre action potentials from bi-dimensional and high density surface electromyogram (EMG). A multi-frame generalization of an optical flow technique including a source term is considered. A model describing generation, extinction and propagation of action potentials is fit to epochs of surface EMG. The algorithm is tested on simulations of high density surface EMG (inter-electrode distance equal to 5mm) from finite length fibres generated using a multi-layer volume conductor model. The flow and source term estimated from interference EMG reflect the anatomy of the muscle, i.e. the direction of the fibres (2° of average estimation error) and the positions of innervation zone and tendons under the electrode grid (mean errors of about 1 and 2mm, respectively). The global conduction velocity of the action potentials from motor units under the detection system is also obtained from the estimated flow. The processing time is about 1 ms per channel for an epoch of EMG of duration 150 ms. A new real time image processing algorithm is proposed to investigate muscle anatomy and activity. Potential applications are proposed in prosthesis control, automatic detection of optimal channels for EMG index extraction and biofeedback. Copyright © 2014 Elsevier Ltd. All rights reserved.

Attraction of Rotors to the Pulmonary Veins in Paroxysmal Atrial Fibrillation: A Modeling Study

PubMed Central

Calvo, Conrado J.; Deo, Makarand; Zlochiver, Sharon; Millet, José; Berenfeld, Omer

2014-01-01

Maintenance of paroxysmal atrial fibrillation (AF) by fast rotors in the left atrium (LA) or at the pulmonary veins (PVs) is not fully understood. To gain insight into this dynamic and complex process, we studied the role of the heterogeneous distribution of transmembrane currents in the PVs and LA junction (PV-LAJ) in the localization of rotors in the PVs. We also investigated whether simple pacing protocols could be used to predict rotor drift in the PV-LAJ. Experimentally observed heterogeneities in IK1, IKs, IKr, Ito, and ICaL in the PV-LAJ were incorporated into two- and pseudo three-dimensional models of Courtemanche-Ramirez-Nattel-Kneller human atrial kinetics to simulate various conditions and investigate rotor drifting mechanisms. Spatial gradients in the currents resulted in shorter action potential duration, minimum diastolic potential that was less negative, and slower upstroke and conduction velocity for rotors in the PV region than in the LA. Rotors under such conditions drifted toward the PV and stabilized at the shortest action potential duration and less-excitable region, consistent with drift direction under intercellular coupling heterogeneities and regardless of the geometrical constraint in the PVs. Simulations with various IK1 gradient conditions and current-voltage relationships substantiated its major role in the rotor drift. In our 1:1 pacing protocol, we found that among various action potential properties, only the minimum diastolic potential gradient was a rate-independent predictor of rotor drift direction. Consistent with experimental and clinical AF studies, simulations in an electrophysiologically heterogeneous model of the PV-LAJ showed rotor attraction toward the PV. Our simulations suggest that IK1 heterogeneity is dominant compared to other currents in determining the drift direction through its impact on the excitability gradient. These results provide a believed novel framework for understanding the complex dynamics of rotors in AF. PMID:24739180

Attraction of rotors to the pulmonary veins in paroxysmal atrial fibrillation: a modeling study.

PubMed

Calvo, Conrado J; Deo, Makarand; Zlochiver, Sharon; Millet, José; Berenfeld, Omer

2014-04-15

Maintenance of paroxysmal atrial fibrillation (AF) by fast rotors in the left atrium (LA) or at the pulmonary veins (PVs) is not fully understood. To gain insight into this dynamic and complex process, we studied the role of the heterogeneous distribution of transmembrane currents in the PVs and LA junction (PV-LAJ) in the localization of rotors in the PVs. We also investigated whether simple pacing protocols could be used to predict rotor drift in the PV-LAJ. Experimentally observed heterogeneities in IK1, IKs, IKr, Ito, and ICaL in the PV-LAJ were incorporated into two- and pseudo three-dimensional models of Courtemanche-Ramirez-Nattel-Kneller human atrial kinetics to simulate various conditions and investigate rotor drifting mechanisms. Spatial gradients in the currents resulted in shorter action potential duration, minimum diastolic potential that was less negative, and slower upstroke and conduction velocity for rotors in the PV region than in the LA. Rotors under such conditions drifted toward the PV and stabilized at the shortest action potential duration and less-excitable region, consistent with drift direction under intercellular coupling heterogeneities and regardless of the geometrical constraint in the PVs. Simulations with various IK1 gradient conditions and current-voltage relationships substantiated its major role in the rotor drift. In our 1:1 pacing protocol, we found that among various action potential properties, only the minimum diastolic potential gradient was a rate-independent predictor of rotor drift direction. Consistent with experimental and clinical AF studies, simulations in an electrophysiologically heterogeneous model of the PV-LAJ showed rotor attraction toward the PV. Our simulations suggest that IK1 heterogeneity is dominant compared to other currents in determining the drift direction through its impact on the excitability gradient. These results provide a believed novel framework for understanding the complex dynamics of rotors in AF. Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Potential weathering by freeze-thaw action in alpine rocks in the European Alps during a nine year monitoring period

NASA Astrophysics Data System (ADS)

Kellerer-Pirklbauer, Andreas

2017-11-01

A quantification of rock weathering by freeze-thaw processes in alpine rocks requires at least rock temperature data in high temporal resolution, in high quality, and over a sufficient period of time. In this study up to nine years of rock temperature data (2006-2015) from eleven rock monitoring sites in two of the highest mountain ranges of Austria were analyzed. Data were recorded at a half-hourly or hourly logging interval and at rock depths of 3, 10, and 30-40 cm. These data have been used to quantify mean conditions, ranges, and relationships of the potential near-surface weathering by freeze-thaw action considering volumetric-expansion of ice and ice segregation. For the former, freeze-thaw cycles and effective freeze-thaw cycles for frost shattering have been considered. For the latter, the intensity and duration of freezing events as well as time within the 'frost cracking window' have been analyzed. Results show that the eleven sites are in rather extreme topoclimatic positions and hence represent some of the highest and coolest parts of Austria and therefore the Eastern Alps. Only four sites are presumably affected by permafrost. Most sites are influenced by a long-lasting seasonal snow cover. Freeze-thaw cycles and effective freeze-thaw cycles for frost shattering are mainly affecting the near-surface and are unimportant at few tens of centimeters below the rock surface. The lowest temperatures during freezing events and the shortest freezing events have been quantified at all eleven monitoring sites very close to the surface. The time within the frost cracking window decreases in most cases from the rock surface inwards apart from very cold years/sites with very low temperatures close to the surface. As shown by this study and predicted climate change scenarios, assumed warmer rock temperature conditions in the future at alpine rock walls in Austria will lead to less severe freezing events and to shorter time periods within the frost-cracking window. Statistical correlation analyses showed furthermore that the longer the duration of the seasonal snow cover, the fewer are freeze-thaw cycles, the fewer are effective freeze-thaw cycles, the longer is the mean and the maximum duration of freezing events, and the lower is the mean annual ground temperature. The interaction of the winter snow cover history and the winter thermal regime has a complex effect on the duration of the frost cracking window but also on the number of freeze-thaw cycles as shown by a conceptual model. Predicted future warmer and snow-depleted winters in the European Alps will therefore have a complex impact on the potential weathering of alpine rocks by frost action which makes potential weathering predictions difficult. Neglecting rock moisture and rock properties in determining rock weathering limits the usefulness of solely rock temperature data. However, rock temperature data allow getting an estimate about potential weathering by freeze-thaw action which is often substantially more than previously known.

Activation of Mechanosensitive Transient Receptor Potential/Piezo Channels in Odontoblasts Generates Action Potentials in Cocultured Isolectin B4-negative Medium-sized Trigeminal Ganglion Neurons.

PubMed

Sato, Masaki; Ogura, Kazuhiro; Kimura, Maki; Nishi, Koichi; Ando, Masayuki; Tazaki, Masakazu; Shibukawa, Yoshiyuki

2018-06-01

Various stimuli to the dentin surface elicit dentinal pain by inducing dentinal fluid movement causing cellular deformation in odontoblasts. Although odontoblasts detect deformation by the activation of mechanosensitive ionic channels, it is still unclear whether odontoblasts are capable of establishing neurotransmission with myelinated A delta (Aδ) neurons. Additionally, it is still unclear whether these neurons evoke action potentials by neurotransmitters from odontoblasts to mediate sensory transduction in dentin. Thus, we investigated evoked inward currents and evoked action potentials form trigeminal ganglion (TG) neurons after odontoblast mechanical stimulation. We used patch clamp recordings to identify electrophysiological properties and record evoked responses in TG neurons. We classified TG cells into small-sized and medium-sized neurons. In both types of neurons, we observed voltage-dependent inward currents. The currents from medium-sized neurons showed fast inactivation kinetics. When mechanical stimuli were applied to odontoblasts, evoked inward currents were recorded from medium-sized neurons. Antagonists for the ionotropic adenosine triphosphate receptor (P2X 3 ), transient receptor potential channel subfamilies, and Piezo1 channel significantly inhibited these inward currents. Mechanical stimulation to odontoblasts also generated action potentials in the isolectin B 4 -negative medium-sized neurons. Action potentials in these isolectin B 4 -negative medium-sized neurons showed a short duration. Overall, electrophysiological properties of neurons indicate that the TG neurons with recorded evoked responses after odontoblast mechanical stimulation were myelinated Aδ neurons. Odontoblasts established neurotransmission with myelinated Aδ neurons via P2X 3 receptor activation. The results also indicated that mechanosensitive TRP/Piezo1 channels were functionally expressed in odontoblasts. The activation of P2X 3 receptors induced an action potential in the Aδ neurons, underlying a sensory generation mechanism of dentinal pain. Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Comparison of the protective effects of ferulic acid and its drug-containing plasma on primary cultured neonatal rat cardiomyocytes with hypoxia/reoxygenation injury

PubMed Central

Ren, Cong; Bao, Yong-rui; Meng, Xian-sheng; Diao, Yun-peng; Kang, Ting-guo

2013-01-01

Backgroud: To simulate the ischemia-reperfusion injury in vivo, hypoxia/reoxygenation injury model was established in vitro and primary cultured neonatal rat cardiomyocytes were underwent hypoxia with hydrosulfite (Na2S2O4) for 1 h followed by 1 h reoxygenation. Materials and Methods: Determination the cell viability by MTT colorimetric assay. We use kit to detect the activity of lactate dehydrogenase (LDH), Na+-K+-ATPase and Ca2+-ATPase. Do research on the effect which ferulic acid and its drug-containing plasma have to self-discipline, conductivity, action potential duration and other electrophysiological phenomena of myocardial cells by direct observation using a microscope and recording method of intracellular action potential. Results: The experimental datum showed that both can reduce the damage hydrosulfite to myocardial cell damage and improve myocardial viability, reduce the amount of LDH leak, increase activity of Na+-K+-ATPase, Ca2+-ATPase, and increase APA (Action potential amplitude), Vmax (Maximum rate of depolarization) and MPD (Maximum potential diastolic). Conclusion: Taken together, therefore, we can get the conclusion that ferulic acid drug-containing plasma has better protective effect injured myocardial cell than ferulic acid. PMID:23930002

Kvβ1.1 (AKR6A8) senses pyridine nucleotide changes in the mouse heart and modulates cardiac electrical activity.

PubMed

Tur, Jared; Chapalamadugu, Kalyan C; Katnik, Christopher; Cuevas, Javier; Bhatnagar, Aruni; Tipparaju, Srinivas M

2017-03-01

The present study investigates the physiological role of Kvβ1 subunit for sensing pyridine nucleotide (NADH/NAD+) changes in the heart. We used Kvβ1.1 knockout (KO) or wild-type (WT) mice and established that Kvβ1.1 preferentially binds with Kv4.2 and senses the pyridine nucleotide changes in the heart. The cellular action potential duration (APD) obtained from WT cardiomyocytes showed longer APDs with lactate perfusion, which increases intracellular NADH levels, while the APDs remained unaltered in the Kvβ1.1 KO. Ex vivo monophasic action potentials showed a similar response, in which the APDs were prolonged in WT mouse hearts with lactate perfusion; however, the Kvβ1.1 KO mouse hearts did not show APD changes upon lactate perfusion. COS-7 cells coexpressing Kv4.2 and Kvβ1.1 were used for whole cell patch-clamp recordings to evaluate changes caused by NADH (lactate). These data reveal that Kvβ1.1 is required in the mediated inactivation of Kv4.2 currents, when NADH (lactate) levels are increased. In vivo, isoproterenol infusion led to increased NADH in the heart along with QTc prolongation in wild-type mice; regardless of the approach, our data show that Kvβ1.1 recognizes NADH changes and modulates Kv4.2 currents affecting AP and QTc durations. Overall, this study uses multiple levels of investigation, including the heterologous overexpression system, cardiomyocyte, ex vivo, and ECG, and clearly depicts that Kvβ1.1 is an obligatory sensor of NADH/NAD changes in vivo, with a physiological role in the heart. NEW & NOTEWORTHY Cardiac electrical activity is mediated by ion channels, and Kv4.2 plays a significant role, along with its binding partner, the Kvβ1.1 subunit. In the present study, we identify Kvβ1.1 as a sensor of pyridine nucleotide changes and as a modulator of Kv4.2 gating, action potential duration, and ECG in the mouse heart. Copyright © 2017 the American Physiological Society.

Psychological issues relevant to astronaut selection for long-duration space flight: a review of the literature.

PubMed

Collins, Daniel L

2003-01-01

This technical paper reviews the current literature on psychological issues relevant to astronaut selection for long-duration space flights. Interpersonal problems have been and remain a recurring problem for both short and long-duration space flights. Even after completion of the space mission, intense psychological aftereffects are reported. The specific behavioral problems experienced during United States and Soviet Union space flights are reviewed, specifically addressing contentious episodes and impaired judgments that occurred during the Mercury, Apollo, and Skylab missions. Psychological tests used in the selection process for the space program have focused primarily on the detection of gross psychopathologies in potential candidates. Although these psychological instruments excluded some people from becoming astronauts, the battery of tests failed to predict which individuals would manifest behavioral aberrations in judgment, cooperative functioning, overt irritability, or destructive interpersonal actions.

Electrophysiological effects of calcitonin gene-related peptide in bull-frog and guinea-pig atrial myocytes.

PubMed Central

Ono, K; Giles, W R

1991-01-01

1. Electrophysiological effects of calcitonin gene-related peptide (CGRP) on action potentials and corresponding transmembrane currents in single myocytes from bull-frog and guinea-pig atria were studied using a whole-cell voltage-clamp method. 2. CGRP at relatively low concentrations increased the height of the action potential plateau in a dose-dependent manner in both bull-frog and guinea-pig myocytes. In addition, in bull-frog cells CGRP accelerated the early phase of repolarization, thus shortening the overall duration of the action potential. In contrast, in guinea-pig myocytes CGRP prolonged the action potential duration at all concentrations that were studied. 3. Voltage-clamp measurements demonstrated that CGRP increased transmembrane calcium current (ICa) in guinea-pig myocytes without a significant change in its voltage dependence. The ED50 value for this effect on ICa was 1.28 +/- 0.55 X 10(-8) M (n = 4). The time course of the inactivation of ICa was not affected by CGRP. 4. CGRP increased the delayed rectifier K+ current (IK) at relatively low concentrations in bull-frog atria, whereas relatively high concentrations were needed to increase IK in guinea-pig myocytes. This effect was observed even after complete inhibition of ICa. 5. CGRP had no significant effect on the inwardly rectifying background K+ current, IK1, even at very high concentrations. 6. Comparison of the time course of ICa augmentation in bull-frog and guinea-pig myocytes revealed an important difference in the effect of CGRP in these two types of cells. CGRP at maximal concentrations increased ICa transiently in bull-frog myocytes, whereas this response was sustained in guinea-pig myocytes. Isoprenaline (Iso) induced sustained increase in ICa in both species. When ICa was fully activated by Iso, CGRP at high concentrations strongly inhibited ICa in the bull-frog, whereas it had little effect on ICa in guinea-pig myocytes. 7. Intracellular application of GTP gamma S (guanosine 5'-O-(3-thiotriphosphate) 10(-4) M) greatly potentiated the CGRP effect on ICa; in contrast, GDP beta S (guanosine 5'-O-(2-thiodiphosphate), 2 x 10(-3) M) partially inhibited the CGRP-induced augmentation of ICa. Taken together, these results indicate that the stimulation of ICa by CGRP is mediated by a GTP-binding protein. 8. The observed dose-dependent changes in ICa and IK in bull-frog and guinea-pig myocytes can explain the different patterns of CGRP-induced changes in action potential shape in these two myocyte preparations. PMID:1905755

A Discrete Electromechanical Model for Human Cardiac Tissue: Effects of Stretch-Activated Currents and Stretch Conditions on Restitution Properties and Spiral Wave Dynamics

PubMed Central

Weise, Louis D.; Panfilov, Alexander V.

2013-01-01

We introduce an electromechanical model for human cardiac tissue which couples a biophysical model of cardiac excitation (Tusscher, Noble, Noble, Panfilov, 2006) and tension development (adjusted Niederer, Hunter, Smith, 2006 model) with a discrete elastic mass-lattice model. The equations for the excitation processes are solved with a finite difference approach, and the equations of the mass-lattice model are solved using Verlet integration. This allows the coupled problem to be solved with high numerical resolution. Passive mechanical properties of the mass-lattice model are described by a generalized Hooke's law for finite deformations (Seth material). Active mechanical contraction is initiated by changes of the intracellular calcium concentration, which is a variable of the electrical model. Mechanical deformation feeds back on the electrophysiology via stretch-activated ion channels whose conductivity is controlled by the local stretch of the medium. We apply the model to study how stretch-activated currents affect the action potential shape, restitution properties, and dynamics of spiral waves, under constant stretch, and dynamic stretch caused by active mechanical contraction. We find that stretch conditions substantially affect these properties via stretch-activated currents. In constantly stretched medium, we observe a substantial decrease in conduction velocity, and an increase of action potential duration; whereas, with dynamic stretch, action potential duration is increased only slightly, and the conduction velocity restitution curve becomes biphasic. Moreover, in constantly stretched medium, we find an increase of the core size and period of a spiral wave, but no change in rotation dynamics; in contrast, in the dynamically stretching medium, we observe spiral drift. Our results may be important to understand how altered stretch conditions affect the heart's functioning. PMID:23527160

A discrete electromechanical model for human cardiac tissue: effects of stretch-activated currents and stretch conditions on restitution properties and spiral wave dynamics.

PubMed

Weise, Louis D; Panfilov, Alexander V

2013-01-01

We introduce an electromechanical model for human cardiac tissue which couples a biophysical model of cardiac excitation (Tusscher, Noble, Noble, Panfilov, 2006) and tension development (adjusted Niederer, Hunter, Smith, 2006 model) with a discrete elastic mass-lattice model. The equations for the excitation processes are solved with a finite difference approach, and the equations of the mass-lattice model are solved using Verlet integration. This allows the coupled problem to be solved with high numerical resolution. Passive mechanical properties of the mass-lattice model are described by a generalized Hooke's law for finite deformations (Seth material). Active mechanical contraction is initiated by changes of the intracellular calcium concentration, which is a variable of the electrical model. Mechanical deformation feeds back on the electrophysiology via stretch-activated ion channels whose conductivity is controlled by the local stretch of the medium. We apply the model to study how stretch-activated currents affect the action potential shape, restitution properties, and dynamics of spiral waves, under constant stretch, and dynamic stretch caused by active mechanical contraction. We find that stretch conditions substantially affect these properties via stretch-activated currents. In constantly stretched medium, we observe a substantial decrease in conduction velocity, and an increase of action potential duration; whereas, with dynamic stretch, action potential duration is increased only slightly, and the conduction velocity restitution curve becomes biphasic. Moreover, in constantly stretched medium, we find an increase of the core size and period of a spiral wave, but no change in rotation dynamics; in contrast, in the dynamically stretching medium, we observe spiral drift. Our results may be important to understand how altered stretch conditions affect the heart's functioning.

Long-Term Fish Oil Supplementation Induces Cardiac Electrical Remodeling by Changing Channel Protein Expression in the Rabbit Model

PubMed Central

Xu, Xulin; Jiang, Min; Wang, Yuhong; Smith, Timothy; Baumgarten, Clive M.; Wood, Mark A.; Tseng, Gea-Ny

2010-01-01

Clinical trials and epidemiological studies have suggested that dietary fish oil (FO) supplementation can provide an anti-arrhythmic benefit in some patient populations. The underlying mechanisms are not entirely clear. We wanted to understand how FO supplementation (for 4 weeks) affected the action potential configuration/duration of ventricular myocytes, and the ionic mechanism(s)/molecular basis for these effects. The experiments were conducted on adult rabbits, a widely used animal model for cardiac electrophysiology and pathophysiology. We used gas chromatography - mass spectroscopy to confirm that FO feeding produced a marked increase in the content of n-3 polyunsaturated fatty acids in the phospholipids of rabbit hearts. Left ventricular myocytes were used in current and voltage clamp experiments to monitor action potentials and ionic currents, respectively. Action potentials of myocytes from FO-fed rabbits exhibited much more positive plateau voltages and prolonged durations. These changes could be explained by an increase in the L-type Ca current (ICaL) and a decrease in the transient outward current (Ito) in these myocytes. FO feeding did not change the delayed rectifier or inward rectifier current. Immunoblot experiments showed that the FO-feeding induced changes in ICaL and Ito were associated with corresponding changes in the protein levels of major pore-forming subunits of these channels: increase in Cav1.2 and decrease in Kv4.2 and Kv1.4. There was no change in other channel subunits (Cav1.1, Kv4.3, KChIP2, and ERG1). We conclude that long-term fish oil supplementation can impact on cardiac electrical activity at least partially by changing channel subunit expression in cardiac myocytes. PMID:20405051

Ranolazine effectively suppresses atrial fibrillation in the setting of heart failure.

PubMed

Burashnikov, Alexander; Di Diego, José M; Barajas-Martínez, Hector; Hu, Dan; Zygmunt, Andrew C; Cordeiro, Jonathan M; Moise, N Sydney; Kornreich, Bruce G; Belardinelli, Luiz; Antzelevitch, Charles

2014-07-01

There is a critical need for safer and more effective pharmacological management of atrial fibrillation (AF) in the setting of heart failure (HF). This study investigates the electrophysiological, antiarrhythmic, and proarrhythmic effects of a clinically relevant concentration of ranolazine (5 μmol/L) in coronary-perfused right atrial and left ventricular preparations isolated from the hearts of HF dogs. HF was induced by ventricular tachypacing (2-6 weeks at 200-240 beats per minute; n=17). Transmembrane action potentials were recorded using standard microelectrode techniques. In atria, ranolazine slightly prolonged action potential duration but significantly depressed sodium channel current-dependent parameters causing a reduction of maximum rate of rise of the action potential upstroke, a prolongation of the effective refractory period secondary to the development of postrepolarization refractoriness, and an increase in diastolic threshold of excitation and atrial conduction time. Ranolazine did not significantly alter these parameters or promote arrhythmias in the ventricles. Ranolazine produced greater inhibition of peak sodium channel current in atrial cells isolated from HF versus normal dogs. A single premature beat reproducibly induced self-terminating AF in 10 of 17 atria. Ranolazine (5 μmol/L) suppressed induction of AF in 7 of 10 (70%) atria. In the remaining 3 atria, ranolazine reduced frequency and duration of AF. Our results demonstrate more potent suppression of AF by ranolazine in the setting of HF than previously demonstrated in nonfailing hearts and absence of ventricular proarrhythmia. The data suggest that ranolazine may be of benefit as an alternative to amiodarone and dofetilide in the management of AF in patients with HF. © 2014 American Heart Association, Inc.

M3 cholinoreceptors alter electrical activity of rat left atrium via suppression of L-type Ca2+ current without affecting K+ conductance.

PubMed

Filatova, Tatiana S; Naumenko, Nikolay; Galenko-Yaroshevsky, Pavel A; Abramochkin, Denis V

2017-05-01

Electrophysiological effects produced by selective activation of M3 cholinoreceptors were studied in isolated left atrium preparations from rat using the standard sharp glass microelectrode technique. The stimulation of M3 receptors was obtained by application of muscarinic agonist pilocarpine (10 -5  M) in the presence of selective M2 antagonist methoctramine (10 -7  M). Stimulation of M3 receptors induced marked reduction of action potential duration by 14.4 ± 2.4% and 16.1 ± 2.5% of control duration measured at 50 and 90% of repolarization, respectively. This effect was completely abolished by selective M3 blocker 4-DAMP (10 -8  M). In isolated myocytes obtained from the rat left atrium, similar pharmacological stimulation of M3 receptors led to suppression of peak L-type calcium current by 13.9 ± 2.6% of control amplitude (measured at +10 mV), but failed to affect K + currents I to , I Kur , and I Kir . In the absence of M2 blocker methoctramine, pilocarpine (10 -5  M) produced stronger attenuation of I CaL and induced an increase in I Kir . This additive inward rectifier current could be abolished by highly selective blocker of K ir 3.1/3.4 channels tertiapin-Q (10 -6  M) and therefore was identified as I KACh . Thus, in the rat atrial myocardium activation of M3 receptors leads to shortening of action potentials via suppression of I CaL , but does not enhance the major potassium currents involved in repolarization. Joint stimulation of M2 and M3 receptors produces stronger action potential shortening due to M2-mediated activation of I KACh.

Antidepressant-like effects of methanol extract of Hibiscus tiliaceus flowers in mice

PubMed Central

2012-01-01

Background Hibiscus tiliaceus L. (Malvaceae) is used in postpartum disorders. Our purpose was to examine the antidepressant, anxiolytic and sedative actions of the methanol extract of H. tiliaceus flowers using animal models. Methods Adult male Swiss albino mice were treated with saline, standard drugs or methanol extract of H. tiliaceus and then subjected to behavioral tests. The forced swimming and tail suspension tests were used as predictive animal models of antidepressant activity, where the time of immobility was considered. The animals were submitted to the elevated plus-maze and ketamine-induced sleeping time to assess anxiolytic and sedative activities, respectively. Results Methanol extract of H. tiliaceus significantly decreased the duration of immobility in both animal models of antidepressant activity, forced swimming and tail suspension tests. This extract did not potentiate the effect of ketamine-induced hypnosis, as determined by the time to onset and duration of sleeping time. Conclusion Our results indicate an antidepressant-like profile of action for the extract of Hibiscus tiliaceus without sedative side effect. PMID:22494845

Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human Na(V)1.1 mutation.

PubMed

Hedrich, Ulrike B S; Liautard, Camille; Kirschenbaum, Daniel; Pofahl, Martin; Lavigne, Jennifer; Liu, Yuanyuan; Theiss, Stephan; Slotta, Johannes; Escayg, Andrew; Dihné, Marcel; Beck, Heinz; Mantegazza, Massimo; Lerche, Holger

2014-11-05

Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the NaV1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na(+) channels in interneurons and persistent Na(+) currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca(2+) imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation. Copyright © 2014 the authors 0270-6474/14/3414874-16$15.00/0.

42 CFR 456.524 - Notification of Administrator's action and duration of variance.

Code of Federal Regulations, 2011 CFR

2011-10-01

..., DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS UTILIZATION CONTROL Utilization Review Plans: FFP, Waivers, and Variances for Hospitals and Mental Hospitals Ur Plan: Remote Facility Variances from Time Requirements § 456.524 Notification of Administrator's action and duration of...

Direct block of inward rectifier potassium channels by nicotine.

PubMed

Wang, H; Yang, B; Zhang, L; Xu, D; Wang, Z

2000-04-01

Nicotine has been shown to depolarize membrane potential and to lengthen action potential duration in isolated cardiac preparations. To investigate whether this is a consequence of direct interaction of nicotine with inward rectifier K(+) channels which are a key determinant of membrane potentials, we assessed the effects of nicotine on two cloned human inward rectifier K(+) channels, Kir2.1 and Kir2.2, expressed in Xenopus oocytes and the native inward rectifier K(+) current I(K1) in canine ventricular myocytes. Nicotine suppressed Kir2.1-expressed currents at varying potentials negative to -20 mV, with more pronounced effects on the outward current between -70 and -20 mV relative to the inward current at hyperpolarized potentials (below -70 mV). The inhibition was concentration dependent. For the outward currents recorded at -50 mV, the IC50 was 165 +/- 18 microM. Similar effects of nicotine were observed for Kir2.2. A more potent effect was seen with I(K1) in canine myocytes. Significant blockade ( approximately 60%) was found at a concentration as low as 0.5 microM and the IC50 was 4.0 +/- 0.4 microM. The effects in both oocytes and myocytes were partially reversible upon washout of nicotine. Antagonists of nicotinic receptors (mecamylamine, 100 microM), muscarinic receptors (atropine, 1 microM), and beta-adrenergic receptors (propranolol, 1 microM) all failed to restore the depressed currents, suggesting that nicotine acted directly on Kir channels, independent of catecholamine release. This property of nicotine may explain its membrane-depolarizing and action potential duration-prolonging effects in cardiac cells and may contribute in part to its ability to promote propensity for cardiac arrhythmias. Copyright 2000 Academic Press.

Effects of astragaloside IV on action potentials and ionic currents in guinea-pig ventricular myocytes.

PubMed

Zhao, Meimi; Zhao, Jinsheng; He, Guilin; Sun, Xuefei; Huang, Xueshi; Hao, Liying

2013-01-01

Astragaloside IV (AS-IV) is one of the main active constituents of Astragalus membranaceus, which has various actions on the cardiovascular system. However, its electrophysiological mechanisms are not clear. In the present study, we investigated the effects of AS-IV on action potentials and membrane currents using the whole-cell patch clamp technique in isolated guinea-pig ventricular myocytes. AS-IV prolonged the action potential duration (APD) at all three tested concentrations. The peak effect was achieved with 1×10(-6) M, at which concentration AS-IV significantly prolonged the APD at 95% repolarization from 313.1±38.9 to 785.3±83.7 ms. AS-IV at 1×10(-6) M also enhanced the inward rectifier K(+) currents (I(K1)) and inhibited the delayed rectifier K(+) currents (I(K)). AS-IV (1×10(-6) M) strongly depressed the peak of voltage-dependent Ca(2+) channel current (I(CaL)) from -607.3±37.5 to -321.1±38.3 pA. However, AS-IV was not found to affect the Na(+) currents. Taken together, AS-IV prolonged APD of guinea-pig ventricular myocytes, which might be explained by its inhibition of I(K). AS-IV also influences Ca(2+) signaling through suppressing ICaL.

Prostaglandin action on transmitter release of adrenergic neuroeffector junctions.

PubMed

Hedqvist, P

1976-01-01

The results presented here indicate that 1. The inhibitory action of the endoperoxides on NE release can be at least partly explained in terms of formation of degradation products, presumably mainly PGE2. 2. PGA2 is less active and the PG analogue 16,16-dimethyl-PGE2 more active than PGEs on transmitter release from adrenergic nerves. 3. PGF2alpha seems to enhance vascular responses to renal nerve activity solely by a postjunctional action. 4. PG synthesis inhibition augments NE turnover in a number of rat organs, thereby increasing the probability of PGs being involved in the control of adrenergic neurotransmission in vivo. 5. Prolongation of the duration of the impulse and action potential counteracts the effect of PGE on NE release, thereby strengthening the view that PGs operate on NE release from adrenergic nerve terminals by interfering with Ca2+ influx.

Curvature Analysis of Cardiac Excitation Wavefronts

DTIC Science & Technology

2013-04-01

required at this level either. To enable this kind of analysis, a type field is added to the polyline data structure, too. The downside of reusing the...GPU-based parallel methods. The wave curvature and the refractory period of the cardiac cells influence the motion of cardiac waves. The role of...propagation speed, the action potential duration, and the refractory period is studied. In the recent work of [26], multiple spirals and their

Impact of Hypokalemia on Electromechanical Window, Excitation Wavelength and Repolarization Gradients in Guinea-Pig and Rabbit Hearts

PubMed Central

Osadchii, Oleg E.

2014-01-01

Normal hearts exhibit a positive time difference between the end of ventricular contraction and the end of QT interval, which is referred to as the electromechanical (EM) window. Drug-induced prolongation of repolarization may lead to the negative EM window, which was proposed to be a novel proarrhythmic marker. This study examined whether abnormal changes in the EM window may account for arrhythmogenic effects produced by hypokalemia. Left ventricular pressure, electrocardiogram, and epicardial monophasic action potentials were recorded in perfused hearts from guinea-pig and rabbit. Hypokalemia (2.5 mM K+) was found to prolong repolarization, reduce the EM window, and promote tachyarrhythmia. Nevertheless, during both regular pacing and extrasystolic excitation, the increased QT interval invariably remained shorter than the duration of mechanical systole, thus yielding positive EM window values. Hypokalemia-induced arrhythmogenicity was associated with slowed ventricular conduction, and shortened effective refractory periods, which translated to a reduced excitation wavelength index. Hypokalemia also evoked non-uniform prolongation of action potential duration in distinct epicardial regions, which resulted in increased spatial variability in the repolarization time. These findings suggest that arrhythmogenic effects of hypokalemia are not accounted for by the negative EM window, and are rather attributed to abnormal changes in ventricular conduction times, refractoriness, excitation wavelength, and spatial repolarization gradients. PMID:25141124

Autonomic nervous system activity during actual and mentally simulated preparation for movement.

PubMed

Bolliet, O; Collet, C; Dittmar, A

2005-03-01

The aim of this study was to compare actual versus mentally simulated preparation for a complex motor skill. Two behavioral periods are observed during weightlifting: (i) an initial phase in which the subject standing behind the bar is thought to focus his attention on forthcoming execution and (ii) a second phase between hands/bar contact and execution during which the subject is thought to increase activation. Such mental processes accompanying behavioral sequences are correlated with autonomic nervous system activity, phasic responses corresponding to allocation of attentional resources, and tonic variations related to increasing general activation. To study mental processes during preparation for action, 12 subjects performed actual and imagined preparation phases of execution. Six autonomic variables were measured continuously. Skin potential (chi2 = 0.16), skin temperature amplitude (Z = -0.66) and duration (Z = -1.78), skin blood flow amplitude (Z = -0.56) and duration (Z = -1.51), respiratory frequency amplitude (Z = -0.14) and duration (Z = -0.13), and duration of heart rate response (Z = -1.25) were shown to be comparable (p > .05), whatever the modality of preparation. However, during mentally simulated preparation, skin resistance response was shorter than in actual preparation (Z = -2.12, p < .05), thus attesting to a weaker load, whereas lower decrease in heart rate was elicited (Z = -1.96, p < .05). This may be explained by this particular experimental condition because mental preparation would not lead to actual action. Such autonomic variables could be used as feedback to improve performance.

Transient Outward K+ Current (Ito) Underlies the Right Ventricular Initiation of Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long-QT Syndrome Type 1.

PubMed

Choi, Bum-Rak; Li, Weiyan; Terentyev, Dmitry; Kabakov, Anatoli Y; Zhong, Mingwang; Rees, Colin M; Terentyeva, Radmila; Kim, Tae Yun; Qu, Zhilin; Peng, Xuwen; Karma, Alain; Koren, Gideon

2018-06-01

Sudden death in long-QT syndrome type 1 (LQT1), an inherited disease caused by loss-of-function mutations in KCNQ1, is triggered by early afterdepolarizations (EADs) that initiate polymorphic ventricular tachycardia (pVT). We investigated ionic mechanisms that underlie pVT in LQT1 using a transgenic rabbit model of LQT1. Optical mapping, cellular patch clamping, and computer modeling were used to elucidate the mechanisms of EADs in transgenic LQT1 rabbits. The results showed that shorter action potential duration in the right ventricle (RV) was associated with focal activity during pVT initiation. RV cardiomyocytes demonstrated higher incidence of EADs under 50 nmol/L isoproterenol. Voltage-clamp studies revealed that the transient outward potassium current (I to ) magnitude was 28% greater in RV associated with KChiP2 but with no differences in terms of calcium-cycling kinetics and other sarcolemmal currents. Perfusing with the I to blocker 4-aminopyridine changed the initial focal sites of pVT from the RV to the left ventricle, corroborating the role of I to in pVT initiation. Computer modeling showed that EADs occur preferentially in the RV because of the larger conductance of the slow-inactivating component of I to , which repolarizes the membrane potential sufficiently rapidly to allow reactivation of I Ca,L before I Kr has had sufficient time to activate. I to heterogeneity creates both triggers and an arrhythmogenic substrate in LQT1. In the absence of I Ks , I to interactions with I Ca,L and I Kr promote EADs in the RV while prolonging action potential duration in the left ventricle. This heterogeneity of action potential enhances dispersion of refractoriness and facilitates conduction blocks that initiate pVTs. © 2018 American Heart Association, Inc.

Arrhythmogenic drugs can amplify spatial heterogeneities in the electrical restitution in perfused guinea-pig heart: An evidence from assessments of monophasic action potential durations and JT intervals

PubMed Central

2018-01-01

Non-uniform shortening of the action potential duration (APD90) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This study examined whether spatial heterogeneities in APD90 restitution can be amplified by drugs with clinically proved proarrhythmic potential (dofetilide, quinidine, procainamide, and flecainide) and, if so, whether these effects can translate to the appropriate changes of the ECG metrics of ventricular repolarization, such as JT intervals. In isolated, perfused guinea-pig heart preparations, monophasic action potentials and volume-conducted ECG were recorded at progressively increased pacing rates. The APD90 measured at distinct ventricular sites, as well as the JTpeak and JTend values were plotted as a function of preceding diastolic interval, and the maximum slopes of the restitution curves were determined at baseline and upon drug administration. Dofetilide, quinidine, and procainamide reverse rate-dependently prolonged APD90 and steepened the restitution curve, with effects being greater at the endocardium than epicardium, and in the right ventricular (RV) vs. the left ventricular (LV) chamber. The restitution slope was increased to a greater extent for the JTend vs. the JTpeak interval. In contrast, flecainide reduced the APD90 restitution slope at LV epicardium without producing effect at LV endocardium and RV epicardium, and reduced the JTpeak restitution slope without changing the JTend restitution. Nevertheless, with all agents, these effects translated to the amplified epicardial-to-endocardial and the LV-to-RV non-uniformities in APD90 restitution, paralleled by the increased JTend vs. JTpeak difference in the restitution slope. In summary, these findings suggest that arrhythmic drug profiles are partly attributable to the accentuated regional heterogeneities in APD90 restitution, which can be indirectly determined through ECG assessments of the JTend vs. JTpeak dynamics at variable pacing rates. PMID:29352276

Arrhythmogenic drugs can amplify spatial heterogeneities in the electrical restitution in perfused guinea-pig heart: An evidence from assessments of monophasic action potential durations and JT intervals.

PubMed

Osadchii, Oleg E

2018-01-01

Non-uniform shortening of the action potential duration (APD90) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This study examined whether spatial heterogeneities in APD90 restitution can be amplified by drugs with clinically proved proarrhythmic potential (dofetilide, quinidine, procainamide, and flecainide) and, if so, whether these effects can translate to the appropriate changes of the ECG metrics of ventricular repolarization, such as JT intervals. In isolated, perfused guinea-pig heart preparations, monophasic action potentials and volume-conducted ECG were recorded at progressively increased pacing rates. The APD90 measured at distinct ventricular sites, as well as the JTpeak and JTend values were plotted as a function of preceding diastolic interval, and the maximum slopes of the restitution curves were determined at baseline and upon drug administration. Dofetilide, quinidine, and procainamide reverse rate-dependently prolonged APD90 and steepened the restitution curve, with effects being greater at the endocardium than epicardium, and in the right ventricular (RV) vs. the left ventricular (LV) chamber. The restitution slope was increased to a greater extent for the JTend vs. the JTpeak interval. In contrast, flecainide reduced the APD90 restitution slope at LV epicardium without producing effect at LV endocardium and RV epicardium, and reduced the JTpeak restitution slope without changing the JTend restitution. Nevertheless, with all agents, these effects translated to the amplified epicardial-to-endocardial and the LV-to-RV non-uniformities in APD90 restitution, paralleled by the increased JTend vs. JTpeak difference in the restitution slope. In summary, these findings suggest that arrhythmic drug profiles are partly attributable to the accentuated regional heterogeneities in APD90 restitution, which can be indirectly determined through ECG assessments of the JTend vs. JTpeak dynamics at variable pacing rates.

N-hexane neuropathy in offset printers.

PubMed Central

Chang, C M; Yu, C W; Fong, K Y; Leung, S Y; Tsin, T W; Yu, Y L; Cheung, T F; Chan, S Y

1993-01-01

In an offset printing factory with 56 workers, 20 (36%) developed symptomatic peripheral neuropathy due to exposure to n-hexane. Another 26 workers (46%) were found to have subclinical neuropathy. The initial change in the nerve conduction study was reduced amplitude of the sensory action potentials, followed by reduced amplitude of the motor action potentials, reduction in motor conduction velocities and increase in distal latencies. These changes indicate primary axonal degeneration with secondary demyelination. Sural nerve biopsy in a severe case showed giant axonal swellings due to accumulation of 10nm neurofilaments, myelin sheath attenuation and widening of nodal gaps. The development of neuropathy bore no direct relationship to the duration of exposure, hence factors such as individual susceptibility may be important. Optic neuropathy and CNS involvement were uncommon and autonomic neuropathy was not encountered. Images PMID:8505647

Low extracellular potassium prolongs repolarization and evokes early afterdepolarization in human induced pluripotent stem cell-derived cardiomyocytes.

PubMed

Kuusela, Jukka; Larsson, Kim; Shah, Disheet; Prajapati, Chandra; Aalto-Setälä, Katriina

2017-06-15

Long QT syndrome (LQTS) is characterized by a prolonged QT-interval on electrocardiogram and by increased risk of sudden death. One of the most common and potentially life-threatening electrolyte disturbances is hypokalemia, characterized by low concentrations of K + Using a multielectrode array platform and current clamp technique, we investigated the effect of low extracellular K + concentration ([K + ] Ex ) on the electrophysiological properties of hiPSC-derived cardiomyocytes (CMs) generated from a healthy control subject (WT) and from two symptomatic patients with type 1 of LQTS carrying G589D (LQT1A) or IVS7-2A>G mutation (LQT1B) in KCNQ1 The baseline prolongations of field potential durations (FPDs) and action potential durations (APDs) were longer in LQT1-CMs than in WT-CMs. Exposure to low [K + ] Ex prolonged FPDs and APDs in a concentration-dependent fashion. LQT1-CMs were found to be more sensitive to low [K + ] Ex compared to WT-CMs. At baseline, LQT1A-CMs had more prolonged APDs than LQT1B-CMs, but low [K + ] Ex caused more pronounced APD prolongation in LQT1B-CMs. Early afterdepolarizations in the action potentials were observed in a subset of LQT1A-CMs with further prolonged baseline APDs and triangular phase 2 profiles. This work demonstrates that the hiPSC-derived CMs are sensitive to low [K + ] Ex and provide a platform to study acquired LQTS. © 2017. Published by The Company of Biologists Ltd.

Single channel analysis of the blocking actions of BIDN and fipronil on a Drosophila melanogaster GABA receptor (RDL) stably expressed in a Drosophila cell line

PubMed Central

Grolleau, Françoise; Sattelle, David B

2000-01-01

Single channel recordings were obtained from a Drosophila S2 cell line stably expressing the wild-type RDLac Drosophila melanogaster homomer-forming ionotropic GABA receptor subunit, a product of the resistance to dieldrin gene, Rdl. GABA (50 μM) was applied by pressure ejection to outside-out patches from S2-RDL cells at a holding potential of −60 mV. The resulting inward current was completely blocked by 100 μM picrotoxin (PTX). The unitary current-voltage relationship was linear at negative potentials but showed slight inward rectification at potentials more positive than 0 mV. The reversal potential of the current (EGABA=−1.4 mV) was close to the calculated chloride equilibrium potential. The single channel conductance elicited by GABA was 36 pS. A 71 pS conductance channel was also observed when the duration of the pulse, used to eject GABA, was longer than 80 ms. The mean open time distribution of the unitary events was fitted best by two exponential functions suggesting two open channel states. When either 1 μM fipronil or 1 μM BIDN was present in the external saline, the GABA-gated channels were completely blocked. When BIDN or fipronil was applied at a concentration close to the IC50 value for suppression of open probability (281 nM, BIDN; 240 nM, fipronil), the duration of channel openings was shortened. In addition, the blocking action of BIDN resulted in the appearance of a novel channel conductance (17 pS). The effects of co-application of BIDN and fipronil were examined. Co-application of BIDN (300 nM) with various concentrations (100–1000 nM) of fipronil resulted in an additional BIDN-induced dose-dependent reduction of the maximum Po value. Thus both BIDN and fipronil shorten the duration of wild-type RDLac GABA receptor channel openings but appear to act at distinct sites. PMID:10952672

Workflow and intervention times of MR-guided focused ultrasound - Predicting the impact of new techniques.

PubMed

Loeve, Arjo J; Al-Issawi, Jumana; Fernandez-Gutiérrez, Fabiola; Langø, Thomas; Strehlow, Jan; Haase, Sabrina; Matzko, Matthias; Napoli, Alessandro; Melzer, Andreas; Dankelman, Jenny

2016-04-01

Magnetic resonance guided focused ultrasound surgery (MRgFUS) has become an attractive, non-invasive treatment for benign and malignant tumours, and offers specific benefits for poorly accessible locations in the liver. However, the presence of the ribcage and the occurrence of liver motion due to respiration limit the applicability MRgFUS. Several techniques are being developed to address these issues or to decrease treatment times in other ways. However, the potential benefit of such improvements has not been quantified. In this research, the detailed workflow of current MRgFUS procedures was determined qualitatively and quantitatively by using observation studies on uterine MRgFUS interventions, and the bottlenecks in MRgFUS were identified. A validated simulation model based on discrete events simulation was developed to quantitatively predict the effect of new technological developments on the intervention duration of MRgFUS on the liver. During the observation studies, the duration and occurrence frequencies of all actions and decisions in the MRgFUS workflow were registered, as were the occurrence frequencies of motion detections and intervention halts. The observation results show that current MRgFUS uterine interventions take on average 213min. Organ motion was detected on average 2.9 times per intervention, of which on average 1.0 actually caused a need for rework. Nevertheless, these motion occurrences and the actions required to continue after their detection consumed on average 11% and up to 29% of the total intervention duration. The simulation results suggest that, depending on the motion occurrence frequency, the addition of new technology to automate currently manual MRgFUS tasks and motion compensation could potentially reduce the intervention durations by 98.4% (from 256h 5min to 4h 4min) in the case of 90% motion occurrence, and with 24% (from 5h 19min to 4h 2min) in the case of no motion. In conclusion, new tools were developed to predict how intervention durations will be affected by future workflow changes and by the introduction of new technology. Copyright © 2016 Elsevier Inc. All rights reserved.

High-Bandwidth Atomic Force Microscopy Reveals A Mechanical spike Accompanying the Action Potential in mammalian Nerve Terminals

NASA Astrophysics Data System (ADS)

Salzberg, Brian M.

2008-03-01

Information transfer from neuron to neuron within nervous systems occurs when the action potential arrives at a nerve terminal and initiates the release of a chemical messenger (neurotransmitter). In the mammalian neurohypophysis (posterior pituitary), large and rapid changes in light scattering accompany secretion of transmitter-like neuropeptides. In the mouse, these intrinsic optical signals are intimately related to the arrival of the action potential (E-wave) and the release of arginine vasopressin and oxytocin (S-wave). We have used a high bandwidth (20 kHz) atomic force microscope (AFM) to demonstrate that these light scattering signals are associated with changes in nerve terminal volume, detected as nanometer-scale movements of a cantilever positioned on top of the neurohypophysis. The most rapid mechanical response, the ``spike'', has duration comparable to that of the action potential (˜2 ms) and probably reflects an increase in terminal volume due to H2O movement associated with Na^+-influx. Elementary calculations suggest that two H2O molecules accompanying each Na^+-ion could account for the ˜0.5-1.0 å increase in the diameter of each terminal during the action potential. Distinguishable from the mechanical ``spike'', a slower mechanical event, the ``dip'', represents a decrease in nerve terminal volume, depends upon Ca^2+-entry, as well as on intra-terminal Ca^2+-transients, and appears to monitor events associated with secretion. A simple hypothesis is that this ``dip'' reflects the extrusion of the dense core granule that comprises the secretory products. These dynamic high bandwidth AFM recordings are the first to monitor mechanical events in nervous systems and may provide novel insights into the mechanism(s) by which excitation is coupled to secretion at nerve terminals.

Effect of knockout of α2δ-1 on action potentials in mouse sensory neurons.

PubMed

Margas, Wojciech; Ferron, Laurent; Nieto-Rostro, Manuela; Schwartz, Arnold; Dolphin, Annette C

2016-08-05

Gene deletion of the voltage-gated calcium channel auxiliary subunit α2δ-1 has been shown previously to have a cardiovascular phenotype, and a reduction in mechano- and cold sensitivity, coupled with delayed development of neuropathic allodynia. We have also previously shown that dorsal root ganglion (DRG) neuron calcium channel currents were significantly reduced in α2δ-1 knockout mice. To extend our findings in these sensory neurons, we have examined here the properties of action potentials (APs) in DRG neurons from α2δ-1 knockout mice in comparison to their wild-type (WT) littermates, in order to dissect how the calcium channels that are affected by α2δ-1 knockout are involved in setting the duration of individual APs and their firing frequency. Our main findings are that there is reduced Ca(2+) entry on single AP stimulation, particularly in the axon proximal segment, reduced AP duration and reduced firing frequency to a 400 ms stimulation in α2δ-1 knockout neurons, consistent with the expected role of voltage-gated calcium channels in these events. Furthermore, lower intracellular Ca(2+) buffering also resulted in reduced AP duration, and a lower frequency of AP firing in WT neurons, mimicking the effect of α2δ-1 knockout. By contrast, we did not obtain any consistent evidence for the involvement of Ca(2+)-activation of large conductance calcium-activated potassium (BK) and small conductance calcium-activated potassium (SK) channels in these events. In conclusion, the reduced Ca(2+) elevation as a result of single AP stimulation is likely to result from the reduced duration of the AP in α2δ-1 knockout sensory neurons.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'. © 2016 The Authors.

Moving time: the influence of action on duration perception.

PubMed

Press, Clare; Berlot, Eva; Bird, Geoffrey; Ivry, Richard; Cook, Richard

2014-10-01

Perceiving the sensory consequences of action accurately is essential for appropriate interaction with our physical and social environments. Prediction mechanisms are considered necessary for fine-tuned sensory control of action, yet paradoxically may distort perception. Here, we examine this paradox by addressing how movement influences the perceived duration of sensory outcomes congruent with action. Experiment 1 required participants to make judgments about the duration of vibrations applied to a moving or stationary finger. In Experiments 2 and 3, participants judged observed finger movements that were congruent or incongruent with their own actions. In all experiments, target events were perceived to be longer when congruent with movement. Interestingly, this temporal dilation did not differ as a function of stimulus perspective (1st or 3rd person) or spatial location. We propose that this bias may reflect the operation of an adaptive mechanism for sensorimotor selection and control that preactivates anticipated outcomes of action. The bias itself may have surprising implications for both action control and perception of others: we may be in contact with grasped objects for less time than we realize, and others' reactions to us may be briefer than we believe.

Formation of correlated states and tunneling for a low energy and controlled pulsed action on particles

NASA Astrophysics Data System (ADS)

Vysotskii, V. I.; Vysotskyy, M. V.

2017-08-01

We consider a method for optimizing the tunnel effect for low-energy particles by using coherent correlated states formed under controllable pulsed action on these particles. Typical examples of such actions are the effect of a pulsed magnetic field on charged particles in a gas or plasma. Coherent correlated states are characterized most comprehensively by the correlation coefficient r( t); an increase of this factor elevates the probability of particle tunneling through a high potential barrier by several orders of magnitude without an appreciable increase in their energy. It is shown for the first time that the formation of coherent correlated states, as well as maximal | r( t)|max and time-averaged 〈| r( t)|〉 amplitudes of the correlation coefficient and the corresponding tunneling probability are characterized by a nonmonotonic (oscillating) dependence on the forming pulse duration and amplitude. This result makes it possible to optimize experiments on the realization of low-energy nuclear fusion and demonstrates the incorrectness of the intuitive idea that the tunneling probability always increases with the amplitude of an external action on a particle. Our conclusions can be used, in particular, for explaining random (unpredictable and low-repeatability) experimental results on optimization of energy release from nuclear reactions occurring under a pulsed action with fluctuations of the amplitude and duration. We also consider physical premises for the observed dependences and obtain optimal relations between the aforementioned parameters, which ensure the formation of an optimal coherent correlated state and optimal low-energy tunneling in various physical systems with allowance for the dephasing action of a random force. The results of theoretical analysis are compared with the data of successful experiments on the generation of neutrons and alpha particles in an electric discharge in air and gaseous deuterium.

Time on your hands: Perceived duration of sensory events is biased toward concurrent actions.

PubMed

Yon, Daniel; Edey, Rosanna; Ivry, Richard B; Press, Clare

2017-02-01

Perceptual systems must rapidly generate accurate representations of the world from sensory inputs that are corrupted by internal and external noise. We can typically obtain more veridical representations by integrating information from multiple channels, but this integration can lead to biases when inputs are, in fact, not from the same source. Although a considerable amount is known about how different sources of information are combined to influence what we perceive, it is not known whether temporal features are combined. It is vital to address this question given the divergent predictions made by different models of cue combination and time perception concerning the plausibility of cross-modal temporal integration, and the implications that such integration would have for research programs in action control and social cognition. Here we present four experiments investigating the influence of movement duration on the perceived duration of an auditory tone. Participants either explicitly (Experiments 1-2) or implicitly (Experiments 3-4) produced hand movements of shorter or longer durations, while judging the duration of a concurrently presented tone (500-950 ms in duration). Across all experiments, judgments of tone duration were attracted toward the duration of executed movements (i.e., tones were perceived to be longer when executing a movement of longer duration). Our results demonstrate that temporal information associated with movement biases perceived auditory duration, placing important constraints on theories modeling cue integration for state estimation, as well as models of time perception, action control and social cognition. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Nitrates and Nitrites in the Treatment of Ischemic Cardiac Disease

PubMed Central

Nossaman, Vaughn E.; Nossaman, Bobby D.; Kadowitz, Philip J.

2010-01-01

The organic nitrite, amyl of nitrite, was initially used as a therapeutic agent in the treatment of angina pectoris in 1867, but was replaced over a decade later by the organic nitrate, nitroglycerin (NTG), due to the ease of administration and longer duration of action. The administration of organic nitrate esters, such as NTG, continues to be used in the treatment of angina pectoris and heart failure during the birth of modern pharmacology. The clinical effectiveness is due to vasodilator activity in large veins and arteries through an as yet unidentified method of delivering nitric oxide (NO), or a NO-like compound to vascular smooth muscle cells. The major drawback with NTG administration is the rapid development of tolerance; and with amyl of nitrite, the duration and route of administration. Although amyl of nitrite are no longer used in the treatments of hypertension or ischemic heart disease, the nitrite anion has recently been discovered to possess novel pharmacologic actions such as modulating hypoxic vasodilation and providing cytoprotection in ischemia-reperfusion injury. Although the actions of these two similar chemical classes (nitrites and organic nitrates) have often been considered to be alike, we still do not understand their mechanism of action. However, the recent discovery that the nitrite anion, derived from either sodium nitrite or an intermediate NTG form, may act as a storage form for NO and provides support for investigating the use of these agents in the treatment of ischemic cardiovascular states. We review what is presently known about the use of nitrites and nitrates, the potential uses of these agents, and their mechanisms of action. PMID:20539102

A Novel Stimulus Artifact Removal Technique for High-Rate Electrical Stimulation

PubMed Central

Heffer, Leon F; Fallon, James B

2008-01-01

Electrical stimulus artifact corrupting electrophysiological recordings often make the subsequent analysis of the underlying neural response difficult. This is particularly evident when investigating short-latency neural activity in response to high-rate electrical stimulation. We developed and evaluated an off-line technique for the removal of stimulus artifact from electrophysiological recordings. Pulsatile electrical stimulation was presented at rates of up to 5000 pulses/s during extracellular recordings of guinea pig auditory nerve fibers. Stimulus artifact was removed by replacing the sample points at each stimulus artifact event with values interpolated along a straight line, computed from neighbouring sample points. This technique required only that artifact events be identifiable and that the artifact duration remained less than both the inter-stimulus interval and the time course of the action potential. We have demonstrated that this computationally efficient sample-and-interpolate technique removes the stimulus artifact with minimal distortion of the action potential waveform. We suggest that this technique may have potential applications in a range of electrophysiological recording systems. PMID:18339428

Optimization of Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for Duration of Action, as an Inhaled Therapy for Lung Remodeling in Pulmonary Arterial Hypertension.

PubMed

Shaw, Duncan E; Baig, Ferheen; Bruce, Ian; Chamoin, Sylvie; Collingwood, Stephen P; Cross, Sarah; Dayal, Satish; Drückes, Peter; Furet, Pascal; Furminger, Vikki; Haggart, Deborah; Hussey, Martin; Konstantinova, Irena; Loren, Jon C; Molteni, Valentina; Roberts, Sonia; Reilly, John; Saunders, Alex M; Stringer, Rowan; Sviridenko, Lilya; Thomas, Matthew; Thomson, Christopher G; Tomlins, Christine; Wen, Ben; Yeh, Vince; Pearce, Andrew C

2016-09-08

A series of potent PDGFR inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after i.t. dosing. Compound 25 shows 24 h occupancy of the PDGFR kinase domain, after a single i.t. dose and has efficacy at 0.03 mg/kg, in the rat moncrotaline model of pulmonary arterial hypertension. Examination of PK/PD data from the optimization effort has revealed in vitro:in vivo correlations which link duration of action in vivo with low permeability and high basicity and demonstrate that nonspecific binding to lung tissue increases with lipophilicity.

The Effect of Substrate Stiffness on Cardiomyocyte Action Potentials.

PubMed

Boothe, Sean D; Myers, Jackson D; Pok, Seokwon; Sun, Junping; Xi, Yutao; Nieto, Raymond M; Cheng, Jie; Jacot, Jeffrey G

2016-12-01

The stiffness of myocardial tissue changes significantly at birth and during neonatal development, concurrent with significant changes in contractile and electrical maturation of cardiomyocytes. Previous studies by our group have shown that cardiomyocytes generate maximum contractile force when cultured on a substrate with a stiffness approximating native cardiac tissue. However, effects of substrate stiffness on the electrophysiology and ion currents in cardiomyocytes have not been fully characterized. In this study, neonatal rat ventricular myocytes were cultured on the surface of flat polyacrylamide hydrogels with elastic moduli ranging from 1 to 25 kPa. Using whole-cell patch clamping, action potentials and L-type calcium currents were recorded. Cardiomyocytes cultured on hydrogels with a 9 kPa elastic modulus, similar to that of native myocardium, had the longest action potential duration. Additionally, the voltage at maximum calcium flux significantly decreased in cardiomyocytes on hydrogels with an elastic modulus higher than 9 kPa, and the mean inactivation voltage decreased with increasing stiffness. Interestingly, the expression of the L-type calcium channel subunit α gene and channel localization did not change with stiffness. Substrate stiffness significantly affects action potential length and calcium flux in cultured neonatal rat cardiomyocytes in a manner that may be unrelated to calcium channel expression. These results may explain functional differences in cardiomyocytes resulting from changes in the elastic modulus of the extracellular matrix, as observed during embryonic development, in ischemic regions of the heart after myocardial infarction, and during dilated cardiomyopathy.

Dorsal–Ventral Gradient for Neuronal Plasticity in the Embryonic Spinal Cord

PubMed Central

Pineda, Ricardo H.; Ribera, Angeles B.

2008-01-01

Within the developing Xenopus spinal cord, voltage-gated potassium (Kv) channel genes display different expression patterns, many of which occur in opposing dorsal–ventral gradients. Regional differences in Kv gene expression would predict different patterns of potassium current (IKv) regulation. However, during the first 24 h of postmitotic differentiation, all primary spinal neurons undergo a temporally coordinated upregulation of IKv density that shortens the duration of the action potential. Here, we tested whether spinal neurons demonstrate regional differences in IKv regulation subsequent to action potential maturation. We show that two types of neurons, I and II, can be identified in culture on the basis of biophysical and pharmacological properties of IKv and different firing patterns. Chronic increases in extracellular potassium, a signature of high neuronal activity, do not alter excitability properties of either neuron type. However, elevating extracellular potassium acutely after the period of action potential maturation leads to different changes in membrane properties of the two types of neurons. IKv of type I neurons gains sensitivity to the blocker XE991, whereas type II neurons increase IKv density and fire fewer action potentials. Moreover, by recording from neurons in vivo, we found that primary spinal neurons can be identified as either type I or type II. Type I neurons predominate in dorsal regions, whereas type II neurons localize to ventral regions. The findings reveal a dorsal–ventral gradient for IKv regulation and a novel form of neuronal plasticity in spinal cord neurons. PMID:18385340

Basis for the Induction of Tissue-Level Phase-2 Reentry as a Repolarization Disorder in the Brugada Syndrome

PubMed Central

Bueno-Orovio, Alfonso; Cherry, Elizabeth M.; Evans, Steven J.; Fenton, Flavio H.

2015-01-01

Aims. Human action potentials in the Brugada syndrome have been characterized by delayed or even complete loss of dome formation, especially in the right ventricular epicardial layers. Such a repolarization pattern is believed to trigger phase-2 reentry (P2R); however, little is known about the conditions necessary for its initiation. This study aims to determine the specific mechanisms that facilitate P2R induction in Brugada-affected cardiac tissue in humans. Methods. Ionic models for Brugada syndrome in human epicardial cells were developed and used to study the induction of P2R in cables, sheets, and a three-dimensional model of the right ventricular free wall. Results. In one-dimensional cables, P2R can be induced by adjoining lost-dome and delayed-dome regions, as mediated by tissue excitability and transmembrane voltage profiles, and reduced coupling facilitates its induction. In two and three dimensions, sustained reentry can arise when three regions (delayed-dome, lost-dome, and normal epicardium) are present. Conclusions. Not only does P2R induction by Brugada syndrome require regions of action potential with delayed-dome and lost-dome, but in order to generate a sustained reentry from a triggered waveback multiple factors are necessary, including heterogeneity in action potential distribution, tissue coupling, direction of stimulation, the shape of the late plateau, the duration of lost-dome action potentials, and recovery of tissue excitability, which is predominantly modulated by tissue coupling. PMID:26583094

Yawn duration predicts brain weight and cortical neuron number in mammals

PubMed Central

Church, Allyson M.; Pelegrino, Anthony J.

2016-01-01

Research indicates that the motor action pattern of yawning functions to promote cortical arousal and state change through enhanced intracranial circulation and brain cooling. Because the magnitude of this response likely corresponds to the degree of neurophysiological change, we hypothesized that interspecies variation in yawn duration would correlate with underlying neurological differences. Using openly accessible data, we show that both the mean and variance in yawn duration are robust predictors of mammalian brain weight and cortical neuron number (ρ-values > 0.9). Consistent with these effects, primates tend to have longer and more variable yawn durations compared with other mammals. Although yawning has long been considered a stereotyped action pattern, these findings reveal substantial variation in this response and highlight the importance of measuring yawn duration in future research. PMID:27703056

The Relative Influences of Phosphometabolites and pH on Action Potential Morphology during Myocardial Reperfusion: A Simulation Study

PubMed Central

Roberts, Byron N.; Christini, David J.

2012-01-01

Myocardial ischemia-reperfusion (IR) injury represents a constellation of pathological processes that occur when ischemic myocardium experiences a restoration of perfusion. Reentrant arrhythmias, which represent a particularly lethal manifestation of IR injury, can result when ischemic tissue exhibits decreased excitability and/or changes of action potential duration (APD), conditions that precipitate unidirectional conduction block. Many of the cellular components that are involved with IR injury are modulated by pH and/or phosphometabolites such as ATP and phosphocreatine (PCr), all of which can be manipulated in vivo and potentially in the clinical setting. Using a mathematical model of the cardiomyocyte that we previously developed to study ischemia and reperfusion, we performed a series of simulations with the aim of determining whether pH- or phosphometabolite-related processes play a more significant role in generating changes in excitability and action potential morphology that are associated with the development of reentry. In our simulations, persistent shortening of APD, action potential amplitude (APA), and depolarization of the resting membrane potential were more severe when ATP and PCr availability were suppressed during reperfusion than when extracellular pH recovery was inhibited. Reduced phosphometabolite availability and pH recovery affected multiple ion channels and exchangers. Some of these effects were the result of direct modulation by phosphometabolites and/or acidosis, while others resulted from elevated sodium and calcium loads during reperfusion. In addition, increasing ATP and PCr availability during reperfusion was more beneficial in terms of increasing APD and APA than was increasing the amount of pH recovery. Together, these results suggest that therapies directed at increasing ATP and/or PCr availability during reperfusion may be more beneficial than perturbing pH recovery with regard to mitigating action potential changes that increase the likelihood of reentrant arrhythmias. PMID:23144801

The sea anemone toxin AdE-1 modifies both sodium and potassium currents of rat cardiomyocytes.

PubMed

Nesher, Nir; Zlotkin, Eliahu; Hochner, Binyamin

2014-07-01

AdE-1, a cardiotonic peptide recently isolated from the sea anemone Aiptasia diaphana, contains 44 amino acids and has a molecular mass of 4907 Da. It was previously found to resemble other sea anemone type 1 and 2 Na+ channel toxins, enhancing contractions of rat cardiomyocytes and slowing their twitch relaxation; however, it did not induce spontaneous twitches. AdE-1 increased the duration of the cardiomyocyte action potential and decreased its amplitude and its time-to-peak in a concentration-dependent manner, without affecting its threshold and cell resting potential. Nor did it generate the early and delayed after-depolarizations characteristic of sea anemone Na+ channel toxins. To further understand its mechanism of action we investigated the effect of AdE-1 on the major ion currents of rat cardiomyocytes. In the present study we show that AdE-1 markedly slowed inactivation of the Na+ current, enhancing and prolonging the current influx with no effect on current activation, possibly through direct interaction with the site 3 receptor of the Na+ channel. No significant effect of AdE-1 on the Ca2+ current was observed, but, unexpectedly, AdE-1 significantly increased the amplitude of the transient component of the K+ current, shifting the current threshold to more negative membrane potentials. This effect on the K+ current has not been found in any other sea anemone toxin and may explain the exclusive reduction in action potential amplitude and the absence of the action potential disorders found with other toxins, such as early and delayed after-depolarizations.

Beat-to-Beat Variation in Periodicity of Local Calcium Releases Contributes to Intrinsic Variations of Spontaneous Cycle Length in Isolated Single Sinoatrial Node Cells

PubMed Central

Monfredi, Oliver; Maltseva, Larissa A.; Spurgeon, Harold A.; Boyett, Mark R.; Lakatta, Edward G.; Maltsev, Victor A.

2013-01-01

Spontaneous, submembrane local Ca2+ releases (LCRs) generated by the sarcoplasmic reticulum in sinoatrial nodal cells, the cells of the primary cardiac pacemaker, activate inward Na+/Ca2+-exchange current to accelerate the diastolic depolarization rate, and therefore to impact on cycle length. Since LCRs are generated by Ca2+ release channel (i.e. ryanodine receptor) openings, they exhibit a degree of stochastic behavior, manifested as notable cycle-to-cycle variations in the time of their occurrence. Aim The present study tested whether variation in LCR periodicity contributes to intrinsic (beat-to-beat) cycle length variability in single sinoatrial nodal cells. Methods We imaged single rabbit sinoatrial nodal cells using a 2D-camera to capture LCRs over the entire cell, and, in selected cells, simultaneously measured action potentials by perforated patch clamp. Results LCRs begin to occur on the descending part of the action potential-induced whole-cell Ca2+ transient, at about the time of the maximum diastolic potential. Shortly after the maximum diastolic potential (mean 54±7.7 ms, n = 14), the ensemble of waxing LCR activity converts the decay of the global Ca2+ transient into a rise, resulting in a late, whole-cell diastolic Ca2+ elevation, accompanied by a notable acceleration in diastolic depolarization rate. On average, cells (n = 9) generate 13.2±3.7 LCRs per cycle (mean±SEM), varying in size (7.1±4.2 µm) and duration (44.2±27.1 ms), with both size and duration being greater for later-occurring LCRs. While the timing of each LCR occurrence also varies, the LCR period (i.e. the time from the preceding Ca2+ transient peak to an LCR’s subsequent occurrence) averaged for all LCRs in a given cycle closely predicts the time of occurrence of the next action potential, i.e. the cycle length. Conclusion Intrinsic cycle length variability in single sinoatrial nodal cells is linked to beat-to-beat variations in the average period of individual LCRs each cycle. PMID:23826247

Electrophysiologic changes following treatment with organophosphorus-induced delayed neuropathy-producing agents in the adult hen.

PubMed

Robertson, D G; Schwab, B W; Sills, R D; Richardson, R J; Anderson, R J

1987-03-15

Although clinical, pathological, and biochemical effects of organophosphorus-induced delayed neuropathy (OPIDN) have been intensively investigated in the adult hen, detailed electrophysiological studies are lacking. Adult white leghorn hens were treated with a single oral dose of either 30 mg/kg tri-2-cresyl phosphate (TOCP), 750 mg/kg TOCP, 4 mg/kg di-n-butyl-2,2-dichlorovinyl phosphate (DBCV), or 30 mg/kg di-n-butyl-2,2-dichlorovinyl phosphinate (DBCV-P). The 750 mg/kg TOCP and DBCV, but not the 30 mg/kg TOCP and DBCV-P, treatments resulted in clinical signs of OPIDN and mild to marked damage of the tibial nerve 21 days after dose. Twenty-four hr lymphocyte neurotoxic esterase (NTE) inhibition was used as an index of brain NTE inhibition for the various organophosphorus compound (OP) treatment. Twenty-four hr lymphocyte NTE inhibition for 30 mg/kg TOCP, 750 mg/kg TOCP, DBCV, and DBCV-P was 54.1, 87.1, 84.8, and 68.3%, respectively. Twenty-one days after dose, the TOCP-treated hens exhibited some abnormalities in conduction velocity and action potential duration in the tibial or sciatic nerves. No abnormalities were observed in action potential parameters of either the DBCV or DBCV-P treatments. Neurotoxic OP (TOCP and DBCV) treatment resulted in decreased refractoriness in the tibial nerve, increased refractoriness in the sciatic nerve, and elevated strength duration threshold for both nerves. These changes were not present in nerves from DBCV-P (a non-neurotoxic NTE inhibitor)-treated hens. These results suggest that refractory period and strength duration abnormalities in peripheral nerve correlate well with the production of OPIDN and are evident without coincident clinical signs or histopathology.

Enhanced cytotoxicity of anticancer drug delivered by novel nanoscale polymeric carrier

NASA Astrophysics Data System (ADS)

Stoika, R.; Boiko, N.; Senkiv, Y.; Shlyakhtina, Y.; Panchuk, R.; Finiuk, N.; Filyak, Y.; Bilyy, R.; Kit, Y.; Skorohyd, N.; Klyuchivska, O.; Zaichenko, A.; Mitina, N.; Ryabceva, A.

2013-04-01

We compared in vitro action of highly toxic anticancer drug doxorubicin under its delivery to the mammalian tumor cells in free form and after encapsulation in novel bio-functionalized nanoscale polymeric carrier. Such encapsulation was found to enhance significantly drug uptake by the targeted cells, as well as its cytotoxic action. 10 times higher cytotoxicity of the carrier-immobilized doxorubicin comparing to its free form was demonstrated by direct cell counting, and 5 times higher cytotoxicity of encapsulated doxorubicin was shown by FACS analysis. The polymeric carrier itself did not possess significant toxicity in vitro or in vivo (laboratory mice). The carrier protected against negative side effects of doxorubicin in mice with experimental NK/Ly lymphoma. The life duration of tumor-bearing animals treated with doxorubicin-carrier complex was significantly longer than life duration in animals treated with free doxorubicin. Besides, the effective treatment dose of the carrier-delivered doxorubicin in tumor-bearing mice was 10 times lower than such dose of free doxorubicin. Thus, novel nanoscale polymers possess high potential as drug carrier.

Dependence of Ca outflow and depression of frog myocardium contraction on ryodipine concentration.

PubMed

Narusevicius, E; Gendviliene, V; Macianskiene, R; Hmelj-Dunai, G; Velena, A; Duburs, G

1988-02-01

The effect of ryodipine on calcium outflow from tissues, on contraction force, the duration of action potentials and the relaxation phase time-constant in the contraction cycles of myocardial strips was studied using frog heart preparations. It was found that calcium outflow (delta Ca) as a function on ryodipine concentration can be represented as: (formula; see text) A linear correlation exists between Ca2+, contraction blocking and the shortening of the action potential in the presence of various ryodipine concentrations. Ryodipine (10(-5) mol/l) decreased the relaxation time-constant by about 20% as compared to controls. It was concluded that calcium outflow from myocardial tissues in response to ryodipine is due to blockade of calcium entry into the cells and their output through the Na+--Ca2+ exchange system. Frog heart myocardial contractions are essentially under the control of calcium entry through sarcolemmal calcium channels.

A specific deficit of imitation in autism spectrum disorder.

PubMed

Stewart, Hannah J; McIntosh, Rob D; Williams, Justin H G

2013-12-01

Imitation is a potentially crucial aspect of social cognitive development. Although deficits in imitation ability have been widely demonstrated in autism spectrum disorder (ASD), the specificity and significance of the findings is unclear, due largely to methodological limitations. We developed a novel assessment of imitation ability, using objective movement parameters (path length and action duration) derived from a touch-sensitive tablet laptop during drawing actions on an identical tablet. By direct comparison of the kinematics of a model's actions with those of the participant who observed them, measures of imitation accuracy were obtained. By replaying the end-point of the movement as a spot on the screen, imitation accuracy was compared against a "ghost control" condition, with no human actor but only the end-point of the movement seen [object movement reenactment (OMR)]. Hence, demands of the control task were closely matched to the experimental task with respect to motor, memory, and attentional abilities. Adolescents with ASD showed poorer accuracy for copying object size and action duration on both the imitation and OMR tasks, but were significantly more impaired for imitation of object size. Our results provide evidence that some of the imitation deficit in ASD is specific to a self-other mapping problem, and cannot be explained by general factors such as memory, spatial reasoning, motor control, or attention, nor related to the social demands of the testing situation. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.

Ventricular action potential adaptation to regular exercise: role of β-adrenergic and KATP channel function.

PubMed

Wang, Xinrui; Fitts, Robert H

2017-08-01

Regular exercise training is known to affect the action potential duration (APD) and improve heart function, but involvement of β-adrenergic receptor (β-AR) subtypes and/or the ATP-sensitive K + (K ATP ) channel is unknown. To address this, female and male Sprague-Dawley rats were randomly assigned to voluntary wheel-running or control groups; they were anesthetized after 6-8 wk of training, and myocytes were isolated. Exercise training significantly increased APD of apex and base myocytes at 1 Hz and decreased APD at 10 Hz. Ca 2+ transient durations reflected the changes in APD, while Ca 2+ transient amplitudes were unaffected by wheel running. The nonselective β-AR agonist isoproterenol shortened the myocyte APD, an effect reduced by wheel running. The isoproterenol-induced shortening of APD was largely reversed by the selective β 1 -AR blocker atenolol, but not the β 2 -AR blocker ICI 118,551, providing evidence that wheel running reduced the sensitivity of the β 1 -AR. At 10 Hz, the K ATP channel inhibitor glibenclamide prolonged the myocyte APD more in exercise-trained than control rats, implicating a role for this channel in the exercise-induced APD shortening at 10 Hz. A novel finding of this work was the dual importance of altered β 1 -AR responsiveness and K ATP channel function in the training-induced regulation of APD. Of physiological importance to the beating heart, the reduced response to adrenergic agonists would enhance cardiac contractility at resting rates, where sympathetic drive is low, by prolonging APD and Ca 2+ influx; during exercise, an increase in K ATP channel activity would shorten APD and, thus, protect the heart against Ca 2+ overload or inadequate filling. NEW & NOTEWORTHY Our data demonstrated that regular exercise prolonged the action potential and Ca 2+ transient durations in myocytes isolated from apex and base regions at 1-Hz and shortened both at 10-Hz stimulation. Novel findings were that wheel running shifted the β-adrenergic receptor agonist dose-response curve rightward compared with controls by reducing β 1 -adrenergic receptor responsiveness and that, at the high activation rate, myocytes from trained animals showed higher K ATP channel function. Copyright © 2017 the American Physiological Society.

45 CFR 284.45 - What are the contents and duration of the corrective action plan?

Code of Federal Regulations, 2011 CFR

2011-10-01

... POVERTY RATE IS THE RESULT OF THE TANF PROGRAM § 284.45 What are the contents and duration of the... manner in which the State or Territory will reduce its child poverty rate; (2) A description of the... corrective action plan until it determines and notifies us that its child poverty rate, as determined in...

45 CFR 284.45 - What are the contents and duration of the corrective action plan?

Code of Federal Regulations, 2014 CFR

2014-10-01

... POVERTY RATE IS THE RESULT OF THE TANF PROGRAM § 284.45 What are the contents and duration of the... manner in which the State or Territory will reduce its child poverty rate; (2) A description of the... corrective action plan until it determines and notifies us that its child poverty rate, as determined in...

45 CFR 284.45 - What are the contents and duration of the corrective action plan?

Code of Federal Regulations, 2013 CFR

2013-10-01

... POVERTY RATE IS THE RESULT OF THE TANF PROGRAM § 284.45 What are the contents and duration of the... manner in which the State or Territory will reduce its child poverty rate; (2) A description of the... corrective action plan until it determines and notifies us that its child poverty rate, as determined in...

45 CFR 284.45 - What are the contents and duration of the corrective action plan?

Code of Federal Regulations, 2012 CFR

2012-10-01

... POVERTY RATE IS THE RESULT OF THE TANF PROGRAM § 284.45 What are the contents and duration of the... manner in which the State or Territory will reduce its child poverty rate; (2) A description of the... corrective action plan until it determines and notifies us that its child poverty rate, as determined in...

45 CFR 284.45 - What are the contents and duration of the corrective action plan?

Code of Federal Regulations, 2010 CFR

2010-10-01

... POVERTY RATE IS THE RESULT OF THE TANF PROGRAM § 284.45 What are the contents and duration of the... manner in which the State or Territory will reduce its child poverty rate; (2) A description of the... corrective action plan until it determines and notifies us that its child poverty rate, as determined in...

Control of spiral waves and turbulent states in a cardiac model by travelling-wave perturbations

NASA Astrophysics Data System (ADS)

Wang, Peng-Ye; Xie, Ping; Yin, Hua-Wei

2003-06-01

We propose a travelling-wave perturbation method to control the spatiotemporal dynamics in a cardiac model. It is numerically demonstrated that the method can successfully suppress the wave instability (alternans in action potential duration) in the one-dimensional case and convert spiral waves and turbulent states to the normal travelling wave states in the two-dimensional case. An experimental scheme is suggested which may provide a new design for a cardiac defibrillator.

Controlling spiral waves and turbulent states in cardiac tissue by traveling wave perturbations

NASA Astrophysics Data System (ADS)

Wang, Peng-Ye; Xie, Ping

2000-03-01

We propose a traveling wave perturbation method to control the spatiotemporal dynamics in cardiac tissue. With a two-variable model we demonstrate that the method can successfully suppress the wave instability (alternans in action potential duration) in the one-dimensional case and convert spiral waves and turbulent states to the normal traveling wave state in the two-dimensional case. An experimental scheme is suggested which may provide a new design for a cardiac defibrillator.

Slow and fast fatigable frog muscle fibres: electrophysiological and histochemical characteristics.

PubMed

Vydevska-Chichova, M; Mileva, K; Todorova, R; Dimitrova, M; Radicheva, N

2005-12-01

Continuous activity of isolated frog gastrocnemius muscle fibres provoked by repetitive stimulation of 5 Hz was used as an experimental model for fatigue development in different fibre types. Parameter changes of the elicited intracellular action potentials and mechanical twitches during the period of uninterrupted activity were used as criteria for fatigue evaluation. Slow fatigable muscle fibre (SMF) and fast fatigable muscle fibre (FMF) types were distinguished depending on the duration of their uninterrupted activity, which was significantly longer in SMFs than in FMFs. The normalized changes of action potential amplitude and duration were significantly smaller in FMFs than in SMFs. The average twitch force and velocity of contraction and relaxation were significantly higher in FMFs than in SMFs. Myosin ATPase (mATPase) and succinate dehydrogenase activity were studied by histochemical assessment in order to validate the fibre type classification based on their electrophysiological characteristics. Based on the relative mATPase reactivity, the fibres of the studied muscle were classified as one of five different types (1-2, 2, 2-3, 3 and tonic). Smaller sized fibres (tonic and type 3) expressed higher succinate dehydrogenase activity than larger sized fibres (type 1-2, 2), which is related to the fatigue resistance. The differences between fatigue development in SMFs and FMFs during continuous activity were associated with fibre-type specific mATPase and succinate dehydrogenase activity.

Simultaneous Quantification of Spatially Discordant Alternans in Voltage and Intracellular Calcium in Langendorff-Perfused Rabbit Hearts and Inconsistencies with Models of Cardiac Action Potentials and Ca Transients

PubMed Central

Uzelac, Ilija; Ji, Yanyan C.; Hornung, Daniel; Schröder-Scheteling, Johannes; Luther, Stefan; Gray, Richard A.; Cherry, Elizabeth M.; Fenton, Flavio H.

2017-01-01

Rationale: Discordant alternans, a phenomenon in which the action potential duration (APDs) and/or intracellular calcium transient durations (CaDs) in different spatial regions of cardiac tissue are out of phase, present a dynamical instability for complex spatial dispersion that can be associated with long-QT syndrome (LQTS) and the initiation of reentrant arrhythmias. Because the use of numerical simulations to investigate arrhythmic effects, such as acquired LQTS by drugs is beginning to be studied by the FDA, it is crucial to validate mathematical models that may be used during this process. Objective: In this study, we characterized with high spatio-temporal resolution the development of discordant alternans patterns in transmembrane voltage (Vm) and intracellular calcium concentration ([Cai]+2) as a function of pacing period in rabbit hearts. Then we compared the dynamics to that of the latest state-of-the-art model for ventricular action potentials and calcium transients to better understand the underlying mechanisms of discordant alternans and compared the experimental data to the mathematical models representing Vm and [Cai]+2 dynamics. Methods and Results: We performed simultaneous dual optical mapping imaging of Vm and [Cai]+2 in Langendorff-perfused rabbit hearts with higher spatial resolutions compared with previous studies. The rabbit hearts developed discordant alternans through decreased pacing period protocols and we quantified the presence of multiple nodal points along the direction of wave propagation, both in APD and CaD, and compared these findings with results from theoretical models. In experiments, the nodal lines of CaD alternans have a steeper slope than those of APD alternans, but not as steep as predicted by numerical simulations in rabbit models. We further quantified several additional discrepancies between models and experiments. Conclusions: Alternans in CaD have nodal lines that are about an order of magnitude steeper compared to those of APD alternans. Current action potential models lack the necessary coupling between voltage and calcium compared to experiments and fail to reproduce some key dynamics such as, voltage amplitude alternans, smooth development of calcium alternans in time, conduction velocity and the steepness of the nodal lines of APD and CaD. PMID:29104543

Big data prediction of durations for online collective actions based on peak's timing

NASA Astrophysics Data System (ADS)

Nie, Shizhao; Wang, Zheng; Pujia, Wangmo; Nie, Yuan; Lu, Peng

2018-02-01

Peak Model states that each collective action has a life circle, which contains four periods of "prepare", "outbreak", "peak", and "vanish"; and the peak determines the max energy and the whole process. The peak model's re-simulation indicates that there seems to be a stable ratio between the peak's timing (TP) and the total span (T) or duration of collective actions, which needs further validations through empirical data of collective actions. Therefore, the daily big data of online collective actions is applied to validate the model; and the key is to check the ratio between peak's timing and the total span. The big data is obtained from online data recording & mining of websites. It is verified by the empirical big data that there is a stable ratio between TP and T; furthermore, it seems to be normally distributed. This rule holds for both the general cases and the sub-types of collective actions. Given the distribution of the ratio, estimated probability density function can be obtained, and therefore the span can be predicted via the peak's timing. Under the scenario of big data, the instant span (how long the collective action lasts or when it ends) will be monitored and predicted in real-time. With denser data (Big Data), the estimation of the ratio's distribution gets more robust, and the prediction of collective actions' spans or durations will be more accurate.

A Compartmentalized Mathematical Model of the β1-Adrenergic Signaling System in Mouse Ventricular Myocytes

PubMed Central

Bondarenko, Vladimir E.

2014-01-01

The β1-adrenergic signaling system plays an important role in the functioning of cardiac cells. Experimental data shows that the activation of this system produces inotropy, lusitropy, and chronotropy in the heart, such as increased magnitude and relaxation rates of [Ca2+]i transients and contraction force, and increased heart rhythm. However, excessive stimulation of β1-adrenergic receptors leads to heart dysfunction and heart failure. In this paper, a comprehensive, experimentally based mathematical model of the β1-adrenergic signaling system for mouse ventricular myocytes is developed, which includes major subcellular functional compartments (caveolae, extracaveolae, and cytosol). The model describes biochemical reactions that occur during stimulation of β1-adrenoceptors, changes in ionic currents, and modifications of Ca2+ handling system. Simulations describe the dynamics of major signaling molecules, such as cyclic AMP and protein kinase A, in different subcellular compartments; the effects of inhibition of phosphodiesterases on cAMP production; kinetics and magnitudes of phosphorylation of ion channels, transporters, and Ca2+ handling proteins; modifications of action potential shape and duration; magnitudes and relaxation rates of [Ca2+]i transients; changes in intracellular and transmembrane Ca2+ fluxes; and [Na+]i fluxes and dynamics. The model elucidates complex interactions of ionic currents upon activation of β1-adrenoceptors at different stimulation frequencies, which ultimately lead to a relatively modest increase in action potential duration and significant increase in [Ca2+]i transients. In particular, the model includes two subpopulations of the L-type Ca2+ channels, in caveolae and extracaveolae compartments, and their effects on the action potential and [Ca2+]i transients are investigated. The presented model can be used by researchers for the interpretation of experimental data and for the developments of mathematical models for other species or for pathological conditions. PMID:24586529

Formulary considerations in selection of beta-blockers.

PubMed

Yedinak, K C

1993-08-01

Selection of beta-adrenergic blockers for formulary addition can be a difficult task, especially with the increasing availability of new beta-blockers, as well as the numerous differences in pharmacodynamic and pharmacokinetic properties of currently available agents. Nevertheless, appropriate evaluation of the important characteristics of beta-blockers should allow selection of the most cost-effective agents for formulary addition. Most importantly, differences in efficacy, product formulation and cost should be carefully considered when making formulary decisions. Notably, evidence from clinical trials indicates differences in efficacy among beta-blockers for post-myocardial infarction prophylaxis, situational anxiety, essential tremor, thyrotoxicosis, migraine prophylaxis and prevention of bleeding associated with oesophageal varices. For many clinical situations, it is also important to select an effective agent that is available in both an oral and intravenous formulation, especially for cardioprotection after acute myocardial infarction and for use in supraventricular arrhythmias. In addition, availability of sustained release products and generic formulations should be considered for their potential to increase compliance and decrease cost, respectively. Comparative drug costs, as well as costs associated with decreased compliance, should also be carefully evaluated. Differences in beta-receptor selectivity, duration of action and presence of intrinsic sympathomimetic activity (ISA) are also important considerations in the selection of beta-blockers for formulary consideration. Although degree of selectivity is relative, beta 1-selective agents may be less likely to induce bronchospasm in patients with chronic obstructive pulmonary disease (COPD) and may be less likely to affect glucose homeostasis in patients with diabetes mellitus. Duration of action of a beta-blocker is an important consideration for evaluation of efficacy throughout the recommended dosage interval. In addition, beta-blockers with a long duration of action can often be administered once or twice daily, potentially leading to increased compliance and thereby improved effectiveness and economic efficiency. The presence of ISA is an important consideration because certain beta-blockers with ISA may be less effective than those without ISA for certain indications. Factors considered to be less important when making formulary decisions of choice of beta-blockers include the route of elimination, lipophilicity and presence of membrane stabilising activity.

UNMEDULLATED FIBERS ORIGINATING IN DORSAL ROOT GANGLIA

PubMed Central

Gasser, Herbert S.

1950-01-01

The compound action potential of the unmedullated fibers arising from dorsal root ganglia, as recorded in cat skin nerves after conduction of simultaneously initiated impulses, shows among its components a temporal dispersion corresponding to velocities between 2.3 and 0.7 M.P.S. The maximum representation of the component velocities is at about 1.2 M.P.S. On both sides of the maximum the representation falls off irregularly, in such a way that groupings in the distribution produce in the action potential a configuration in which successive features appear always in the same positions at a given conduction distance. Through this demonstration of a characteristic configuration the system of the unmedullated fibers is brought into analogy with that of the medullated fibers. The unmedullated fibers originating in the dorsal root ganglia have distinctive physiological properties, among which is a large positive potential which reaches its maximum immediately after the spike and decrements to half relaxation in about 50 msec., at 37°C. The positive phases of the unit potentials in the compound action potential, owing to their duration, sum to a much greater extent than the temporally dispersed spikes; and, since they have sizes such that one equivalent to 25 per cent of the spike height would not be at the limit, in the summation process the major portion of the compound action potential is caused to be written at a potential level positive to the starting base line. The position of the spikes in the sequence can be seen in the analyses in Section III. The course of the activity in unit fibers is subject to variation in ways affecting the positive potential. Preliminary descriptions, based on orienting experiments, of how these variations are conditioned are given in Section I. Two of the findings are particularly noteworthy. One is the high sensitivity of the dimensions of the postspike positivity to temperature in the range of temperatures at which skin nerves may be expected to function, even when the environmental temperatures of an animal are moderate. The other is the high sensitivity to conditioning by previous activity. The positivity is first decreased, then replaced by a negative potential of similar duration. Reasons have been given why it is inadvisable at the present time to call the postspike potential an after-potential. A comparison has been made of the properties of the unmedullated fibers arising from dorsal root ganglia with those of fibers arising from sympathetic ganglia. The differences are so great that, in the interest of precision in designation, a division of the C group of fibers into two subgroups is indicated. It is suggested that the two subgroups be named respectively d.r.C and s.C. Measurements have been made of the diameters of the d.r.C fibers in a saphenous nerve stained with silver. Graphs showing the number of fibers at each diameter are presented in Section II. In Section III there are shown constructions, from histological data, of the action potential as it would appear, after 3 cm. of conduction, with the correlation between diameter and velocity in strict linearity. The degree of fit between the constructed and recorded potentials can be seen in Fig. 18. PMID:15428610

Treatment of allergic rhinitis and urticaria: a review of the newest antihistamine drug bilastine.

PubMed

Wang, Xue Yan; Lim-Jurado, Margaret; Prepageran, Narayanan; Tantilipikorn, Pongsakorn; Wang, De Yun

2016-01-01

Allergic rhinitis and urticaria are common allergic diseases that may have a major negative impact on patients' quality of life. Bilastine, a novel new-generation antihistamine that is highly selective for the H1 histamine receptor, has a rapid onset and prolonged duration of action. This agent does not interact with the cytochrome P450 system and does not undergo significant metabolism in humans, suggesting that it has very low potential for drug-drug interactions, and does not require dose adjustment in renal impairment. As bilastine is not metabolized and is excreted largely unchanged, hepatic impairment is not expected to increase systemic exposure above the drug's safety margin. Bilastine has demonstrated similar efficacy to cetirizine and desloratadine in patients with seasonal allergic rhinitis and, in a Vienna Chamber study, a potentially longer duration of action than fexofenadine in patients with asymptomatic seasonal allergic rhinitis. It has also shown significant efficacy (similar to that of cetirizine) and safety in the long-term treatment of perennial allergic rhinitis. Bilastine showed similar efficacy to levocetirizine in patients with chronic spontaneous urticaria and can be safely used at doses of up to fourfold higher than standard dosage (80 mg once daily). The fourfold higher than standard dose is specified as an acceptable second-line treatment option for urticaria in international guidelines. Bilastine is generally well tolerated, both at standard and at supratherapeutic doses, appears to have less sedative potential than other second-generation antihistamines, and has no cardiotoxicity. Based on its pharmacokinetic properties, efficacy, and tolerability profile, bilastine will be valuable in the management of allergic rhinitis and urticaria.

Enhanced effect of VEGF165 on L-type calcium currents in guinea-pig cardiac ventricular myocytes.

PubMed

Xing, Wenlu; Gao, Chuanyu; Qi, Datun; Zhang, You; Hao, Peiyuan; Dai, Guoyou; Yan, Ganxin

2017-01-01

The mechanisms of vascular endothelial growth factor 165 (VEGF165) on electrical properties of cardiomyocytes have not been fully elucidated. The aim of this study is to test the hypothesis that VEGF165, an angiogenesis-initiating factor, affects L-type calcium currents (I Ca,L ) and cell membrane potential in cardiac myocytes by acting on VEGF type-2 receptors (VEGFR2). I Ca,L and action potentials (AP) were recorded by the whole-cell patch clamp method in isolated guinea-pig ventricular myocytes treated with different concentrations of VEGF165 proteins. Using a VEGFR2 inhibitor, we also tested the receptor of VEGF165 in cardiomyocytes. We found that VEGF165 increased I Ca,L in a concentration-dependent manner. SU5416, a VEGFR2 inhibitor, almost completely eliminated VEGF165-induced I Ca,L increase. VEGF165 had no significant influence on action potential 90 (APD90) and other properties of AP. We conclude that in guinea-pig ventricular myocytes, I Ca,L can be increased by VEGF165 in a concentration-dependent manner through binding to VEGFR2 without causing any significant alteration to action potential duration. Results of this study may further expound the safety of VEGF165 when used in the intervention of heart diseases. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Effects of Sulbutiamine on Diabetic Polyneuropathy: An Open Randomised Controlled Study in Type 2 Diabetics

PubMed Central

Kiew, K.K.; Wan Mohamad, W.B.; Ridzuan, A.; Mafauzy, M.

2002-01-01

Thirty patients with diabetic polyneuropathy were recruited from the diabetic clinic in Hospital Universiti Sains Malaysia from 1996 to 1998. They were randomly assigned either sulbutiamine (Arcalion®) (15 patients) or no treatment (control group; 15 patients). Glycaemic control was assessed by blood glucose and HbA1. Severity of neuropathy was assessed by symptom and sign score, and electrophysiological parameters (nerve conduction velocity and compound muscle action potential) at entry to the study and after 6 weeks. There were improvements in the electrophysiological parameters in the treatment group when compared to the controls with significant improvement in the median nerve conduction velocity (p<0.001), median compound muscle action potential (p<0.001), peroneal nerve conduction velocity (p<0.001), and peroneal compound muscle action potential (p<0.001). No significant improvement in symptom and sign scores were noted between the groups but a significant improvement compared to base line was noted for the sulbutiamine treated group. (p< 0.05). The glycaemic control in both groups was not significantly different at base line and was stable throughout the study. Sulbutiamine objectively improved peripheral nerve function in diabetic polyneuropathy although the symptom score did not improve, possibly due to the short duration of the study. PMID:22969314

Effects of sulbutiamine on diabetic polyneuropathy: an open randomised controlled study in type 2 diabetics.

PubMed

Kiew, K K; Wan Mohamad, W B; Ridzuan, A; Mafauzy, M

2002-01-01

Thirty patients with diabetic polyneuropathy were recruited from the diabetic clinic in Hospital Universiti Sains Malaysia from 1996 to 1998. They were randomly assigned either sulbutiamine (Arcalion(®)) (15 patients) or no treatment (control group; 15 patients). Glycaemic control was assessed by blood glucose and HbA1. Severity of neuropathy was assessed by symptom and sign score, and electrophysiological parameters (nerve conduction velocity and compound muscle action potential) at entry to the study and after 6 weeks. There were improvements in the electrophysiological parameters in the treatment group when compared to the controls with significant improvement in the median nerve conduction velocity (p<0.001), median compound muscle action potential (p<0.001), peroneal nerve conduction velocity (p<0.001), and peroneal compound muscle action potential (p<0.001). No significant improvement in symptom and sign scores were noted between the groups but a significant improvement compared to base line was noted for the sulbutiamine treated group. (p< 0.05). The glycaemic control in both groups was not significantly different at base line and was stable throughout the study. Sulbutiamine objectively improved peripheral nerve function in diabetic polyneuropathy although the symptom score did not improve, possibly due to the short duration of the study.

Motor unit recruitment and bursts of activity in the surface electromyogram during a sustained contraction.

PubMed

Riley, Zachary A; Terry, Mary E; Mendez-Villanueva, Alberto; Litsey, Jane C; Enoka, Roger M

2008-06-01

Bursts of activity in the surface electromyogram (EMG) during a sustained contraction have been interpreted as corresponding to the transient recruitment of motor units, but this association has never been confirmed. The current study compared the timing of trains of action potentials discharged by single motor units during a sustained contraction with the bursts of activity detected in the surface EMG signal. The 20 motor units from 6 subjects [recruitment threshold, 35.3 +/- 11.3% maximal voluntary contraction (MVC) force] that were detected with fine wire electrodes discharged 2-9 trains of action potentials (7.2 +/- 5.6 s in duration) when recruited during a contraction that was sustained at a force below its recruitment threshold (target force, 25.4 +/- 10.6% MVC force). High-pass filtering the bipolar surface EMG signal improved its correlation with the single motor unit signal. An algorithm applied to the surface EMG was able to detect 75% of the trains of motor unit action potentials. The results indicate that bursts of activity in the surface EMG during a constant-force contraction correspond to the transient recruitment of higher-threshold motor units in healthy individuals, and these results could assist in the diagnosis and design of treatment in individuals who demonstrate deficits in motor unit activation.

Electrophysiologic and functional evaluations of regenerated facial nerve defects with a tube containing dental pulp cells in rats.

PubMed

Sasaki, Ryo; Matsumine, Hajime; Watanabe, Yorikatsu; Takeuchi, Yuichi; Yamato, Masayuki; Okano, Teruo; Miyata, Mariko; Ando, Tomohiro

2014-11-01

Dental pulp tissue contains Schwann and neural progenitor cells. Tissue-engineered nerve conduits with dental pulp cells promote facial nerve regeneration in rats. However, no nerve functional or electrophysiologic evaluations were performed. This study investigated the compound muscle action potential recordings and facial functional analysis of dental pulp cell regenerated nerve in rats. A silicone tube containing rat dental pulp cells in type I collagen gel was transplanted into a 7-mm gap of the buccal branch of the facial nerve in Lewis rats; the same defect was created in the marginal mandibular branch, which was ligatured. Compound muscle action potential recordings of vibrissal muscles and facial functional analysis with facial palsy score of the nerve were performed. Tubulation with dental pulp cells showed significantly lower facial palsy scores than the autograft group between 3 and 10 weeks postoperatively. However, the dental pulp cell facial palsy scores showed no significant difference from those of autograft after 11 weeks. Amplitude and duration of compound muscle action potentials in the dental pulp cell group showed no significant difference from those of the intact and autograft groups, and there was no significant difference in the latency of compound muscle action potentials between the groups at 13 weeks postoperatively. However, the latency in the dental pulp cell group was prolonged more than that of the intact group. Tubulation with dental pulp cells could recover facial nerve defects functionally and electrophysiologically, and the recovery became comparable to that of nerve autografting in rats.

Vitamin K modulates cardiac action potential by blocking sodium and potassium ion channels.

PubMed

Drolet, B; Emond, A; Fortin, V; Daleau, P; Rousseau, G; Cardinal, R; Turgeon, J

2000-10-01

Cardiovascular collapses, syncopes, and sudden deaths have been observed following the rapid administration of intravenous vitamin K. Our objectives were to characterize the effects of vitamin K on cardiac action potentials and to evaluate effects of vitamin K on sodium and potassium currents, namely I(Na), I(Kr), and I(Ks). Guinea pig hearts (n = 21) were paced at a cycle length of 250 msec and exposed to vitamin K at 1.15-4.6 micromol/L (2.5-10 mg/L). Monophasic action potential duration measured at 90% repolarization (MAPD(90)) was not significantly reduced (-1.6 +/- 0.3 msec; P >.05; N.S.) at 1.15 micromol/L, but increased by 6.5 +/- 0.4 msec (P <.05) at 2.3 micromol/L. MAPD(90) was not measurable at 4.6 micromol/L, as a result of inexcitability. Patch-clamp experiments in ventricular myocytes demonstrated a approximately 50% reduction in I(Na) by 10 micromol/L vitamin K and a concentration-dependent reduction of the K(+) current elicited by short depolarizations (250 msec; I(K250)). Estimated IC(50) for I(K250), mostly representing I(Kr), was 2.3 micromol/L. Vitamin K was less potent to block the K(+) current elicited by long depolarizations (5,000 msec; I(K5000)), mostly representing I(Ks), with an estimated IC(50) over 100 micromol/L. Therapeutic concentrations ( approximately 1.5 micromol/L) of intravenous vitamin K modulate cardiac action potential by blocking ionic currents involved in cardiac depolarization and repolarization.

Computation and projection of spiral wave trajectories during atrial fibrillation: a computational study.

PubMed

Pashaei, Ali; Bayer, Jason; Meillet, Valentin; Dubois, Rémi; Vigmond, Edward

2015-03-01

To show how atrial fibrillation rotor activity on the heart surface manifests as phase on the torso, fibrillation was induced on a geometrically accurate computer model of the human atria. The Hilbert transform, time embedding, and filament detection were compared. Electrical activity on the epicardium was used to compute potentials on different surfaces from the atria to the torso. The Hilbert transform produces erroneous phase when pacing for longer than the action potential duration. The number of phase singularities, frequency content, and the dominant frequency decreased with distance from the heart, except for the convex hull. Copyright © 2015 Elsevier Inc. All rights reserved.

Investigation of Collision-Induced Fluorescence in D2:Ar and D2:HD:Ar Mixtures at 200 k,

DTIC Science & Technology

1985-07-01

a total density of 730 amagat. (One amagat is the density at STP.) Due to various practical difficulties associated with the design of a potential...any laser design . The pulse duration is required to be short compared with the vibrational lifetime, but not short enough to give problems with...laser action of the gas media investigated. 2. M EPERIMENTAL ARRANGEMENT The experimental arrangement is shown in Fig. 1. The output of the hydrogen

The Electrical Network of Maize Root Apex is Gravity Dependent

PubMed Central

Masi, Elisa; Ciszak, Marzena; Comparini, Diego; Monetti, Emanuela; Pandolfi, Camilla; Azzarello, Elisa; Mugnai, Sergio; Baluška, Frantisek; Mancuso, Stefano

2015-01-01

Investigations carried out on maize roots under microgravity and hypergravity revealed that gravity conditions have strong effects on the network of plant electrical activity. Both the duration of action potentials (APs) and their propagation velocities were significantly affected by gravity. Similarly to what was reported for animals, increased gravity forces speed-up APs and enhance synchronized electrical events also in plants. The root apex transition zone emerges as the most active, as well as the most sensitive, root region in this respect. PMID:25588706

The electrical network of maize root apex is gravity dependent.

PubMed

Masi, Elisa; Ciszak, Marzena; Comparini, Diego; Monetti, Emanuela; Pandolfi, Camilla; Azzarello, Elisa; Mugnai, Sergio; Baluška, Frantisek; Mancuso, Stefano

2015-01-15

Investigations carried out on maize roots under microgravity and hypergravity revealed that gravity conditions have strong effects on the network of plant electrical activity. Both the duration of action potentials (APs) and their propagation velocities were significantly affected by gravity. Similarly to what was reported for animals, increased gravity forces speed-up APs and enhance synchronized electrical events also in plants. The root apex transition zone emerges as the most active, as well as the most sensitive, root region in this respect.

High level of oxygen treatment causes cardiotoxicity with arrhythmias and redox modulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chapalamadugu, Kalyan C.; Panguluri, Siva K.; Bennett, Eric S.

2015-01-01

Hyperoxia exposure in mice leads to cardiac hypertrophy and voltage-gated potassium (Kv) channel remodeling. Because redox balance of pyridine nucleotides affects Kv function and hyperoxia alters cellular redox potential, we hypothesized that hyperoxia exposure leads to cardiac ion channel disturbances and redox changes resulting in arrhythmias. In the present study, we investigated the electrical changes and redox abnormalities caused by 72 h hyperoxia treatment in mice. Cardiac repolarization changes were assessed by acquiring electrocardiogram (ECG) and cardiac action potentials (AP). Biochemical assays were employed to identify the pyridine nucleotide changes, Kv1.5 expression and myocardial injury. Hyperoxia treatment caused marked bradycardia,more » arrhythmia and significantly prolonged (ms) the, RR (186.2 ± 10.7 vs. 146.4 ± 6.2), PR (46.8 ± 3.1 vs. 39.3 ± 1.6), QRS (10.8 ± 0.6 vs. 8.5 ± 0.2), QTc (57.1 ± 3.5 vs. 40 ± 1.4) and JT (13.4 ± 2.1 vs. 7.0 ± 0.5) intervals, when compared with normoxia group. Hyperoxia treatment also induced significant increase in cardiac action potential duration (APD) (ex-APD{sub 90}; 73.8 ± 9.5 vs. 50.9 ± 3.1 ms) and elevated levels of serum markers of myocardial injury; cardiac troponin I (TnI) and lactate dehydrogenase (LDH). Hyperoxia exposure altered cardiac levels of mRNA/protein expression of; Kv1.5, Kvβ subunits and SiRT1, and increased ratios of reduced pyridine nucleotides (NADH/NAD and NADPH/NADP). Inhibition of SiRT1 in H9C2 cells using Splitomicin resulted in decreased SiRT1 and Kv1.5 expression, suggesting that SiRT1 may mediate Kv1.5 downregulation. In conclusion, the cardiotoxic effects of hyperoxia exposure involve ion channel disturbances and redox changes resulting in arrhythmias. - Highlights: • Hyperoxia treatment leads to arrhythmia with prolonged QTc and action potential duration. • Hyperoxia treatment alters cardiac pyridine nucleotide [NAD(P)H/NAD(P)] levels. • SiRT1 and Kv1.5 are co-regulated in hyperoxic heart injury. • Hyperoxia may lead to cardiotoxicity.« less

Differential calcium sensitivity in NaV 1.5 mixed syndrome mutants.

PubMed

Abdelsayed, Mena; Baruteau, Alban-Elouen; Gibbs, Karen; Sanatani, Shubhayan; Krahn, Andrew D; Probst, Vincent; Ruben, Peter C

2017-09-15

SCN5a mutations may express gain-of-function (Long QT Syndrome-3), loss-of-function (Brugada Syndrome 1) or both (mixed syndromes), depending on the mutation and environmental triggers. One such trigger may be an increase in cytosolic calcium, accompanying exercise. Many mixed syndromes mutants, including ∆KPQ, E1784K, 1795insD and Q1909R, are found in calcium-sensitive regions. Elevated cytosolic calcium attenuates gain-of-function properties in ∆KPQ, 1795insD and Q1909R, but not in E1784K. By contrast, elevated cytosolic calcium further exacerbates gain-of-function in E1784K by destabilizing slow inactivation. Action potential modelling, using a modified O'Hara Rudy model, suggests that elevated heart rate rescues action potential duration in ∆KPQ, 1795insD and Q1909R, but not in E1784K. Action potential simulations suggest that E1784K carriers have an increased intracellular sodium-to-calcium ratio under bradycardia and tachycardia conditions. Elevated cytosolic calcium, which is common during high heart rates, ameliorates or exacerbates the mixed syndrome phenotype depending on the genetic signature. Inherited arrhythmias may arise from mutations in the gene for SCN5a, which encodes the cardiac voltage-gated sodium channel, Na V 1.5. Mutants in Na V 1.5 result in Brugada Syndrome (BrS1), Long-QT Syndrome (LQT3) or mixed syndromes (an overlap of BrS1/LQT3). Exercise is a potential arrhythmogenic trigger in mixed syndromes. We aimed to determine the effects of elevated cytosolic calcium, which is common during exercise, in mixed syndrome Na V 1.5 mutants. We used whole-cell patch clamp to assess the biophysical properties of Na V 1.5 wild-type (WT), ∆KPQ, E1784K, 1795insD and Q1909R mutants in human embryonic kidney 293 cells transiently transfected with the Na V 1.5 α subunit (WT or mutants), β1 subunit and enhanced green fluorescent protein. Voltage-dependence and kinetics were measured at cytosolic calcium levels of approximately 0, 500 and 2500 nm. In silico, action potential (AP) model simulations were performed using a modified O'Hara Rudy model. Elevated cytosolic calcium attenuates the late sodium current in ∆KPQ, 1795insD and Q1909R, but not in E1784K. Elevated cytosolic calcium restores steady-state slow inactivation (SSSI) to the WT-form in Q1909R, but depolarized SSSI in E1784K. Our AP simulations showed a frequency-dependent reduction of AP duration in ∆KPQ, 1795insD and Q1909R carriers. In E1784K, AP duration is relatively prolonged at both low and high heart rates, resulting in a sodium overload. Cellular perturbations during exercise may affect BrS1/LQT3 patients differently depending on their individual genetic signature. Thus, exercise may be therapeutic or may be an arrhythmogenic trigger in some SCN5a patients. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Do nitrates differ?

PubMed Central

Fung, H.-L.

1992-01-01

1 The organic nitrates all share a common biochemical and physiological mechanism of action. 2 The organic nitrates differ substantially in their pharmacologic potency and pharmacokinetics. In vitro potency differences appear larger than the corresponding in vivo activities. 3 The duration of action of organic nitrates, after a single immediate-release dose, is governed by the pharmacokinetics of the drug. However, the duration of action of available sustained-release preparations, whatever the nitrate or formulation, is limited to about 12 h, due to the development of pharmacologic tolerance. 4 Nitrates do not appear to differ in their production of undesirable effects. PMID:1633079

Can we use digital life-log images to investigate active and sedentary travel behaviour? Results from a pilot study

PubMed Central

2011-01-01

Background Active travel such as walking and cycling has potential to increase physical activity levels in sedentary individuals. Motorised car travel is a sedentary behaviour that contributes to carbon emissions. There have been recent calls for technology that will improve our ability to measure these travel behaviours, and in particular evaluate modes and volumes of active versus sedentary travel. The purpose of this pilot study is to investigate the potential efficacy of a new electronic measurement device, a wearable digital camera called SenseCam, in travel research. Methods Participants (n = 20) were required to wear the SenseCam device for one full day of travel. The device automatically records approximately 3,600 time-stamped, first-person point-of-view images per day, without any action required by the wearer. Participants also completed a self-report travel diary over the same period for comparison, and were interviewed afterwards to assess user burden and experience. Results There were a total of 105 confirmed journeys in this pilot. The new SenseCam device recorded more journeys than the travel diary (99 vs. 94). Although the two measures demonstrated an acceptable correlation for journey duration (r = 0.92, p < 0.001) self-reported journey duration was over-reported (mean difference 154 s per journey; 95% CI = 89 to 218 s; 95% limits of agreement = 154 ± 598 s (-444 to 752 s)). The device also provided visual data that was used for directed interviews about sources of error. Conclusions Direct observation of travel behaviour from time-stamped images shows considerable potential in the field of travel research. Journey duration derived from direct observation of travel behaviour from time-stamped images appears to suggest over-reporting of self-reported journey duration. PMID:21599935

Can we use digital life-log images to investigate active and sedentary travel behaviour? Results from a pilot study.

PubMed

Kelly, Paul; Doherty, Aiden; Berry, Emma; Hodges, Steve; Batterham, Alan M; Foster, Charlie

2011-05-20

Active travel such as walking and cycling has potential to increase physical activity levels in sedentary individuals. Motorised car travel is a sedentary behaviour that contributes to carbon emissions. There have been recent calls for technology that will improve our ability to measure these travel behaviours, and in particular evaluate modes and volumes of active versus sedentary travel. The purpose of this pilot study is to investigate the potential efficacy of a new electronic measurement device, a wearable digital camera called SenseCam, in travel research. Participants (n = 20) were required to wear the SenseCam device for one full day of travel. The device automatically records approximately 3,600 time-stamped, first-person point-of-view images per day, without any action required by the wearer. Participants also completed a self-report travel diary over the same period for comparison, and were interviewed afterwards to assess user burden and experience. There were a total of 105 confirmed journeys in this pilot. The new SenseCam device recorded more journeys than the travel diary (99 vs. 94). Although the two measures demonstrated an acceptable correlation for journey duration (r = 0.92, p < 0.001) self-reported journey duration was over-reported (mean difference 154 s per journey; 95% CI = 89 to 218 s; 95% limits of agreement = 154 ± 598 s (-444 to 752 s)). The device also provided visual data that was used for directed interviews about sources of error. Direct observation of travel behaviour from time-stamped images shows considerable potential in the field of travel research. Journey duration derived from direct observation of travel behaviour from time-stamped images appears to suggest over-reporting of self-reported journey duration.

Action potential-based MEA platform for in vitro screening of drug-induced cardiotoxicity using human iPSCs and rat neonatal myocytes.

PubMed

Jans, Danny; Callewaert, Geert; Krylychkina, Olga; Hoffman, Luis; Gullo, Francesco; Prodanov, Dimiter; Braeken, Dries

2017-09-01

Drug-induced cardiotoxicity poses a negative impact on public health and drug development. Cardiac safety pharmacology issues urged for the preclinical assessment of drug-induced ventricular arrhythmia leading to the design of several in vitro electrophysiological screening assays. In general, patch clamp systems allow for intracellular recordings, while multi-electrode array (MEA) technology detect extracellular activity. Here, we demonstrate a complementary metal oxide semiconductor (CMOS)-based MEA system as a reliable platform for non-invasive, long-term intracellular recording of cardiac action potentials at high resolution. Quinidine (8 concentrations from 10 -7 to 2.10 -5 M) and verapamil (7 concentrations from 10 -11 to 10 -5 M) were tested for dose-dependent responses in a network of cardiomyocytes. Electrophysiological parameters, such as the action potential duration (APD), rates of depolarization and repolarization and beating frequency were assessed. In hiPSC, quinidine prolonged APD with EC 50 of 2.2·10 -6 M. Further analysis indicated a multifactorial action potential prolongation by quinidine: (1) decreasing fast repolarization with IC 50 of 1.1·10 -6 M; (2) reducing maximum upstroke velocity with IC 50 of 2.6·10 -6 M; and (3) suppressing spontaneous activity with EC 50 of 3.8·10 -6 M. In rat neonatal cardiomyocytes, verapamil blocked spontaneous activity with EC 50 of 5.3·10 -8 M and prolonged the APD with EC 50 of 2.5·10 -8 M. Verapamil reduced rates of fast depolarization and repolarization with IC 50 s of 1.8 and 2.2·10 -7 M, respectively. In conclusion, the proposed action potential-based MEA platform offers high quality and stable long-term recordings with high information content allowing to characterize multi-ion channel blocking drugs. We anticipate application of the system as a screening platform to efficiently and cost-effectively test drugs for cardiac safety. Copyright © 2017 Elsevier Inc. All rights reserved.

Prolonged intra-myocardial growth hormone administration ameliorates post-infarction electrophysiologic remodeling in rats.

PubMed

Kontonika, Marianthi; Barka, Eleonora; Roumpi, Maria; La Rocca, Vassilios; Lekkas, Panagiotis; Daskalopoulos, Evangelos P; Vilaeti, Agapi D; Baltogiannis, Giannis G; Vlahos, Antonios P; Agathopoulos, Simeon; Kolettis, Theofilos M

2017-02-01

Experimental studies indicate improved ventricular function after treatment with growth hormone (GH) post-myocardial infarction, but its effect on arrhythmogenesis is unknown. Here, we assessed the medium-term electrophysiologic remodeling after intra-myocardial GH administration in (n = 33) rats. GH was released from an alginate scaffold, injected around the ischemic myocardium after coronary ligation. Two weeks thereafter, ventricular tachyarrhythmias were induced by programmed electrical stimulation. Monophasic action potentials were recorded from the infarct border, coupled with evaluation of electrical conduction and repolarization from a multi-electrode array. The arrhythmia score was lower in GH-treated rats than in alginate-treated rats or controls. The shape and the duration of the action potential at the infarct border were preserved, and repolarization-dispersion was attenuated after GH; moreover, voltage rise was higher and activation delay was shorter. GH normalized also right ventricular parameters. Intra-myocardial GH preserved electrical conduction and repolarization-dispersion at the infarct border and decreased the incidence of induced tachyarrhythmias in rats post-ligation. The long-term antiarrhythmic potential of GH merits further study.

A Description of the Practice Pattern Characteristics of Anesthesia Care in Small, Medium and Large Teaching and Non-Teaching Medical Treatment Facilities in the Air Force

DTIC Science & Technology

1999-05-20

include Fentanyl, Propofol, Versed, Desflurane, Isoflurane, Lidocaine and Rocuronium ; others, Bupivicaine, Cisatricurium and Remifentanyl are rarely used...39 Figure 9. Use of Succinycholine by Air Force Anesthesia Providers ....................... 41 Figure 10. Use of Rocuronium by...and short duration of action, the newest of which is Rocuronium . Although Rocuronium approaches Succinycholine in quick onset its duration of action

Dendritic mechanisms underlying the coupling of the dendritic with the axonal action potential initiation zone of adult rat layer 5 pyramidal neurons

PubMed Central

Larkum, M E; Zhu, J J; Sakmann, B

2001-01-01

Double, triple and quadruple whole-cell voltage recordings were made simultaneously from different parts of the apical dendritic arbor and the soma of adult layer 5 (L5) pyramidal neurons. We investigated the membrane mechanisms that support the conduction of dendritic action potentials (APs) between the dendritic and axonal AP initiation zones and their influence on the subsequent AP pattern. The duration of the current injection to the distal dendritic initiation zone controlled the degree of coupling with the axonal initiation zone and the AP pattern. Two components of the distally evoked regenerative potential were pharmacologically distinguished: a rapidly rising peak potential that was TTX sensitive and a slowly rising plateau-like potential that was Cd2+ and Ni2+ sensitive and present only with longer-duration current injection. The amplitude of the faster forward-propagating Na+-dependent component and the amplitude of the back-propagating AP fell into two classes (more distinctly in the forward-propagating case). Current injection into the dendrite altered propagation in both directions. Somatic current injections that elicited single Na+ APs evoked bursts of Na+ APs when current was injected simultaneously into the proximal apical dendrite. The mechanism did not depend on dendritic Na+–Ca2+ APs. A three-compartment model of a L5 pyramidal neuron is proposed. It comprises the distal dendritic and axonal AP initiation zones and the proximal apical dendrite. Each compartment contributes to the initiation and to the pattern of AP discharge in a distinct manner. Input to the three main dendritic arbors (tuft dendrites, apical oblique dendrites and basal dendrites) has a dominant influence on only one of these compartments. Thus, the AP pattern of L5 pyramids reflects the laminar distribution of synaptic activity in a cortical column. PMID:11389204

Effects of Na(+) and K(+) channel blockade on vulnerability to and termination of fibrillation in simulated normal cardiac tissue.

PubMed

Qu, Zhilin; Weiss, James N

2005-10-01

Na(+) and K(+) channel-blocking drugs have anti- and proarrhythmic effects. Their effects during fibrillation, however, remain poorly understood. We used computer simulation of a two-dimensional (2-D) structurally normal tissue model with phase I of the Luo-Rudy action potential model to study the effects of Na(+) and K(+) channel blockade on vulnerability to and termination of reentry in simulated multiple-wavelet and mother rotor fibrillation. Our main findings are as follows: 1) Na(+) channel blockade decreased, whereas K(+) channel blockade increased, the vulnerable window of reentry in heterogeneous 2-D tissue because of opposing effects on dynamical wave instability. 2) Na(+) channel blockade increased the cycle length of reentry more than it increased refractoriness. In multiple-wavelet fibrillation, Na(+) channel blockade first increased and then decreased the average duration or transient time () of fibrillation. In mother rotor fibrillation, Na(+) channel blockade caused peripheral fibrillatory conduction block to resolve and the mother rotor to drift, leading to self-termination or sustained tachycardia. 3) K(+) channel blockade increased dynamical instability by steepening action potential duration restitution. In multiple-wavelet fibrillation, this effect shortened because of enhanced wave instability. In mother rotor fibrillation, this effect converted mother rotor fibrillation to multiple-wavelet fibrillation, which then could self-terminate. Our findings help illuminate, from a theoretical perspective, the possible underlying mechanisms of termination of different types of fibrillation by antiarrhythmic drugs.

Effects of temperature and calcium availability on ventricular myocardium from rainbow trout.

PubMed

Coyne, M D; Kim, C S; Cameron, J S; Gwathmey, J K

2000-06-01

We studied the mechanical and electrophysiological properties of ventricular myocardium from rainbow trout (Oncorhynchus mykiss) in vitro at 4, 10, and 18 degrees C from fish acclimated at 10 degrees C. Temperature alone did not significantly alter the contractile force of the myocardium, but the time to peak tension and time to 80% relaxation were prolonged at 4 degrees C and shortened at 18 degrees C. The duration of the action potential was also prolonged at 4 degrees C and progressively shortened at higher temperatures. An alteration of the stimulation frequency did not affect contraction amplitude at any temperature. Calcium influx via L-type calcium channels was increased by raising extracellular calcium concentration (¿Ca(2+)(o)) or including Bay K 8644 (Bay K) and isoproterenol in the bathing medium. These treatments significantly enhanced the contractile force at all temperatures. Calcium channel blockers had a reverse-negative inotropic effect. Unexpectedly, the duration of the action potential at 10 degrees C was shortened as ¿Ca(2+)(o) increased. However, Bay K prolonged the plateau phase at 4 degrees C. Caffeine, which promotes the release of sarcoplasmic reticulum (SR) calcium, increased contractile force eightfold at all three temperatures, but the SR blocker ryanodine was only inhibitory at 4 degrees C. Our results suggest that contractile force in ventricular myocardium from Oncorhynchus mykiss is primarily regulated by sarcolemmal calcium influx and that ventricular contractility is maintained during exposure to a wide range of temperatures.

Effect of clebopride, antidopaminergic gastrointestinal prokinetics, on cardiac repolarization.

PubMed

Kim, Ki-Suk; Shin, Won-Ho; Park, Sang-joon; Kim, Eun-Joo

2007-01-01

The inhibition of the potassium current I(Kr) and QT prolongation has been known to be associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. In this study, the authors investigated the cardiac electrophysiological effects of clebopride, a class of antidopaminergic gastrointestinal prokinetic, that has been reported to prolong the QT interval by using the conventional microelectrode recording techniques in isolated rabbit Purkinje fiber and whole-cell patch clamp techniques in human ether-à-go-go-related gene (hERG)-stably transfected Chinese hamster ovarian (CHO) cells. Clebopride at 10 microM significantly decreased the Vmax of phase 0 depolarization (p < .05) and significantly prolonged the action potential duration at 90% repolarization (APD90) (p < .01), whereas the action potential duration at 50% repolarization (APD50) was not prolonged. For hERG potassium channel currents, the IC50 value was 0.62 +/- 0.30 microM. Clebopride was found to have no effect on sodium channel currents. When these results were compared with Cmax (1.02 nM) of clinical dosage (1 mg, [p.o.]), it can be suggested that clebopride is safe at the clinical dosage of 1 mg from the electrophysiological aspect. These findings indicate that clebopride, an antidopaminergic gastrointestinal prokinetic drug, may provide a sufficient "safety factor" in terms of the electrophysiological threshold concentration. But, in a supratherapeutic concentration that might possibly be encountered during overdose or impaired metabolism, clebopride may have torsadogenic potency.

Two-Term Asymptotic Approximation of a Cardiac Restitution Curve*

PubMed Central

Cain, John W.; Schaeffer, David G.

2007-01-01

If spatial extent is neglected, ionic models of cardiac cells consist of systems of ordinary differential equations (ODEs) which have the property of excitability, i.e., a brief stimulus produces a prolonged evolution (called an action potential in the cardiac context) before the eventual return to equilibrium. Under repeated stimulation, or pacing, cardiac tissue exhibits electrical restitution: the steady-state action potential duration (APD) at a given pacing period B shortens as B is decreased. Independent of ionic models, restitution is often modeled phenomenologically by a one-dimensional mapping of the form APDnext = f(B – APDprevious). Under some circumstances, a restitution function f can be derived as an asymptotic approximation to the behavior of an ionic model. In this paper, extending previous work, we derive the next term in such an asymptotic approximation for a particular ionic model consisting of two ODEs. The two-term approximation exhibits excellent quantitative agreement with the actual restitution curve, whereas the leading-order approximation significantly underestimates actual APD values. PMID:18080006

Early assessment of proarrhythmic risk of drugs using the in vitro data and single-cell-based in silico models: proof of concept.

PubMed

Abbasi, Mitra; Small, Ben G; Patel, Nikunjkumar; Jamei, Masoud; Polak, Sebastian

2017-02-01

To determine the predictive performance of in silico models using drug-specific preclinical cardiac electrophysiology data to investigate drug-induced arrhythmia risk (e.g. Torsade de pointes (TdP)) in virtual human subjects. To assess drug proarrhythmic risk, we used a set of in vitro electrophysiological measurements describing ion channel inhibition triggered by the investigated drugs. The Cardiac Safety Simulator version 2.0 (CSS; Simcyp, Sheffield, UK) platform was used to simulate human left ventricular cardiac myocyte action potential models. This study shows the impact of drug concentration changes on particular ionic currents by using available experimental data. The simulation results display safety threshold according to drug concentration threshold and log (threshold concentration/ effective therapeutic plasma concentration (ETPC)). We reproduced the underlying biophysical characteristics of cardiac cells resulted in effects of drugs associated with cardiac arrhythmias (action potential duration (APD) and QT prolongation and TdP) which were observed in published 3D simulations, yet with much less computational burden.

Processing and analysis of cardiac optical mapping data obtained with potentiometric dyes

PubMed Central

Laughner, Jacob I.; Ng, Fu Siong; Sulkin, Matthew S.; Arthur, R. Martin

2012-01-01

Optical mapping has become an increasingly important tool to study cardiac electrophysiology in the past 20 years. Multiple methods are used to process and analyze cardiac optical mapping data, and no consensus currently exists regarding the optimum methods. The specific methods chosen to process optical mapping data are important because inappropriate data processing can affect the content of the data and thus alter the conclusions of the studies. Details of the different steps in processing optical imaging data, including image segmentation, spatial filtering, temporal filtering, and baseline drift removal, are provided in this review. We also provide descriptions of the common analyses performed on data obtained from cardiac optical imaging, including activation mapping, action potential duration mapping, repolarization mapping, conduction velocity measurements, and optical action potential upstroke analysis. Optical mapping is often used to study complex arrhythmias, and we also discuss dominant frequency analysis and phase mapping techniques used for the analysis of cardiac fibrillation. PMID:22821993

Scroll wave dynamics in a three-dimensional cardiac tissue model: roles of restitution, thickness, and fiber rotation.

PubMed Central

Qu, Z; Kil, J; Xie, F; Garfinkel, A; Weiss, J N

2000-01-01

Scroll wave (vortex) breakup is hypothesized to underlie ventricular fibrillation, the leading cause of sudden cardiac death. We simulated scroll wave behaviors in a three-dimensional cardiac tissue model, using phase I of the Luo-Rudy (LR1) action potential model. The effects of action potential duration (APD) restitution, tissue thickness, filament twist, and fiber rotation were studied. We found that APD restitution is the major determinant of scroll wave behavior and that instabilities arising from APD restitution are the main determinants of scroll wave breakup in this cardiac model. We did not see a "thickness-induced instability" in the LR1 model, but a minimum thickness is required for scroll breakup in the presence of fiber rotation. The major effect of fiber rotation is to maintain twist in a scroll wave, promoting filament bending and thus scroll breakup. In addition, fiber rotation induces curvature in the scroll wave, which weakens conduction and further facilitates wave break. PMID:10827961

Comparison of the effect of rocuronium dosing based on corrected or lean body weight on rapid sequence induction and neuromuscular blockade duration in obese female patients

PubMed Central

Sakızcı-Uyar, Bahar; Çelik, Şeref; Postacı, Aysun; Bayraktar, Yeşim; Dikmen, Bayazit; Özkoçak-Turan, Işıl; Saçan, Özlem

2016-01-01

Objectives: To compare onset time, duration of action, and tracheal intubation conditions in obese patients when the intubation dose of rocuronium was based on corrected body weight (CBW) versus lean body weight (LBW) for rapid sequence induction. Methods: This prospective study was carried out at Numune Education and Research Hospital, Ankara, Turkey between August 2013 and May 2014. Forty female obese patients scheduled for laparoscopic surgery under general anesthesia were randomized into 2 groups. Group CBW (n=20) received 1.2 mg/kg rocuronium based on CBW, and group LBW (n=20) received 1.2 mg/kg rocuronium based on LBW. Endotracheal intubation was performed 60 seconds after injection of muscle relaxant, and intubating conditions were evaluated. Neuromuscular transmission was monitored using acceleromyography of the adductor pollicis. Onset time, defined as time to depression of the twitch tension to 95% of its control value, and duration of action, defined as time to achieve one response to train-of-four stimulation (T1) were recorded. Results: No significant differences were observed between the groups in intubation conditions or onset time (50-60 seconds median, 30-30 interquartile range [IQR]). Duration of action was significantly longer in the CBW group (60 minutes median, 12 IQR) than the LBW group (35 minutes median, 16 IQR; p<0.01). Conclusion: In obese patients, dosing of 1.2 mg/kg rocuronium based on LBW provides excellent or good tracheal intubating conditions within 60 seconds after administration and does not lead to prolonged duration of action. PMID:26739976

Breastfeeding: what changed after a decade? 1

PubMed Central

Toryiama, Áurea Tamami Minagawa; Fujimori, Elizabeth; Palombo, Claudia Nery Teixeira; Duarte, Luciane Simões; Borges, Ana Luiza Vilela; Chofakian, Christiane Borges do Nascimento

2017-01-01

ABSTRACT Objective: to analyze the changes in prevalence, median duration and correlates of breastfeeding in a small city in São Paulo state, Brazil. Method: analysis of two cross-sectional studies, conducted at intervals of one decade, with 261 and 302 children younger than two years, respectively. We used Kaplan-Meier survival analysis for calculation of the median duration of breastfeeding, and Cox regression for correlates analysis, with significance level of 5%. Results: an increase of 33.4% in the prevalence of exclusive breastfeeding and 20.9% in breastfeeding was identified. Regarding the latter, the median duration increased from 7.2 to 12 months. In the most recent study, the median duration was lower in first-born children who used pacifiers, and it was not associated with breastfeeding incentive actions. Conclusions: advances in the prevalence and duration of breastfeeding were observed during the 10 year-period, however, pacifier use still remains associated to a shorter median duration of breastfeeding. Our findings contribute to highlighting the need for intensification of nursing actions in the promotion of breastfeeding, and discouragement regarding the use of pacifiers. PMID:29091126

Breastfeeding: what changed after a decade?1.

PubMed

Toryiama, Áurea Tamami Minagawa; Fujimori, Elizabeth; Palombo, Claudia Nery Teixeira; Duarte, Luciane Simões; Borges, Ana Luiza Vilela; Chofakian, Christiane Borges do Nascimento

2017-10-30

to analyze the changes in prevalence, median duration and correlates of breastfeeding in a small city in São Paulo state, Brazil. analysis of two cross-sectional studies, conducted at intervals of one decade, with 261 and 302 children younger than two years, respectively. We used Kaplan-Meier survival analysis for calculation of the median duration of breastfeeding, and Cox regression for correlates analysis, with significance level of 5%. an increase of 33.4% in the prevalence of exclusive breastfeeding and 20.9% in breastfeeding was identified. Regarding the latter, the median duration increased from 7.2 to 12 months. In the most recent study, the median duration was lower in first-born children who used pacifiers, and it was not associated with breastfeeding incentive actions. advances in the prevalence and duration of breastfeeding were observed during the 10 year-period, however, pacifier use still remains associated to a shorter median duration of breastfeeding. Our findings contribute to highlighting the need for intensification of nursing actions in the promotion of breastfeeding, and discouragement regarding the use of pacifiers.

Adverse remodeling of the electrophysiological response to ischemia-reperfusion in human heart failure is associated with remodeling of metabolic gene expression.

PubMed

Ng, Fu Siong; Holzem, Katherine M; Koppel, Aaron C; Janks, Deborah; Gordon, Fabiana; Wit, Andrew L; Peters, Nicholas S; Efimov, Igor R

2014-10-01

Ventricular arrhythmias occur more frequently in heart failure during episodes of ischemia-reperfusion although the mechanisms underlying this in humans are unclear. We assessed, in explanted human hearts, the remodeled electrophysiological response to acute ischemia-reperfusion in heart failure and its potential causes, including the remodeling of metabolic gene expression. We optically mapped coronary-perfused left ventricular wedge preparations from 6 human end-stage failing hearts (F) and 6 donor hearts rejected for transplantation (D). Preparations were subjected to 30 minutes of global ischemia, followed by 30 minutes of reperfusion. Failing hearts had exaggerated electrophysiological responses to ischemia-reperfusion, with greater action potential duration shortening (P<0.001 at 8-minute ischemia; P=0.001 at 12-minute ischemia) and greater conduction slowing during ischemia, delayed recovery of electric excitability after reperfusion (F, 4.8±1.8 versus D, 1.0±0 minutes; P<0.05), and incomplete restoration of action potential duration and conduction velocity early after reperfusion. Expression of 46 metabolic genes was probed using custom-designed TaqMan arrays, using extracted RNA from 15 failing and 9 donor hearts. Ten genes important in cardiac metabolism were downregulated in heart failure, with SLC27A4 and KCNJ11 significantly downregulated at a false discovery rate of 0%. We demonstrate, for the first time in human hearts, that the electrophysiological response to ischemia-reperfusion in heart failure is accelerated during ischemia with slower recovery after reperfusion. This can enhance spatial conduction and repolarization gradients across the ischemic border and increase arrhythmia susceptibility. This adverse response was associated with downregulation of expression of cardiac metabolic genes. © 2014 American Heart Association, Inc.

High LET radiation shows no major cellular and functional effects on primary cardiomyocytes in vitro

NASA Astrophysics Data System (ADS)

Heselich, Anja; Frieß, Johannes L.; Ritter, Sylvia; Benz, Naja P.; Layer, Paul G.; Thielemann, Christiane

2018-02-01

It is well known that ionizing radiation causes adverse effects on various mammalian tissues. However, there is little information on the biological effects of heavy ion radiation on the heart. In order to fill this gap, we systematically examined DNA-damage induction and repair, as well as proliferation and apoptosis in avian cardiomyocyte cultures irradiated with heavy ions such as titanium and iron, relevant for manned space-flight, and carbon ions, as used for radiotherapy. Further, and to our knowledge for the first time, we analyzed the effect of heavy ion radiation on the electrophysiology of primary cardiomyocytes derived from chicken embryos using the non-invasive microelectrode array (MEA) technology. As electrophysiological endpoints beat rate and field action potential duration were analyzed. The cultures clearly exhibited the capacity to repair induced DNA damage almost completely within 24 h, even at doses of 7 Gy, and almost completely recovered from radiation-induced changes in proliferative behavior. Interestingly, no significant effects on apoptosis could be detected. Especially the functionality of primary cardiac cells exhibited a surprisingly high robustness against heavy ion radiation, even at doses of up to 7 Gy. In contrast to our previous study with X-rays the beat rate remained more or less unaffected after heavy ion radiation, independently of beam quality. The only change we could observe was an increase of the field action potential duration of up to 30% after titanium irradiation, diminishing within the following three days. This potentially pathological observation may be an indication that heavy ion irradiation at high doses could bear a long-term risk for cardiovascular disease induction.

Treatment of allergic rhinitis and urticaria: a review of the newest antihistamine drug bilastine

PubMed Central

Wang, Xue Yan; Lim-Jurado, Margaret; Prepageran, Narayanan; Tantilipikorn, Pongsakorn; Wang, De Yun

2016-01-01

Allergic rhinitis and urticaria are common allergic diseases that may have a major negative impact on patients’ quality of life. Bilastine, a novel new-generation antihistamine that is highly selective for the H1 histamine receptor, has a rapid onset and prolonged duration of action. This agent does not interact with the cytochrome P450 system and does not undergo significant metabolism in humans, suggesting that it has very low potential for drug–drug interactions, and does not require dose adjustment in renal impairment. As bilastine is not metabolized and is excreted largely unchanged, hepatic impairment is not expected to increase systemic exposure above the drug’s safety margin. Bilastine has demonstrated similar efficacy to cetirizine and desloratadine in patients with seasonal allergic rhinitis and, in a Vienna Chamber study, a potentially longer duration of action than fexofenadine in patients with asymptomatic seasonal allergic rhinitis. It has also shown significant efficacy (similar to that of cetirizine) and safety in the long-term treatment of perennial allergic rhinitis. Bilastine showed similar efficacy to levocetirizine in patients with chronic spontaneous urticaria and can be safely used at doses of up to fourfold higher than standard dosage (80 mg once daily). The fourfold higher than standard dose is specified as an acceptable second-line treatment option for urticaria in international guidelines. Bilastine is generally well tolerated, both at standard and at supratherapeutic doses, appears to have less sedative potential than other second-generation antihistamines, and has no cardiotoxicity. Based on its pharmacokinetic properties, efficacy, and tolerability profile, bilastine will be valuable in the management of allergic rhinitis and urticaria. PMID:27110120

Computational Modeling Reveals Key Contributions of KCNQ and hERG Currents to the Malleability of Uterine Action Potentials Underpinning Labor

PubMed Central

Tong, Wing-Chiu; Tribe, Rachel M.; Smith, Roger; Taggart, Michael J.

2014-01-01

The electrical excitability of uterine smooth muscle cells is a key determinant of the contraction of the organ during labor and is manifested by spontaneous, periodic action potentials (APs). Near the end of term, APs vary in shape and size reflecting an ability to change the frequency, duration and amplitude of uterine contractions. A recent mathematical model quantified several ionic features of the electrical excitability in uterine smooth muscle cells. It replicated many of the experimentally recorded uterine AP configurations but its limitations were evident when trying to simulate the long-duration bursting APs characteristic of labor. A computational parameter search suggested that delayed rectifying K+ currents could be a key model component requiring improvement to produce the longer-lasting bursting APs. Of the delayed rectifying K+ currents family it is of interest that KCNQ and hERG channels have been reported to be gestationally regulated in the uterus. These currents exhibit features similar to the broadly defined uterine I K1 of the original mathematical model. We thus formulated new quantitative descriptions for several I KCNQ and I hERG. Incorporation of these currents into the uterine cell model enabled simulations of the long-lasting bursting APs. Moreover, we used this modified model to simulate the effects of different contributions of I KCNQ and I hERG on AP form. Our findings suggest that the alterations in expression of hERG and KCNQ channels can potentially provide a mechanism for fine tuning of AP forms that lends a malleability for changing between plateau-like and long-lasting bursting-type APs as uterine cells prepare for parturition. PMID:25474527

Effects of changing the ionic environment on passive and active membrane properties of pregnant rat uterus

PubMed Central

Abe, Y.

1971-01-01

1. In pregnant rat myometrium electrotonic potentials, produced by externally applied current, were recorded intracellularly. 2. The space constant, λ, was 1·8 mm, the time constant, τm, 120 msec. The values obtained on the 7th day and on the 20th day of pregnancy were the same. 3. The magnitude of the electrotonic potential and the time constant of the membrane were increased in the absence of potassium from the external solution and decreased by excess potassium. 4. The magnitude of the electrotonic potential and the time constant of the membrane were increased by the replacement of chloride with C6H5SO3- or SO42-, and decreased with NO3- or I- replacement. 5. When the sodium chloride was replaced with sucrose (16·7 mM sodium remaining in the buffers) the spontaneous spikes deteriorated and activity stopped within 30 min. However, for periods up to 4 hr, a spike of larger amplitude and faster rate of rise than in normal solution could be evoked when a depolarizing current was applied. 6. When the external calcium concentration was raised (5 and 10 mM) the amplitude and the rate of rise of the evoked spike were increased. They were decreased by reducing calcium. In zero calcium spontaneous activity stopped within 15 min. 7. The effects of calcium deficiency were much less marked and slower in onset when, simultaneously, the sodium concentration was reduced to 16·7 mM. 8. When calcium was replaced with strontium (2·5 mM), the membrane was depolarized and the duration of the spontaneous and evoked action potential was prolonged, mainly due to a slowed rate of repolarization. When the concentration of strontium was raised to 7·5 or 12·5 mM the membrane was hyperpolarized, the duration of the action potential became short and the amplitude of the spike was increased. 9. Addition of barium or the replacement of calcium with barium caused depolarization and oscillatory membrane activity. However, a spike could be evoked by applying conditioning hyperpolarization. 10. Manganese abolished the spontaneous and evoked spike. Tetrodotoxin had no effect. 11. The results show that rat uterus has cable-like properties. The action potential may be due to calcium entry, while sodium, by influencing the membrane potential in competition with calcium, may be involved in the spontaneous spike generation and the spread of excitation. PMID:5103422

Probing the modulation of acute ethanol intoxication by pharmacological manipulation of the NMDAR glycine coagonist site

PubMed Central

Debrouse, Lauren; Hurd, Benita; Kiselycznyk, Carly; Plitt, Aaron; Todaro, Alyssa; Mishina, Masayoshi; Grant, Seth; Camp, Marguerite; Gunduz-Cinar, Ozge; Holmes, Andrew

2012-01-01

BACKGROUND Stimulating the glycineB binding site on the N-methyl-D-aspartate receptor (NMDAR) has been proposed as a novel mechanism for modulating behavioral effects of ethanol (EtOH) that are mediated via the NMDAR, including acute intoxication. Here, we pharmacologically interrogated this hypothesis in mice. METHODS Effects of systemic injection of the glycineB agonist, D-serine, the GlyT-1 glycine transporter inhibitor, ALX-5407, and the glycineB antagonist, L-701,324, were tested for effects on EtOH-induced ataxia, hypothermia, loss of righting reflex duration (LORR) in C57BL/6J (B6) and 129S1/SvImJ (S1) inbred mice. Effects of the glycineB partial agonist, D-cycloserine, the GlyT-1 inhibitor, NFPS, and the glycineB antagonist, DCKA, on EtOH-induced LORR duration were also tested. Interaction effects on EtOH-induced LORR duration were examined via combined treatment with D-serine and ALX-5407, D-serine and MK-801, D-serine and L-701,324, as well as L-701,324 and ALX-5407, in B6 mice, as D-serine in GluN2A and PSD-95 KO mice. The effect of dietary depletion of Magnesium (Mg), an element which interacts the glycineB site, was also tested. RESULTS Neither D-serine, D-cycloserine, ALX-5407, nor NFPS significantly affected EtOH intoxication on any of the measures or strains studied. L-701,324, but not DCKA, dose-dependently potentiated the ataxia-inducing effects of EtOH and increased EtOH-induced (but not pentobarbital-induced) LORR duration. D-serine did not have interactive effects on EtOH-induced LORR duration when combined with ALX-5407. The EtOH-potentiating effects of L-701,324, but not MK-801, on LORR duration were prevented by D-serine, but not ALX-5407. Mg depletion potentiated LORR duration in B6 mice and was lethal in a large proportion of S1 mice. CONCLUSIONS GlycineB site activation failed to produce the hypothesized reduction in EtOH intoxication across a range of measures and genetic strains, but blockade of the glycineB site potentiated EtOH intoxication. These data suggest endogenous activity at the glycineB opposes EtOH intoxication, but it may be difficult to pharmacologically augment this action, at least in non-dependent subjects, perhaps due to physiological saturation of the glycineB site. PMID:22934986

Action of certain tropine esters on voltage-clamped lobster axon.

PubMed

Blaustein, M P

1968-03-01

Tropine p-tolylacetate (TPTA) and its quaternary analogue, tropine p-tolylacetate methiodide (TPTA MeI) decrease the early transient (Na) and late (K) currents in the voltage-clamped lobster giant axon. These agents, which block the nerve action potential, reduce the maximum Na and K conductance increases associated with membrane depolarization. They also slow the rate at which the sodium conductance is increased and shift the (normalized) membrane conductance vs. voltage curves in the direction of depolarization along the voltage axis. All these effects are qualitatively similar to those resulting from the action of procaine on the voltage-clamped axon. One unusual effect of the tropine esters, noticeable particularly at large depolarization steps, is that they cause the late, K current to reach a peak and then fall off with increasing pulse duration. This effect has not been reported to occur as a result of procaine action. Tropine p-chlorophenyl acetate (TPClphiA), which differs from TPTA only by the substitution of a p-Cl for a p-CH(3) group on the benzene ring, had a negligible effect on axonal excitability.

Action of Certain Tropine Esters on Voltage-Clamped Lobster Axon

PubMed Central

Blaustein, M. P.

1968-01-01

Tropine p-tolylacetate (TPTA) and its quaternary analogue, tropine p-tolylacetate methiodide (TPTA MeI) decrease the early transient (Na) and late (K) currents in the voltage-clamped lobster giant axon. These agents, which block the nerve action potential, reduce the maximum Na and K conductance increases associated with membrane depolarization. They also slow the rate at which the sodium conductance is increased and shift the (normalized) membrane conductance vs. voltage curves in the direction of depolarization along the voltage axis. All these effects are qualitatively similar to those resulting from the action of procaine on the voltage-clamped axon. One unusual effect of the tropine esters, noticeable particularly at large depolarization steps, is that they cause the late, K current to reach a peak and then fall off with increasing pulse duration. This effect has not been reported to occur as a result of procaine action. Tropine p-chlorophenyl acetate (TPClφA), which differs from TPTA only by the substitution of a p-Cl for a p-CH3 group on the benzene ring, had a negligible effect on axonal excitability. PMID:5648830

Electrophysiological properties of computational human ventricular cell action potential models under acute ischemic conditions.

PubMed

Dutta, Sara; Mincholé, Ana; Quinn, T Alexander; Rodriguez, Blanca

2017-10-01

Acute myocardial ischemia is one of the main causes of sudden cardiac death. The mechanisms have been investigated primarily in experimental and computational studies using different animal species, but human studies remain scarce. In this study, we assess the ability of four human ventricular action potential models (ten Tusscher and Panfilov, 2006; Grandi et al., 2010; Carro et al., 2011; O'Hara et al., 2011) to simulate key electrophysiological consequences of acute myocardial ischemia in single cell and tissue simulations. We specifically focus on evaluating the effect of extracellular potassium concentration and activation of the ATP-sensitive inward-rectifying potassium current on action potential duration, post-repolarization refractoriness, and conduction velocity, as the most critical factors in determining reentry vulnerability during ischemia. Our results show that the Grandi and O'Hara models required modifications to reproduce expected ischemic changes, specifically modifying the intracellular potassium concentration in the Grandi model and the sodium current in the O'Hara model. With these modifications, the four human ventricular cell AP models analyzed in this study reproduce the electrophysiological alterations in repolarization, refractoriness, and conduction velocity caused by acute myocardial ischemia. However, quantitative differences are observed between the models and overall, the ten Tusscher and modified O'Hara models show closest agreement to experimental data. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

An infrared optical pacing system for screening cardiac electrophysiology in human cardiomyocytes.

PubMed

McPheeters, Matthew T; Wang, Yves T; Werdich, Andreas A; Jenkins, Michael W; Laurita, Kenneth R

2017-01-01

Human cardiac myocytes derived from pluripotent stem cells (hCM) have invigorated interest in genetic disease mechanisms and cardiac safety testing; however, the technology to fully assess electrophysiological function in an assay that is amenable to high throughput screening has lagged. We describe a fully contactless system using optical pacing with an infrared (IR) laser and multi-site high fidelity fluorescence imaging to assess multiple electrophysiological parameters from hCM monolayers in a standard 96-well plate. Simultaneous multi-site action potentials (FluoVolt) or Ca2+ transients (Fluo4-AM) were measured, from which high resolution maps of conduction velocity and action potential duration (APD) were obtained in a single well. Energy thresholds for optical pacing were determined for cell plating density, laser spot size, pulse width, and wavelength and found to be within ranges reported previously for reliable pacing. Action potentials measured using FluoVolt and a microelectrode exhibited the same morphology and rate of depolarization. Importantly, we show that this can be achieved accurately with minimal damage to hCM due to optical pacing or fluorescence excitation. Finally, using this assay we demonstrate that hCM exhibit reproducible changes in repolarization and impulse conduction velocity for Flecainide and Quinidine, two well described reference compounds. In conclusion, we demonstrate a high fidelity electrophysiological screening assay that incorporates optical pacing with IR light to control beating rate of hCM monolayers.

Differential facilitation of N- and P/Q-type calcium channels during trains of action potential-like waveforms

PubMed Central

Currie, Kevin P M; Fox, Aaron P

2002-01-01

Inhibition of presynaptic voltage-gated calcium channels by direct G-protein βγ subunit binding is a widespread mechanism that regulates neurotransmitter release. Voltage-dependent relief of this inhibition (facilitation), most likely to be due to dissociation of the G-protein from the channel, may occur during bursts of action potentials. In this paper we compare the facilitation of N- and P/Q-type Ca2+ channels during short trains of action potential-like waveforms (APWs) using both native channels in adrenal chromaffin cells and heterologously expressed channels in tsA201 cells. While both N- and P/Q-type Ca2+ channels exhibit facilitation that is dependent on the frequency of the APW train, there are important quantitative differences. Approximately 20 % of the voltage-dependent inhibition of N-type ICa was reversed during a train while greater than 40 % of the inhibition of P/Q-type ICa was relieved. Changing the duration or amplitude of the APW dramatically affected the facilitation of N-type channels but had little effect on the facilitation of P/Q-type channels. Since the ratio of N-type to P/Q-type Ca2+ channels varies widely between synapses, differential facilitation may contribute to the fine tuning of synaptic transmission, thereby increasing the computational repertoire of neurons. PMID:11882675

Sensitivity of Rabbit Ventricular Action Potential and Ca2+ Dynamics to Small Variations in Membrane Currents and Ion Diffusion Coefficients

PubMed Central

Lo, Yuan Hung; Peachey, Tom; Abramson, David; McCulloch, Andrew

2013-01-01

Little is known about how small variations in ionic currents and Ca2+ and Na+ diffusion coefficients impact action potential and Ca2+ dynamics in rabbit ventricular myocytes. We applied sensitivity analysis to quantify the sensitivity of Shannon et al. model (Biophys. J., 2004) to 5%–10% changes in currents conductance, channels distribution, and ion diffusion in rabbit ventricular cells. We found that action potential duration and Ca2+ peaks are highly sensitive to 10% increase in L-type Ca2+ current; moderately influenced by 10% increase in Na+-Ca2+ exchanger, Na+-K+ pump, rapid delayed and slow transient outward K+ currents, and Cl− background current; insensitive to 10% increases in all other ionic currents and sarcoplasmic reticulum Ca2+ fluxes. Cell electrical activity is strongly affected by 5% shift of L-type Ca2+ channels and Na+-Ca2+ exchanger in between junctional and submembrane spaces while Ca2+-activated Cl−-channel redistribution has the modest effect. Small changes in submembrane and cytosolic diffusion coefficients for Ca2+, but not in Na+ transfer, may alter notably myocyte contraction. Our studies highlight the need for more precise measurements and further extending and testing of the Shannon et al. model. Our results demonstrate usefulness of sensitivity analysis to identify specific knowledge gaps and controversies related to ventricular cell electrophysiology and Ca2+ signaling. PMID:24222910

The prevalence of early subclinical somatic neuropathy in children and adolescents with Type 1 diabetes mellitus and its association with the persistence of autoantibodies to glutamic acid decarboxylase (GAD) and islet antigen-2 (IA-2).

PubMed

Louraki, Maria; Katsalouli, Marina; Kanaka-Gantenbein, Christina; Kafassi, Nikolitsa; Critselis, Eleni; Kallinikou, Dimitra; Tsentidis, Charalampos; Karavanaki, Kyriaki

2016-07-01

To evaluate the prevalence of early somatic neuropathy in children and adolescents with Type 1 diabetes mellitus (Type 1 DM) and its association with the presence of glutamic acid decarboxylase and islet antigen-2 autoantibodies (GADA and IA-2A). A cross-sectional study was conducted in a hospital-based cohort of pediatric Type 1 DM patients (n=85, mean(±SD) age: 13.5±3.4years, mean(±SD) disease duration 5.5±3.4years). Peripheral neuropathy was assessed with nerve conduction studies (NCS). GADA and IA-2A titers were measured with radioligand assays. Among the study population, 34.1% had at least one abnormal electrophysiological parameter, although predominantly asymptomatic. The highest rates of abnormality were detected in sensory peroneal nerve (25.9%) followed by sural nerve (15.3%). Affected patients were not different in terms of age, diabetes duration or glycaemic control. Among the participants, 62.4% had positive GADA, 58.8% positive IA-2A and 42.4% double antibody positivity. Abnormal NCS correlated neither with GADA nor with IA-2A levels or positivity. However lower sensory nerve action potential in the peroneal nerve, indicative of early axonal dysfunction, was observed in patients with GADA or IA-2A positivity. Absence of both antibodies was associated with better action potentials in all the examined nerves of the lower limbs. Impaired indices of subclinical peripheral primarily sensory neuropathy were present among one third of Type 1 DM children and adolescents, with no impact of diabetes duration or glycaemic control. GADA and IA-2A seem to be involved in the development of axonal degeneration, in a pathway which remains to be identified. Copyright © 2016. Published by Elsevier Ireland Ltd.

Modeling cardiac action potential shortening driven by oxidative stress-induced mitochondrial oscillations in guinea pig cardiomyocytes.

PubMed

Zhou, Lufang; Cortassa, Sonia; Wei, An-Chi; Aon, Miguel A; Winslow, Raimond L; O'Rourke, Brian

2009-10-07

Ischemia-induced shortening of the cardiac action potential and its heterogeneous recovery upon reperfusion are thought to set the stage for reentrant arrhythmias and sudden cardiac death. We have recently reported that the collapse of mitochondrial membrane potential (DeltaPsi(m)) through a mechanism triggered by reactive oxygen species (ROS), coupled to the opening of sarcolemmal ATP-sensitive potassium (K(ATP)) channels, contributes to electrical dysfunction during ischemia-reperfusion. Here we present a computational model of excitation-contraction coupling linked to mitochondrial bioenergetics that incorporates mitochondrial ROS-induced ROS release with coupling between the mitochondrial energy state and electrical excitability mediated by the sarcolemmal K(ATP) current (I(K,ATP)). Whole-cell model simulations demonstrate that increasing the fraction of oxygen diverted from the respiratory chain to ROS production triggers limit-cycle oscillations of DeltaPsi(m), redox potential, and mitochondrial respiration through the activation of a ROS-sensitive inner membrane anion channel. The periods of transient mitochondrial uncoupling decrease the cytosolic ATP/ADP ratio and activate I(K,ATP), consequently shortening the cellular action potential duration and ultimately suppressing electrical excitability. The model simulates emergent behavior observed in cardiomyocytes subjected to metabolic stress and provides a new tool for examining how alterations in mitochondrial oxidative phosphorylation will impact the electrophysiological, contractile, and Ca(2+) handling properties of the cardiac cell. Moreover, the model is an important step toward building multiscale models that will permit investigation of the role of spatiotemporal heterogeneity of mitochondrial metabolism in the mechanisms of arrhythmogenesis and contractile dysfunction in cardiac muscle.

Action potentials in primary osteoblasts and in the MG-63 osteoblast-like cell line.

PubMed

Pangalos, Maria; Bintig, Willem; Schlingmann, Barbara; Feyerabend, Frank; Witte, Frank; Begandt, Daniela; Heisterkamp, Alexander; Ngezahayo, Anaclet

2011-06-01

Whole-cell patch-clamp analysis revealed a resting membrane potential of -60 mV in primary osteoblasts and in the MG-63 osteoblast-like cells. Depolarization-induced action potentials were characterized by duration of 60 ms, a minimal peak-to-peak distance of 180 ms, a threshold value of -20 mV and a repolarization between the spikes to -45 mV. Expressed channels were characterized by application of voltage pulses between -150 mV and 90 mV in 10 mV steps, from a holding potential of -40 mV. Voltages below -60 mV induced an inward current. Depolarizing voltages above -30 mV evoked two currents: (a) a fast activated and inactivated inward current at voltages between -30 and 30 mV, and (b) a delayed-activated outward current that was induced by voltages above -30 mV. Electrophysiological and pharmacological parameters indicated that hyperpolarization activated strongly rectifying K(+) (K(ir)) channels, whereas depolarization activated tetrodotoxin sensitive voltage gated Na(+) (Na(v)) channels as well as delayed, slowly activated, non-inactivating, and tetraethylammonium sensitive voltage gated K(+) (K(v)) channels. In addition, RT-PCR showed expression of Na(v)1.3, Na(v)1.4, Na(v)1.5, Na(v)1.6, Na(v)1.7, and K(ir)2.1, K(ir)2.3, and K(ir)2.4 as well as K(v)2.1. We conclude that osteoblasts express channels that allow firing of action potentials.

Rainfall intensity-duration thresholds for postfire debris-flow emergency-response planning

USGS Publications Warehouse

Cannon, S.H.; Boldt, E.M.; Laber, J.L.; Kean, J.W.; Staley, D.M.

2011-01-01

Following wildfires, emergency-response and public-safety agencies can be faced with evacuation and resource-deployment decisions well in advance of coming winter storms and during storms themselves. Information critical to these decisions is provided for recently burned areas in the San Gabriel Mountains of southern California. A compilation of information on the hydrologic response to winter storms from recently burned areas in southern California steeplands is used to develop a system for classifying magnitudes of hydrologic response. The four-class system describes combinations of reported volumes of individual debris flows, consequences of debris flows and floods in an urban setting, and spatial extents of the hydrologic response. The range of rainfall conditions associated with different magnitude classes is defined by integrating local rainfall data with the response magnitude information. Magnitude I events can be expected when within-storm rainfall accumulations (A) of given durations (D) fall above the threshold A = 0.4D0.5 and below A = 0.5D0.6 for durations greater than 1 h. Magnitude II events will be generated in response to rainfall accumulations and durations between A = 0.4D0.5 and A = 0.9D0.5 for durations less than 1 h, and between A = 0.5D0.6 and A = 0.9D0.5 or durations greater than 1 h. Magnitude III events can be expected in response to rainfall conditions above the threshold A = 0.9D0.5. Rainfall threshold-magnitude relations are linked with potential emergency-response actions as an emergency-response decision chart, which leads a user through steps to determine potential event magnitudes and identify possible evacuation and resource-deployment levels. Use of this information in planning and response decision-making process could result in increased safety for both the public and emergency responders. ?? 2011 US Government.

The preventive effect and duration of action of two doses of inhaled furosemide on exercise-induced asthma in children.

PubMed

Novembre, E; Frongia, G; Lombardi, E; Resti, M; Zammarchi, E; Vierucci, A

1995-12-01

Exercise-induced asthma can be prevented by treatment with inhaled furosemide. In this study we evaluated the effect and duration of action of two doses (15 and 30 mg) of inhaled furosemide in prevention of exercise-induced asthma in children. Ten children with exercise-induced asthma (8 boys and 2 girls, aged 6 to 13 years) were included in the study. Each patient was tested with three treatment regimens (placebo, 15 mg of furosemide, and 30 mg of furosemide) in random order on 3 separate days. Patients performed exercise challenges on a treadmill at 20 minutes and 1, 2, 3, and 6 hours after each treatment. Pulmonary function, urinary output, and fluid intake were monitored. Both doses of furosemide had a significantly greater protective effect than placebo, but there was no significant difference between the two doses of furosemide. The higher dose of furosemide was associated with increased urinary output and had a longer duration of action. A 30 mg dose of furosemide is more effective for treatment of exercise-induced asthma in terms of duration but has a significant diuretic effect.

Toward a More Efficient Implementation of Antifibrillation Pacing

PubMed Central

Wilson, Dan; Moehlis, Jeff

2016-01-01

We devise a methodology to determine an optimal pattern of inputs to synchronize firing patterns of cardiac cells which only requires the ability to measure action potential durations in individual cells. In numerical bidomain simulations, the resulting synchronizing inputs are shown to terminate spiral waves with a higher probability than comparable inputs that do not synchronize the cells as strongly. These results suggest that designing stimuli which promote synchronization in cardiac tissue could improve the success rate of defibrillation, and point towards novel strategies for optimizing antifibrillation pacing. PMID:27391010

Decreasing temperature shifts hippocampal function from memory formation to modulation of hibernation bout duration in Syrian hamsters.

PubMed

Arant, Ryan J; Goo, Marisa S; Gill, Phoebe D; Nguyen, Yen; Watson, Katherine D; Hamilton, Jock S; Horowitz, John M; Horwitz, Barbara A

2011-08-01

Previous studies in hibernating species have characterized two forms of neural plasticity in the hippocampus, long-term potentiation (LTP) and its reversal, depotentiation, but not de novo long-term depression (LTD), which is also associated with memory formation. Studies have also shown that histamine injected into the hippocampus prolonged hibernation bout duration. However, spillover into the ventricles may have affected brain stem regions, not the hippocampus. Here, we tested the hypothesis that decreased brain temperature shifts the major function of the hippocampus in the Syrian hamster (Mesocricetus auratus) from one of memory formation (via LTP, depotentiation, and de novo LTD) to increasing hibernation bout duration. We found reduced evoked responses in hippocampal CA1 pyramidal neurons following low-frequency stimulation in young (<30 days old) and adult (>60 days old) hamsters, indicating that de novo LTD was generated in hippocampal slices from both pups and adults at temperatures >20°C. However, at temperatures below 20°C, synchronization of neural assemblies (a requirement for LTD generation) was markedly degraded, implying that de novo LTD cannot be generated in hibernating hamsters. Nonetheless, even at temperatures below 16°C, pyramidal neurons could still generate action potentials that may traverse a neural pathway, suppressing the ascending arousal system (ARS). In addition, histamine increased the excitability of these pyramidal cells. Taken together, these findings are consistent with the hypothesis that hippocampal circuits remain operational at low brain temperatures in Syrian hamsters and suppress the ARS to prolong bout duration, even though memory formation is muted at these low temperatures.

Evolution of vocal patterns: tuning hindbrain circuits during species divergence.

PubMed

Barkan, Charlotte L; Zornik, Erik; Kelley, Darcy B

2017-03-01

The neural circuits underlying divergent courtship behaviors of closely related species provide a framework for insight into the evolution of motor patterns. In frogs, male advertisement calls serve as unique species identifiers and females prefer conspecific to heterospecific calls. Advertisement calls of three relatively recently (∼8.5 Mya) diverged species - Xenopus laevis , X. petersii and X. victorianus - include rapid trains of sound pulses (fast trills). We show that while fast trills are similar in pulse rate (∼60 pulses s -1 ) across the three species, they differ in call duration and period (time from the onset of one call to the onset of the following call). Previous studies of call production in X. laevis used an isolated brain preparation in which the laryngeal nerve produces compound action potentials that correspond to the advertisement call pattern (fictive calling). Here, we show that serotonin evokes fictive calling in X. petersii and X. victorianus as it does in X. laevis As in X. laevis , fictive fast trill in X. petersii and X. victorianus is accompanied by an N -methyl-d-aspartate receptor-dependent local field potential wave in a rostral hindbrain nucleus, DTAM. Across the three species, wave duration and period are strongly correlated with species-specific fast trill duration and period, respectively. When DTAM is isolated from the more rostral forebrain and midbrain and/or more caudal laryngeal motor nucleus, the wave persists at species-typical durations and periods. Thus, intrinsic differences within DTAM could be responsible for the evolutionary divergence of call patterns across these related species. © 2017. Published by The Company of Biologists Ltd.

A new structurally atypical bradykinin-potentiating peptide isolated from Crotalus durissus cascavella venom (South American rattlesnake).

PubMed

Lopes, Denise M; Junior, Norberto E G; Costa, Paula P C; Martins, Patrícia L; Santos, Cláudia F; Carvalho, Ellaine D F; Carvalho, Maria D F; Pimenta, Daniel C; Cardi, Bruno A; Fonteles, Manassés C; Nascimento, Nilberto R F; Carvalho, Krishnamurti M

2014-11-01

Venom glands of some snakes synthesize bradykinin-potentiating peptides (BPP's) which increase bradykinin-induced hypotensive effect and decrease angiotensin I vasopressor effect by angiotensin-converting enzyme (ACE) inhibition. The present study shows a new BPP (BPP-Cdc) isolated from Crotalus durissus cascavella venom: Pro-Asn-Leu-Pro-Asn-Tyr-Leu-Gly-Ile-Pro-Pro. Although BPP-Cdc presents the classical sequence IPP in the C-terminus, it has a completely atypical N-terminal sequence, which shows very low homology with all other BPPs isolated to date. The pharmacological effects of BPP-Cdc were compared to BBP9a from Bothrops jararaca and captopril. BPP-Cdc (1 μM) significantly increased BK-induced contractions (BK; 1 μM) on the guinea pig ileum by 267.8% and decreased angiotensin I-induced contractions (AngI; 10 nM) by 62.4% and these effects were not significantly different from those of BPP9a (1 μM) or captopril (200 nM). Experiments with 4-week hypertensive 2K-1C rats show that the vasopressor effect of AngI (10 ng) was decreased by 50 μg BPP-Cdc (69.7%), and this result was similar to that obtained with 50 μg BPP9a (69.8%). However, the action duration of BPP-Cdc (60 min) was 2 times greater than that of BPP-9a (30 min). On the other hand, the hypotensive effect of BK (250 ng) was significantly increased by 176.6% after BPP-Cdc (50 μg) administration, value 2.5 times greater than that obtained with BPP9a administered at the same doses (71.4%). In addition, the duration of the action of BPP-Cdc (120 min) was also at least 4 times greater than that of BPP-9a (30 min). Taken together, these results suggest that BPP-Cdc presents more selective action on arterial blood system than BPP9a. Besides the inhibition of ACE, it may present other mechanisms of action yet to be elucidated. Copyright © 2014 Elsevier Ltd. All rights reserved.

Fluoride’s Effects on the Formation of Teeth and Bones, and the Influence of Genetics

PubMed Central

Everett, E.T.

2011-01-01

Fluorides are present in the environment. Excessive systemic exposure to fluorides can lead to disturbances of bone homeostasis (skeletal fluorosis) and enamel development (dental/enamel fluorosis). The severity of dental fluorosis is also dependent upon fluoride dose and the timing and duration of fluoride exposure. Fluoride’s actions on bone cells predominate as anabolic effects both in vitro and in vivo. More recently, fluoride has been shown to induce osteoclastogenesis in mice. Fluorides appear to mediate their actions through the MAPK signaling pathway and can lead to changes in gene expression, cell stress, and cell death. Different strains of inbred mice demonstrate differential physiological responses to ingested fluoride. Genetic studies in mice are capable of identifying and characterizing fluoride-responsive genetic variations. Ultimately, this can lead to the identification of at-risk human populations who are susceptible to the unwanted or potentially adverse effects of fluoride action and to the elucidation of fundamental mechanisms by which fluoride affects biomineralization. PMID:20929720

Heterogeneous CPA sensitivity of spontaneous excitation in smooth muscle of the rabbit urethra.

PubMed

Hashitani, Hikaru; Yanai, Yoshimasa; Kohri, Kenjiro; Suzuki, Hikaru

2006-06-01

1. To investigate the role of intracellular Ca stores in generating spontaneous excitation of the urethra, the effects of cyclopiazonic acid (CPA) on spontaneous contractions, transient increases in intracellular calcium concentration ([Ca2+]i; Ca transients) and depolarizations were examined in smooth muscles of the rabbit urethra. 2. In about 90% of circular smooth muscle (CSM) preparations, CPA (10 microM) increased the amplitude of spontaneous contractions by about 180% and reduced their frequency to some 25% of control values (CPA-resistant), while it readily abolished the contractions in the remaining preparations. 3. In about 70% of CSM preparations, CPA prevented the generation of spontaneous depolarizations termed slow waves, but increased their amplitude and duration in the remainder. CPA also prevented the generation of spontaneous Ca transients in about 40% of CSM preparations, while increasing their amplitude and duration in the remaining preparations. In CPA-resistant preparations that had been exposed to nicardipine (1 microM), subsequent CPA invariably abolished residual spontaneous depolarizations or Ca transients. CPA abolished caffeine-induced Ca transients in Ca-free solutions, suggesting that it effectively depleted intracellular Ca stores. 4. Longitudinal smooth muscles generated spontaneous action potentials, which had a shape distinct from that of slow waves in CSM. Spontaneous action potentials were abolished by nicardipine but not CPA. 5. Transmural nerve stimulation increased the frequency of Ca transients to give a sustained rise in [Ca2+]i, but inhibited their generation after blocking alpha-adrenoceptors with phentolamine (1 microM). These nerve-evoked responses were preserved in preparations that had been exposed to CPA. Similarly, both in control and CPA-treated CSM preparations, spontaneous Ca transients were accelerated by noradrenaline (NAd, 1 microM) and were suppressed by 3-morpholino-sydnonimine (SIN-1, 10 microM), a nitric oxide (NO) donor. 6. In conclusion, CSM of the urethra generates spontaneous activity, which depends on Ca release from intracellular Ca stores. However, after blocking this primary pacemaking mechanism, L-type Ca channel-dependent action potentials may drive CSM. Irrespective of the origin of pacemaking, neurally-released NAd and NO are capable of modulating spontaneous excitation.

Motor unit recruitment in human biceps brachii during sustained voluntary contractions.

PubMed

Riley, Zachary A; Maerz, Adam H; Litsey, Jane C; Enoka, Roger M

2008-04-15

The purpose of the study was to examine the influence of the difference between the recruitment threshold of a motor unit and the target force of the sustained contraction on the discharge of the motor unit at recruitment. The discharge characteristics of 53 motor units in biceps brachii were recorded after being recruited during a sustained contraction. Some motor units (n = 22) discharged action potentials tonically after being recruited, whereas others (n = 31) discharged intermittent trains of action potentials. The two groups of motor units were distinguished by the difference between the recruitment threshold of the motor unit and the target force for the sustained contraction: tonic, 5.9 +/- 2.5%; intermittent, 10.7 +/- 2.9%. Discharge rate for the tonic units decreased progressively (13.9 +/- 2.7 to 11.7 +/- 2.6 pulses s(-1); P = 0.04) during the 99 +/- 111 s contraction. Train rate, train duration and average discharge rate for the intermittent motor units did not change across 211 +/- 153 s of intermittent discharge. The initial discharge rate at recruitment during the sustained contraction was lower for the intermittent motor units (11.0 +/- 3.3 pulses s(-1)) than the tonic motor units (13.7 +/- 3.3 pulses s(-1); P = 0.005), and the coefficient of variation for interspike interval was higher for the intermittent motor units (34.6 +/- 12.3%) than the tonic motor units (21.2 +/- 9.4%) at recruitment (P = 0.001) and remained elevated for discharge duration (34.6 +/- 9.2% versus 19.1 +/- 11.7%, P < 0.001). In an additional experiment, 12 motor units were recorded at two different target forces below recruitment threshold (5.7 +/- 1.9% and 10.5 +/- 2.4%). Each motor unit exhibited the two discharge patterns (tonic and intermittent) as observed for the 53 motor units. The results suggest that newly recruited motor units with recruitment thresholds closer to the target force experienced less synaptic noise at the time of recruitment that resulted in them discharging action potentials at more regular and greater rates than motor units with recruitment thresholds further from the target force.

Enhanced excitability of small dorsal root ganglion neurons in rats with bone cancer pain

PubMed Central

2012-01-01

Background Primary and metastatic cancers that affect bone are frequently associated with severe and intractable pain. The mechanisms underlying the development of bone cancer pain are largely unknown. The aim of this study was to determine whether enhanced excitability of primary sensory neurons contributed to peripheral sensitization and tumor-induced hyperalgesia during cancer condition. In this study, using techniques of whole-cell patch-clamp recording associated with immunofluorescent staining, single-cell reverse-transcriptase PCR and behavioral test, we investigated whether the intrinsic membrane properties and the excitability of small-sized dorsal root ganglion (DRG) neurons altered in a rat model of bone cancer pain, and whether suppression of DRG neurons activity inhibited the bone cancer-induced pain. Results Our present study showed that implantation of MRMT-1 tumor cells into the tibial canal in rats produced significant mechanical and thermal hyperalgesia in the ipsilateral hind paw. Moreover, implantation of tumor cells provoked spontaneous discharges and tonic excitatory discharges evoked by a depolarizing current pulse in small-sized DRG neurons. In line with these findings, alterations in intrinsic membrane properties that reflect the enhanced neuronal excitability were observed in small DRG neurons in bone cancer rats, of which including: 1) depolarized resting membrane potential (RMP); 2) decreased input resistance (Rin); 3) a marked reduction in current threshold (CT) and voltage threshold (TP) of action potential (AP); 4) a dramatic decrease in amplitude, overshot, and duration of evoked action potentials as well as in amplitude and duration of afterhyperpolarization (AHP); and 5) a significant increase in the firing frequency of evoked action potentials. Here, the decreased AP threshold and increased firing frequency of evoked action potentials implicate the occurrence of hyperexcitability in small-sized DRG neurons in bone cancer rats. In addiotion, immunofluorescent staining and single-cell reverse-transcriptase PCR revealed that in isolated small DRG neurons, most neurons were IB4-positive, or expressed TRPV1 or CGRP, indicating that most recorded small DRG neurons were nociceptive neurons. Finally, using in vivo behavioral test, we found that blockade of DRG neurons activity by TTX inhibited the tumor-evoked mechanical allodynia and thermal hyperalgesia in bone cancer rats, implicating that the enhanced excitability of primary sensory neurons underlied the development of bone cancer pain. Conclusions Our present results suggest that implantation of tumor cells into the tibial canal in rats induces an enhanced excitability of small-sized DRG neurons that is probably as results of alterations in intrinsic electrogenic properties of these neurons. Therefore, alterations in intrinsic membrane properties associated with the hyperexcitability of primary sensory neurons likely contribute to the peripheral sensitization and tumor-induced hyperalgesia under cancer condition. PMID:22472208

Differential responses of rabbit ventricular and atrial transient outward current (Ito) to the Ito modulator NS5806.

PubMed

Cheng, Hongwei; Cannell, Mark B; Hancox, Jules C

2017-03-01

Transient outward potassium current (I to ) in the heart underlies phase 1 repolarization of cardiac action potentials and thereby affects excitation-contraction coupling. Small molecule activators of I to may therefore offer novel treatments for cardiac dysfunction, including heart failure and atrial fibrillation. NS5806 has been identified as a prototypic activator of canine I to This study investigated, for the first time, actions of NS5806 on rabbit atrial and ventricular I to Whole cell patch-clamp recordings of I to and action potentials were made at physiological temperature from rabbit ventricular and atrial myocytes. 10  μ mol/L NS5806 increased ventricular I to with a leftward shift in I to activation and accelerated restitution. At higher concentrations, stimulation of I to was followed by inhibition. The EC 50 for stimulation was 1.6  μ mol/L and inhibition had an IC 50 of 40.7  μ mol/L. NS5806 only inhibited atrial I to (IC 50 of 18  μ mol/L) and produced a modest leftward shifts in I to activation and inactivation, without an effect on restitution. 10  μ mol/L NS5806 shortened ventricular action potential duration (APD) at APD 20 -APD 90 but prolonged atrial APD NS5806 also reduced atrial AP upstroke and amplitude, consistent with an additional atrio-selective effect on Na + channels. In contrast to NS5806, flecainide, which discriminates between Kv1.4 and 4.x channels, produced similar levels of inhibition of ventricular and atrial I to NS5806 discriminates between rabbit ventricular and atrial I to, with mixed activator and inhibitor actions on the former and inhibitor actions against the later. NS5806 may be of significant value for pharmacological interrogation of regional differences in native cardiac I to . © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Liposomal bupivacaine and clinical outcomes.

PubMed

Tong, Yi Cai Isaac; Kaye, Alan David; Urman, Richard D

2014-03-01

In the multimodal approach to the management of postoperative pain, local infiltration and regional blocks have been increasingly utilized for pain control. One of the limitations of local anesthetics in the postoperative setting is its relatively short duration of action. Multivesicular liposomes containing bupivacaine have been increasingly utilized for their increased duration of action. Compared with bupivacaine HCl, local infiltration of liposomal bupivacaine has shown to have an increase in duration of action and causes delay in peak plasma concentration. In this article, we attempt to review the clinical literature surrounding liposomal bupivacaine and its evolving role in perioperative analgesia. This new bupivacaine formation may have promising implications in postoperative pain control, resulting in increased patient satisfaction and a decrease in both hospital stay and opioid-induced adverse events (AEs). Although more studies are needed, the preliminary clinical trials suggest that liposomal bupivacaine has predictable pharmacokinetics, a similar side effect profile compared with bupivacaine HCl, and is effective in providing increased postoperative pain control. Copyright © 2014 Elsevier Ltd. All rights reserved.

Ventral tegmental area neurons are either excited or inhibited by cocaine’s actions in the peripheral nervous system

PubMed Central

Mejías-Aponte, Carlos A.; Kiyatkin, Eugene A.

2012-01-01

Cocaine’s multiple pharmacological substrates are ubiquitously present in the peripheral and central nervous system. Thus, upon its administration, cocaine acts in the periphery before directly acting in the brain. We determined whether cocaine alters ventral tegmental area (VTA) neuronal activity via peripheral actions, and whether this precedes its central actions. In urethane-anesthetized rats, we recorded VTA neurons responses to intravenous injections of two cocaine analogs: cocaine-hydrochloride (HCl, 0.25 mg/kg) that readily cross the blood-brain barrier (BBB) and cocaine-methiodide (MI, 0.33 mg/kg) that does not cross the BBB. Both cocaine analogs produced sustained changes in discharge rates that began 5s after the initiation of a 10s drug infusion. Within the first 90s post-injection the magnitudes of neuronal responsive of both cocaine analogs were comparable, but later in time the effects of cocaine-HCl were stronger and persisted longer than those of cocaine-MI. The proportion of neurons responsive to cocaine-HCl was twice to that of cocaine-MI (74% and 35% respectively). Both analogs also differed in the response onsets. Cocaine-MI rarely evoked responses after 1 min whereas cocaine-HCl continued to evoke responses within 3 min post-injection. VTA neurons were either excited or inhibited by both cocaine analogs. Most units responsive to cocaine-MI, regardless of excitation or inhibition, had electrophysiological characteristics of putative DA neurons. Units inhibited by cocaine-HCl also had characteristic of DA neurons whereas excited neurons had widely varying action potential durations and discharge rates. Cocaine-MI and cocaine-HCl each produced changes in VTA neuron activity under full DA receptor blockade. However, the duration of inhibition was shortened, the number of excitations increased, and they occurred with an earlier onset during DA receptor blockade. These findings indicate that cocaine acts peripherally with a short latency and alters the activity of VTA neurons prior to its well-known direct actions in the brain. PMID:22300980

Phrenic nerve conduction studies: normative data and technical aspects.

PubMed

Maranhão, Analucia Abreu; Carvalho, Sonia Regina da Silva; Caetano, Marcelo Ribeiro; Alamy, Alexandre Hofke; Peixoto, Eduardo Mesquita; Filgueiras, Pedro Del Esporte Peçanha

2017-12-01

The aim of the present study was to define normative data of phrenic nerve conduction parameters of a healthy population. Phrenic nerve conduction studies were performed in 27 healthy volunteers. The normative limits for expiratory phrenic nerve compound muscle action potential were: amplitude (0.47 mv - 0.83 mv), latency (5.74 ms - 7.10 ms), area (6.20 ms/mv - 7.20 ms/mv) and duration (18.30 ms - 20.96 ms). Inspiratory normative limits were: amplitude (0.67 mv - 1.11 mv), latency (5.90 ms - 6.34 ms), area (5.62 ms/mv - 6.72 ms/mv) and duration (13.77 ms - 15.37 ms). The best point of phrenic nerve stimulus in the neck varies among individuals between the medial and lateral border of the clavicular head of the sternocleidomastoid muscle and stimulation of both sites, then choosing the best phrenic nerve response, seems to be the appropriate procedure.

Adding Dopamine to Proxymetacaine or Oxybuprocaine Solutions Potentiates and Prolongs the Cutaneous Antinociception in Rats.

PubMed

Chen, Yu-Wen; Chiu, Chong-Chi; Lin, Heng-Teng; Wang, Jhi-Joung; Hung, Ching-Hsia

2018-05-01

We evaluated the interaction of dopamine-proxymetacaine and dopamine- oxybuprocaine antinociception using isobolograms. This experiment uses subcutaneous drug (proxymetacaine, oxybuprocaine, and dopamine) injections under the skin of the rat's back, thus simulating infiltration blocks. The dose-related antinociceptive curves of proxymetacaine and oxybuprocaine alone and in combination with dopamine were constructed, and then the antinociceptive interactions between the local anesthetic and dopamine were analyzed using isobolograms. Subcutaneous proxymetacaine, oxybuprocaine, and dopamine produced a sensory block to local skin pinpricks in a dose-dependent fashion. The rank order of potency was proxymetacaine (0.57 [0.52-0.63] μmol/kg) > oxybuprocaine (1.05 [0.96-1.15] μmol/kg) > dopamine (165 [154-177] μmol/kg; P < .01 for each comparison) based on the 50% effective dose values. On the equianesthetic basis (25% effective dose, 50% effective dose, and 75% effective dose), the nociceptive block duration of proxymetacaine or oxybuprocaine was shorter than that of dopamine (P < .01). Oxybuprocaine or proxymetacaine coinjected with dopamine elicited a synergistic antinociceptive effect and extended the duration of action. Oxybuprocaine and proxymetacaine had a higher potency and provoked a shorter duration of sensory block compared with dopamine. The use of dopamine increased the quality and duration of skin antinociception caused by oxybuprocaine and proxymetacaine.

On the Dynamics of Action Representations Evoked by Names of Manipulable Objects

ERIC Educational Resources Information Center

Bub, Daniel N.; Masson, Michael E. J.

2012-01-01

Two classes of hand action representations are shown to be activated by listening to the name of a manipulable object (e.g., cellphone). The functional action associated with the proper use of an object is evoked soon after the onset of its name, as indicated by primed execution of that action. Priming is sustained throughout the duration of the…

Theory of the development of alternans in the heart during controlled diastolic interval pacing

NASA Astrophysics Data System (ADS)

Otani, Niels F.

2017-09-01

The beat-to-beat alternation in action potential durations (APDs) in the heart, called APD alternans, has been linked to the development of serious cardiac rhythm disorders, including ventricular tachycardia and fibrillation. The length of the period between action potentials, called the diastolic interval (DI), is a key dynamical variable in the standard theory of alternans development. Thus, methods that control the DI may be useful in preventing dangerous cardiac rhythms. In this study, we examine the dynamics of alternans during controlled-DI pacing using a series of single-cell and one-dimensional (1D) fiber models of alternans dynamics. We find that a model that combines a so-called memory model with a calcium cycling model can reasonably explain two key experimental results: the possibility of alternans during constant-DI pacing and the phase lag of APDs behind DIs during sinusoidal-DI pacing. We also find that these results can be replicated by incorporating the memory model into an amplitude equation description of a 1D fiber. The 1D fiber result is potentially concerning because it seems to suggest that constant-DI control of alternans can only be effective over only a limited region in space.

Napping: A public health issue. From epidemiological to laboratory studies.

PubMed

Faraut, Brice; Andrillon, Thomas; Vecchierini, Marie-Françoise; Leger, Damien

2017-10-01

Sleep specialists have proposed measures to counteract the negative short- and long-term consequences of sleep debt, and some have suggested the nap as a potential and powerful "public health tool". Here, we address this countermeasure aspect of napping viewed as an action against sleep deprivation rather than an action associated with poor health. We review the physiological functions that have been associated positively with napping in both public health and clinical settings (sleep-related accidents, work and school, and cardiovascular risk) and in laboratory-based studies with potential public health issues (cognitive performance, stress, immune function and pain sensitivity). We also discuss the circumstances in which napping-depending on several factors, including nap duration, frequency, and age-could be a potential public health tool and a countermeasure for sleep loss in terms of reducing accidents and cardiovascular events and improving sleep-restriction-sensitive working performance. However, the impact of napping and the nature of the sleep stage(s) involved still need to be evaluated, especially from the perspective of coping strategies in populations with chronic sleep debt, such as night and shift workers. Copyright © 2016 Elsevier Ltd. All rights reserved.

Comparison of rocuronium at two different doses and succinylcholine for endotracheal intubation in adult patients for elective surgeries.

PubMed

Chavan, S G; Gangadharan, S; Gopakumar, A K

2016-01-01

The effects of rocuronium at two different doses, that is, 0.6 mg/kg (2 × ED95) and 0.9 mg/kg (3 × ED95), were compared with succinylcholine (2 mg/kg) when used for endotracheal intubation in adult patients for elective surgeries under general anesthesia. Ninety patients were divided into three groups of 30 each. Groups A, B received injection rocuronium at 0.6 mg/kg, 0.9 mg/kg respectively and Group C received succinylcholine at 2 mg/kg. Onset of action of relaxant, intubation conditions, time taken to intubate and duration of action were compared. To compare the statistical difference in the age, weight, height of the study subjects, onset of action of relaxant, intubation conditions, time taken to intubate, and duration of action analysis of variance and unpaired t -test were used. The onset time was considerably shorter with rocuronium 0.9 mg/kg than 0.6 mg/kg. The onset time of rocuronium 0.9 mg/kg was found to be significantly longer than succinylcholine 2 mg/kg. Time taken to intubate was shortest with succinylcholine 2 mg/kg. The time taken to intubate with the rocuronium 0.9 mg/kg was found to be comparable to that of rocuronium 0.6 mg/kg. Intubation score of rocuronium 0.9 mg/kg was the best (17.75), which was comparable with succinylcholine. However, the intubation score obtained with rocuronium 0.6 mg/kg was inferior. Duration of action was shortest with succinylcholine. The duration of action is prolonged when the dose of rocuronium is increased from 0.6 to 0.9 mg/kg. Rapid sequence induction of anesthesia with propofol and fentanyl, succinylcholine allowed a more rapid endotracheal intubation sequence and created superior intubation conditions than rocuronium. However, the technique of using a large dose of rocuronium to achieve perfect conditions for tracheal intubation may have application whenever succinylcholine is relatively contraindicated.

The changes of potassium currents in rabbit ventricle with healed myocardial infarction.

PubMed

Liu, Nian; Niu, Huiyan; Li, Yang; Zhang, Cuntai; Zhou, Qiang; Ruan, Yanfei; Pu, Jun; Lu, Zaiying

2004-01-01

To elucidate the mechanism of arrhythmia in healed myocardial infarction (HMI), the changes of action potential duration (APD), transient outward potassium current (Ito), delayed rectifier potassium current (IK) and inward rectifier potassium current (IK1) of left ventricular myocytes in non-infarcted zone of HMI were investigated. Rabbits were randomly assigned into two groups: HMI group, in which animals were subjected to thoracotomy and ligation of the circumflex coronary and sham-operated group, in which rabbits underwent thoracotomy but no conorary ligation. 3 months after the operation, the whole myocyte patch clamp technique was used to record APD, Ito, IK, and IK1 of ventricular myocytes in non-infarcted zone. Our results showed that the membrane capacitance was larger in HMI group than in sham-operated group. Action potential duration was significantly lengthened in HMI group and early afterdepolarization (EAD) appeared in HMI group. The densities of Ito, I(K, tail), and IK1 were reduced significantly in HMI group, from 6.72 +/- 0.42 pA/pF, 1.54 +/- 0.13 pA/pF and 25.6 +/- 2.6 pA/pF in sham-operated group to 4.03 +/- 0.33 pA/pF, 1.14 +/- 0.11 pA/pF and 17.6 +/- 2.3 pA/pF, respectively. It is concluded that the reduced densities of Ito, I(K, tail) and IK1 in ventricular myocytes of non-infarcted zone in HMI were responsible for the prolongation of APD and the presentation of EAD which played important roles in the development of malignant arrhythmia in HMI.

R-type Ca(2+) channels contribute to fast synaptic excitation and action potentials in subsets of myenteric neurons in the guinea pig intestine.

PubMed

Naidoo, V; Dai, X; Galligan, J J

2010-12-01

R-type Ca(2+) channels are expressed by myenteric neurons in the guinea pig ileum but the specific function of these channels is unknown. In the present study, we used intracellular electrophysiological techniques to determine the function of R-type Ca(2+) channels in myenteric neurons in the acutely isolated longitudinal musclemyenteric plexus. We used immunohistochemical methods to localize the Ca(V)2.3 subunit of the R-type Ca(2+) channel in myenteric neurons. We also studied the effects of the non-selective Ca(2+) channel antagonist, CdCl₂ (100 μmol L⁻¹), the R-type Ca(2+) channel blockers NiCl₂ (50 μmol L⁻¹) and SNX-482 (0.1 μmol L⁻¹), and the N-type Ca(2+) channel blocker x-conotoxin GVIA (CTX 0.1 μmol L⁻¹) on action potentials and fast and slow excitatory postsynaptic potentials (fEPSPs and sEPSPs) in S and AH neurons in vitro. Ca(V)2.3 co-localized with calretinin and calbindin in myenteric neurons. NiCl₂ and SNX-482 reduced the duration and amplitude of action potentials in AH but not S neurons. NiCl₂ inhibited the afterhyperpolarization in AH neurons. x-conotoxin GVIA, but not NiCl₂, blocked sEPSPs in AH neurons. NiCl₂ and SNX-482 inhibited cholinergic, but not cholinergic/purinergic, fEPSPs in S neurons. These data show that R-type Ca(2+) channels contribute to action potentials, but not slow synaptic transmission, in AH neurons. R-type Ca(2+) channels contribute to release of acetylcholine as the mediator of fEPSPs in some S neurons. These data indicate that R-type Ca(2+) channels may be a target for drugs that selectively modulate activity of AH neurons or could alter fast synaptic excitation in specific pathways in the myenteric plexus.

Electrophysiological effects of Chinese medicine Shen song Yang xin (SSYX) on Chinese miniature swine heart and isolated guinea pig ventricular myocytes.

PubMed

Feng, Li; Gong, Jing; Jin, Zhen-yi; Li, Ning; Sun, Li-ping; Wu, Yi-ling; Pu, Jie-lin

2009-07-05

Shen song Yang xin (SSYX) is a compound of Chinese medicine with the effect of increasing heart rate (HR). This study aimed to evaluate its electrophysiological properties at heart and cellular levels. The Chinese miniature swines were randomly assigned to two groups, administered with SSYX or placebo for 4 weeks (n = 8 per group). Cardiac electrophysiological study (EPS) was performed before and after drug administration. The guinea pig ventricular myocytes were enzymatically isolated and whole cell voltage-clamp technique was used to evaluate the effect of SSYX on cardiac action potential (AP). SSYX treatment accelerated the HR from (141.8 +/- 36.0) beats per minute to (163.0 +/- 38.0) beats per minute (P = 0.013) without changing the other parameters in surface electrocardiogram. After blockage of the autonomic nervous system with metoprolol and atropin, SSYX had no effect on intrinsic HR (IHR), but decreased corrected sinus node recovery time (CSNRT) and sinus atrium conducting time (SACT). Intra cardiac EPS showed that SSYX significantly decreased the A-H and A-V intervals as well as shortened the atrial (A), atrioventricular node (AVN) and ventricular (V) effective refractory period (ERP). In isolated guinea pig ventricular myocytes, the most obvious effect of SSYX on action potential was a shortening of the action potential duration (APD) without change in shape of action potential. The shortening rates of APD(30), APD(50) and APD(90) were 19.5%, 17.8% and 15.3%, respectively. The resting potential (Em) and the interval between the end of APD(30) and APD(90) did not significantly change. The present study demonstrates that SSYX increases the HR and enhances the conducting capacity of the heart in the condition of the intact autonomic nervous system. SSYX homogenously decreases the ERP of the heart and shortens the APD of the myocytes, suggesting its antiarrhythmic effect without proarrhythmia.

Upregulation of K(2P)3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation.

PubMed

Schmidt, Constanze; Wiedmann, Felix; Voigt, Niels; Zhou, Xiao-Bo; Heijman, Jordi; Lang, Siegfried; Albert, Virginia; Kallenberger, Stefan; Ruhparwar, Arjang; Szabó, Gábor; Kallenbach, Klaus; Karck, Matthias; Borggrefe, Martin; Biliczki, Peter; Ehrlich, Joachim R; Baczkó, István; Lugenbiel, Patrick; Schweizer, Patrick A; Donner, Birgit C; Katus, Hugo A; Dobrev, Dobromir; Thomas, Dierk

2015-07-14

Antiarrhythmic management of atrial fibrillation (AF) remains a major clinical challenge. Mechanism-based approaches to AF therapy are sought to increase effectiveness and to provide individualized patient care. K(2P)3.1 (TASK-1 [tandem of P domains in a weak inward-rectifying K+ channel-related acid-sensitive K+ channel-1]) 2-pore-domain K+ (K(2P)) channels have been implicated in action potential regulation in animal models. However, their role in the pathophysiology and treatment of paroxysmal and chronic patients with AF is unknown. Right and left atrial tissue was obtained from patients with paroxysmal or chronic AF and from control subjects in sinus rhythm. Ion channel expression was analyzed by quantitative real-time polymerase chain reaction and Western blot. Membrane currents and action potentials were recorded using voltage- and current-clamp techniques. K(2P)3.1 subunits exhibited predominantly atrial expression, and atrial K(2P)3.1 transcript levels were highest among functional K(2P) channels. K(2P)3.1 mRNA and protein levels were increased in chronic AF. Enhancement of corresponding currents in the right atrium resulted in shortened action potential duration at 90% of repolarization (APD90) compared with patients in sinus rhythm. In contrast, K(2P)3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K(2P)3.1 inhibition prolonged APD90 in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm. Enhancement of atrium-selective K(2P)3.1 currents contributes to APD shortening in patients with chronic AF, and K(2P)3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K(2P)3.1 as a novel drug target for mechanism-based AF therapy. © 2015 American Heart Association, Inc.

Planning Under Continuous Time and Resource Uncertainty: A Challenge for AI

NASA Technical Reports Server (NTRS)

Bresina, John; Dearden, Richard; Meuleau, Nicolas; Smith, David; Washington, Rich; Clancy, Daniel (Technical Monitor)

2002-01-01

There has been considerable work in Al on decision-theoretic planning and planning under uncertainty. Unfortunately, all of this work suffers from one or more of the following limitations: 1) it relies on very simple models of actions and time, 2) it assumes that uncertainty is manifested in discrete action outcomes, and 3) it is only practical for very small problems. For many real world problems, these assumptions fail to hold. A case in point is planning the activities for a Mars rover. For this domain none of the above assumptions are valid: 1) actions can be concurrent and have differing durations, 2) there is uncertainty concerning action durations and consumption of continuous resources like power, and 3) typical daily plans involve on the order of a hundred actions. We describe the rover problem, discuss previous work on planning under uncertainty, and present a detailed. but very small, example illustrating some of the difficulties of finding good plans.

[The algorithm for planning cosmonauts' timeline in flight (by the results of long-duration Mir mission)].

PubMed

Nechaev, A P

2001-01-01

Results of the investigation of the interrelation between cosmonauts' erroneous actions and work and rest schedule intensity in fourteen long-duration Mir missions are presented in the paper. The statistical significance of this dependence has been established, and its nonlinear character has been revealed. An algorithm of short-range planning of crew operations has been developed based on determination of critical crew work loads deduced from increases in erroneous actions. Together with other methods the suggested approach may be used to raise cosmonauts' performance reliability.

Sarcoplasmic reticulum calcium release compared in slow-twitch and fast-twitch fibres of mouse muscle.

PubMed

Baylor, S M; Hollingworth, S

2003-08-15

Experiments were carried out to compare the amplitude and time course of Ca2+ release from the sarcoplasmic reticulum (SR) in intact slow-twitch and fast-twitch mouse fibres. Individual fibres within small bundles were injected with furaptra, a low-affinity, rapidly responding Ca2+ indicator. In response to a single action potential at 16 degrees C, the peak amplitude and half-duration of the change in myoplasmic free [Ca2+] (Delta[Ca2+]) differed significantly between fibre types (slow-twitch: peak amplitude, 9.4 +/- 1.0 microM (mean +/- S.E.M.); half-duration, 7.7 +/- 0.6 ms; fast-twitch: peak amplitude 18.5 +/- 0.5 microM; half-duration, 4.9 +/- 0.3 ms). SR Ca2+ release was estimated from Delta[Ca2+] with a computational model that calculated Ca2+ binding to the major myoplasmic Ca2+ buffers (troponin, ATP and parvalbumin); buffer concentrations and reaction rate constants were adjusted to reflect fibre-type differences. In response to an action potential, the total concentration of released Ca2+ (Delta[CaT]) and the peak rate of Ca2+ release ((d/dt)Delta[CaT]) differed about 3-fold between the fibre types (slow-twitch: Delta[CaT], 127 +/- 7 microM; (d/dt)Delta[CaT], 70 +/- 6 microM ms-1; fast-twitch: Delta[CaT], 346 +/- 6 microM; (d/dt)Delta[CaT], 212 +/- 4 microM ms-1). In contrast, the half-duration of (d/dt)Delta[CaT] was very similar in the two fibre types (slow-twitch, 1.8 +/- 0.1 ms; fast-twitch, 1.6 +/- 0.0 ms). When fibres were stimulated with a 5-shock train at 67 Hz, the peaks of (d/dt)Delta[CaT] in response to the second and subsequent shocks were much smaller than that due to the first shock; the later peaks, expressed as a fraction of the amplitude of the first peak, were similar in the two fibre types (slow-twitch, 0.2-0.3; fast-twitch, 0.1-0.3). The results support the conclusion that individual SR Ca2+ release units function similarly in slow-twitch and fast-twitch mammalian fibres.

Basophil FcεRI Expression in Chronic Spontaneous Urticaria: A Potential Immunological Predictor of Response to Omalizumab Therapy.

PubMed

Deza, Gustavo; Bertolín-Colilla, Marta; Pujol, Ramon M; Curto-Barredo, Laia; Soto, Dulce; García, Maribel; Hernández, Pilar; Gimeno, Ramon; Giménez-Arnau, Ana M

2017-06-09

Although the efficacy of omalizumab has been clearly demonstrated in the treatment of chronic spontaneous urticaria (CSU), its mechanism of action, which results in improvement in CSU symptoms, is not entirely understood. This study investigated the effect of omalizumab on expression of the high-affinity IgE receptor (FcεRI) on blood basophils from patients with active CSU, and its association with the clinical response. Patients exhibiting significant clinical improvement showed a sharp reduction in the levels of basophil FcεRI after 4 weeks, which was maintained throughout the total duration of the treatment. Such evolution was not observed in non-responder patients. Furthermore, non-responders showed significantly lower baseline levels of FcεRI than responders. Baseline basophil FcεRI expression was found to be a potential immunological predictor of response to omalizumab (100% sensitivity and 73.2% specificity). The results of this study contribute to our knowledge of the therapeutic benefit and mechanism of action of anti-IgE therapy in CSU.

Properties of an intermediate-duration inactivation process of the voltage-gated sodium conductance in rat hippocampal CA1 neurons.

PubMed

French, Christopher R; Zeng, Zhen; Williams, David A; Hill-Yardin, Elisa L; O'Brien, Terence J

2016-02-01

Rapid transmembrane flow of sodium ions produces the depolarizing phase of action potentials (APs) in most excitable tissue through voltage-gated sodium channels (NaV). Macroscopic currents display rapid activation followed by fast inactivation (IF) within milliseconds. Slow inactivation (IS) has been subsequently observed in several preparations including neuronal tissues. IS serves important physiological functions, but the kinetic properties are incompletely characterized, especially the operative timescales. Here we present evidence for an "intermediate inactivation" (II) process in rat hippocampal CA1 neurons with time constants of the order of 100 ms. The half-inactivation potentials (V0.5) of steady-state inactivation curves were hyperpolarized by increasing conditioning pulse duration from 50 to 500 ms and could be described by a sum of Boltzmann relations. II state transitions were observed after opening as well as subthreshold potentials. Entry into II after opening was relatively insensitive to membrane potential, and recovery of II became more rapid at hyperpolarized potentials. Removal of fast inactivation with cytoplasmic papaine revealed time constants of INa decay corresponding to II and IS with long depolarizations. Dynamic clamp revealed attenuation of trains of APs over the 10(2)-ms timescale, suggesting a functional role of II in repetitive firing accommodation. These experimental findings could be reproduced with a five-state Markov model. It is likely that II affects important aspects of hippocampal neuron response and may provide a drug target for sodium channel modulation. Copyright © 2016 the American Physiological Society.

Functional role of A-type potassium currents in rat presympathetic PVN neurones

PubMed Central

Sonner, Patrick M; Stern, Javier E

2007-01-01

Despite the fact that paraventricular nucleus (PVN) neurones innervating the rostral ventrolateral medulla (RVLM) play important roles in the control of sympathetic function both in physiological and pathological conditions, the precise mechanisms controlling their activity are still incompletely understood. In the present study, we evaluated whether the transient outward potassium current IA is expressed in PVN-RVLM neurones, characterized its biophysical and pharmacological properties, and determined its role in shaping action potentials and firing discharge in these neurones. Patch-clamp recordings obtained from retrogradely labelled, PVN-RVLM neurones indicate that a 4-AP sensitive, TEA insensitive current, with biophysical properties consistent with IA, is present in these neurones. Pharmacological blockade of IA depolarized resting Vm and prolonged Na+ action potential duration, by increasing its width and by slowing down its decay time course. Interestingly, blockade of IA either increased or decreased the firing activity of PVN-RVLM neurones, supporting the presence of subsets of PVN-RVLM neurones differentially modulated by IA. In all cases, the effects of IA on firing activity were prevented by a broad spectrum Ca2+ channel blocker. Immunohistochemical studies suggest that IA in PVN-RVLM neurons is mediated by Kv1.4 and/or Kv4.3 channel subunits. Overall, our results demonstrate the presence of IA in PVN-RVLM neurones, which actively modulates their action potential waveform and firing activity. These studies support IA as an important intrinsic mechanism controlling neuronal excitability in this central presympathetic neuronal population. PMID:17525115

Long-lasting potassium channel inactivation in myoepithelial fibres is related to characteristics of swimming in diphyid siphonophores.

PubMed

Inoue, Isao; Tsutsui, Izuo; Bone, Quentin

2005-12-01

Diphyid siphonophores swim using bursts of propulsive jets, which are produced by contractions of a monolayer of subumbrellar myoepithelial fibres lining the nectophore. This swimming behaviour is characterised by successive increases in the force generating the jets during the initial jets of the burst. Action potentials that generate the contractions propagate throughout the myoepithelial layer: both their amplitude and duration successively increase during the first part of the burst. To investigate the ionic mechanism of this action potential augmentation, single myoepithelial cells were enzymatically dissociated and whole-cell voltage clamped. Na+, Ca2+ and K+ currents were recorded under different internal and external salt compositions. The Na+ current was blocked by a relatively high concentration (4 micromol l-1 or higher) of tetrodotoxin (TTX), indicating that the Na+ channel belongs to a group of TTX-resistant Na+ channels. The Ca2+ current was blocked by nifedipine (10 micromol l-1) and Co2+ (5 mmol l-1), indicating that the Ca2+ channel is L-type. The K+ current possessed a unique property of long-lasting inactivation. The K+ current fully inactivated during a depolarisation to +30 mV with a time-constant of approximately 9 ms, and the time constant of recovery from inactivation at -70 mV was 13.2 s. This long-lasting inactivation of the K+ channel was the major factor in the augmentation of both action potentials and contractions of the myoepithelial sheet during the initial part of the burst.

A mathematical model of action potential heterogeneity in adult rat left ventricular myocytes.

PubMed Central

Pandit, S V; Clark, R B; Giles, W R; Demir, S S

2001-01-01

Mathematical models were developed to reconstruct the action potentials (AP) recorded in epicardial and endocardial myocytes isolated from the adult rat left ventricle. The main goal was to obtain additional insight into the ionic mechanisms responsible for the transmural AP heterogeneity. The simulation results support the hypothesis that the smaller density and the slower reactivation kinetics of the Ca(2+)-independent transient outward K(+) current (I(t)) in the endocardial myocytes can account for the longer action potential duration (APD), and more prominent rate dependence in that cell type. The larger density of the Na(+) current (I(Na)) in the endocardial myocytes results in a faster upstroke (dV/dt(max)). This, in addition to the smaller magnitude of I(t), is responsible for the larger peak overshoot of the simulated endocardial AP. The prolonged APD in the endocardial cell also leads to an enhanced amplitude of the sustained K(+) current (I(ss)), and a larger influx of Ca(2+) ions via the L-type Ca(2+) current (I(CaL)). The latter results in an increased sarcoplasmic reticulum (SR) load, which is mainly responsible for the higher peak systolic value of the Ca(2+) transient [Ca(2+)](i), and the resultant increase in the Na(+)-Ca(2+) exchanger (I(NaCa)) activity, associated with the simulated endocardial AP. In combination, these calculations provide novel, quantitative insights into the repolarization process and its naturally occurring transmural variations in the rat left ventricle. PMID:11720973

Enhancing voluntary imitation through attention and motor imagery.

PubMed

Bek, Judith; Poliakoff, Ellen; Marshall, Hannah; Trueman, Sophie; Gowen, Emma

2016-07-01

Action observation activates brain areas involved in performing the same action and has been shown to increase motor learning, with potential implications for neurorehabilitation. Recent work indicates that the effects of action observation on movement can be increased by motor imagery or by directing attention to observed actions. In voluntary imitation, activation of the motor system during action observation is already increased. We therefore explored whether imitation could be further enhanced by imagery or attention. Healthy participants observed and then immediately imitated videos of human hand movement sequences, while movement kinematics were recorded. Two blocks of trials were completed, and after the first block participants were instructed to imagine performing the observed movement (Imagery group, N = 18) or attend closely to the characteristics of the movement (Attention group, N = 15), or received no further instructions (Control group, N = 17). Kinematics of the imitated movements were modulated by instructions, with both Imagery and Attention groups being closer in duration, peak velocity and amplitude to the observed model compared with controls. These findings show that both attention and motor imagery can increase the accuracy of imitation and have implications for motor learning and rehabilitation. Future work is required to understand the mechanisms by which these two strategies influence imitation accuracy.

Relationships between types of father breastfeeding support and breastfeeding outcomes.

PubMed

Rempel, Lynn A; Rempel, John K; Moore, Katrina C J

2017-07-01

Fathers' support can influence mothers' breastfeeding decisions and behavior. Potentially supportive behaviors have been reported in previous studies, but no studies have directly examined which, if any, of those actions are actually more likely to result in desired breastfeeding outcomes. The two studies reported in this paper address this gap by examining relationships between fathers' reported breastfeeding support and mothers' perceptions of received support and breastfeeding intentions, satisfaction, and duration. The Partner Breastfeeding Influence Scale (PBIS) was used in an online survey with 64 women and 41 men (34 couples) and a telephone survey with 80 mothers and 65 fathers (63 couples). Fathers' and mothers' reports of how often fathers engage in the types of support measured by the PBIS were used to predict breastfeeding intentions, satisfaction, and duration. In Study 1, responsiveness predicted breastfeeding success and satisfaction for men and satisfaction for women. However, mothers' intended breastfeeding duration was shorter when fathers both wanted them to breastfeed for a long time and were more appreciative and savvy about breastfeeding. In Study 2, when fathers reported being more appreciative and directly involved in breastfeeding, mothers reported shorter breastfeeding duration. In both studies, mothers' perceptions of their partners' responsiveness and fathers' reports of their own responsiveness predicted longer breastfeeding intentions and duration. These findings suggest that the most effective breastfeeding support is delivered using a sensitive, coordinated teamwork approach that is responsive to the mother's needs. © 2016 John Wiley & Sons Ltd.

Institutional environmental impact statement (space shuttle development and operations) amendment no. 1. [space shuttle operations at Kennedy Space Center

NASA Technical Reports Server (NTRS)

1973-01-01

Data are presented to support the environmental impact statement on space shuttle actions at Kennedy Space Center. Studies indicate that land use to accommodate space shuttle operations may have the most significant impact. The impacts on air, water and noise quality are predicted to be less on the on-site environment. Considerations of operating modes indicate that long and short term land use will not affect wildlife productivity. The potential for adverse environmental impact is small and such impacts will be local, short in duration, controllable, and environmentally acceptable.

Retinogeniculate transmission in wakefulness.

PubMed

Weyand, Theodore G

2007-08-01

Despite popular belief that the primary function of the thalamus is to "gate" sensory inputs by state, few studies have attempted to directly characterize the efficacy of such gating in the awake, behaving animal. I measured the efficacy of retinogeniculate transmission in the awake cat by taking advantage of the fact that many neurons in the lateral geniculate nucleus (LGN) are dominated by a single retinal input, and that this input produces a distinct event known as the S-potential. Retinal input failed to produce an LGN action potential half of the time. However, success or failure was powerfully tied to the recency of the S-potential. Short intervals tend to be successful and long intervals unsuccessful. For four of 12 neurons, the probability that a given S-potential could cause a spike exceeded 90% if that S-potential was preceded by an S-potential within the previous 10 ms (100 Hz). Whereas this temporal influence on efficacy has been demonstrated extensively in anesthetized animals, wakefulness is different in several ways. Overall efficacy is better in wakefulness than in anesthesia, the durations of facilitating effects are briefer in wakefulness, efficacy of long intervals is superior in wakefulness, and the temporal dependence can be briefly disrupted by altering background illumination. The last two observations may be particularly significant. Increased success at long intervals in wakefulness provides additional evidence that the spike code of the anesthetized animal is not the spike code of the awake animal. Altering retinogeniculate efficacy by altering visual conditions undermines the influence inter-S-potential interval might have in determining efficacy in the real world. Finally, S-potential amplitude, duration, and even slope are dynamic and systematic within wakefulness; providing further support that the S-potential is the extracellular signature of the retinal EPSP.

Enhanced visual short-term memory in action video game players.

PubMed

Blacker, Kara J; Curby, Kim M

2013-08-01

Visual short-term memory (VSTM) is critical for acquiring visual knowledge and shows marked individual variability. Previous work has illustrated a VSTM advantage among action video game players (Boot et al. Acta Psychologica 129:387-398, 2008). A growing body of literature has suggested that action video game playing can bolster visual cognitive abilities in a domain-general manner, including abilities related to visual attention and the speed of processing, providing some potential bases for this VSTM advantage. In the present study, we investigated the VSTM advantage among video game players and assessed whether enhanced processing speed can account for this advantage. Experiment 1, using simple colored stimuli, revealed that action video game players demonstrate a similar VSTM advantage over nongamers, regardless of whether they are given limited or ample time to encode items into memory. Experiment 2, using complex shapes as the stimuli to increase the processing demands of the task, replicated this VSTM advantage, irrespective of encoding duration. These findings are inconsistent with a speed-of-processing account of this advantage. An alternative, attentional account, grounded in the existing literature on the visuo-cognitive consequences of video game play, is discussed.

Probabilistic Reasoning for Robustness in Automated Planning

NASA Technical Reports Server (NTRS)

Schaffer, Steven; Clement, Bradley; Chien, Steve

2007-01-01

A general-purpose computer program for planning the actions of a spacecraft or other complex system has been augmented by incorporating a subprogram that reasons about uncertainties in such continuous variables as times taken to perform tasks and amounts of resources to be consumed. This subprogram computes parametric probability distributions for time and resource variables on the basis of user-supplied models of actions and resources that they consume. The current system accepts bounded Gaussian distributions over action duration and resource use. The distributions are then combined during planning to determine the net probability distribution of each resource at any time point. In addition to a full combinatoric approach, several approximations for arriving at these combined distributions are available, including maximum-likelihood and pessimistic algorithms. Each such probability distribution can then be integrated to obtain a probability that execution of the plan under consideration would violate any constraints on the resource. The key idea is to use these probabilities of conflict to score potential plans and drive a search toward planning low-risk actions. An output plan provides a balance between the user s specified averseness to risk and other measures of optimality.

[Influence exogenous nicotinamide adenine dinucleotide (NAD+) on contractile and bioelectric activity of the rat heart].

PubMed

Pustovit, K B; Kuz'min, V S; Sukhova, G S

2014-04-01

This study is aimed to the investigation of the nicotinamide adenine dinucleotide (NAD+) effects and mechanisms of action in a heart. NAD+ (mcM) induces multiphase alternation of contractile activity of isolated rat heart: short positive inotropic action is followed by a negative inotropic phase. NAD+ (1-100 mcM) induces decreasing of action potential duration (APD) in rat atrial myocardium (from 45 +/- 0.82 ms in control experiments to 39 +/- 1.05 (n = 8) and 32 +/- 2 (n = 8) during application of 10 and 100 mcM of NAD+, respectively). Significant APD increase (from 45 +/- 0.82 ms to 74 +/- 1.89 (n = 8) ms) was observed during washing out of NAD+ (100 mcM). ATP or adenosine was unable to increase APD both during application or washing out. NAD+ induced APD decrease was not suppressed by P1-antagonist theophylline. P1-purinoreceptor and metabolite independent direct action of NAD+ in rat heart is suggested. Activation of P2X or P2Y receptors, cyclic ADP-ribose accumulation in cardiomyocytes is proposed as a main mechanism of NAD(+)-induced effects in the heart.

[Mechanism of action of neurotoxins acting on the inactivation of voltage-gated sodium channels].

PubMed

Benoit, E

1998-01-01

This review focuses on the mechanism(s) of action of neurotoxins acting on the inactivation of voltage-gated Na channels. Na channels are transmembrane proteins which are fundamental for cellular communication. These proteins form pores in the plasma membrane allowing passive ionic movements to occur. Their opening and closing are controlled by gating systems which depend on both membrane potential and time. Na channels have three functional properties, mainly studied using electrophysiological and biochemical techniques, to ensure their role in the generation and propagation of action potentials: 1) a highly selectivity for Na ions, 2) a rapid opening ("activation"), responsible for the depolarizing phase of the action potential, and 3) a late closing ("inactivation") involved in the repolarizing phase of the action potential. As an essential protein for membrane excitability, the Na channel is the specific target of a number of vegetal and animal toxins which, by binding to the channel, alter its activity by affecting one or more of its properties. At least six toxin receptor sites have been identified on the neuronal Na channel on the basis of binding studies. However, only toxins interacting with four of these sites (sites 2, 3, 5 et 6) produce alterations of channel inactivation. The maximal percentage of Na channels modified by the binding of neurotoxins to sites 2 (batrachotoxin and some alkaloids), 3 (alpha-scorpion and sea anemone toxins), 5 (brevetoxins and ciguatoxins) et 6 (delta-conotoxins) is different according to the site considered. However, in all cases, these channels do not inactivate. Moreover, Na channels modified by toxins which bind to sites 2, 5 and 6 activate at membrane potentials more negative than do unmodified channels. The physiological consequences of Na channel modifications, induced by the binding of neurotoxins to sites 2, 3, 5 and 6, are (i) an inhibition of cellular excitability due to an important membrane depolarization (site 2), (ii) a decrease of cellular excitability due to an important increase in the action potential duration (site 3) and (iii) an increase in cellular excitability which results in spontaneous and repetitive firing of action potentials (sites 5 and 6). The biochemical and electrophysiological studies performed with these toxins, as well as the determination of their molecular structure, have given basic information on the function and structure of the Na channel protein. Therefore, various models representing the different states of Na channels have been proposed to account for the neurotoxin-induced modifications of Na inactivation. Moreover, the localization of receptor binding sites 2, 3, 5 et 6 for these toxins on the neuronal Na channel has been deduced and the molecular identification of the recognition site(s) for some of them has been established on the alpha sub-unit forming the Na channel protein.

Exploration of pyrrole derivatives to find an effective potassium-competitive acid blocker with moderately long-lasting suppression of gastric acid secretion.

PubMed

Nishida, Haruyuki; Fujimori, Ikuo; Arikawa, Yasuyoshi; Hirase, Keizo; Ono, Koji; Nakai, Kazuo; Inatomi, Nobuhiro; Hori, Yasunobu; Matsukawa, Jun; Fujioka, Yasushi; Imanishi, Akio; Fukui, Hideo; Itoh, Fumio

2017-07-01

With the aim to discover a novel excellent potassium-competitive acid blocker (P-CAB) that could perfectly overcome the limitations of proton pump inhibitors (PPIs), we tested various approaches based on pyrrole derivative 1 as a lead compound. As part of a comprehensive approach to identify a new effective drug, we tried to optimize the duration of action of the pyrrole derivative. Among the compounds synthesized, fluoropyrrole derivative 20j, which has a 2-F-3-Py group at position 5, fluorine atom at position 4, and a 4-Me-2-Py sulfonyl group at the first position of the pyrrole ring, showed potent gastric acid-suppressive action and moderate duration of action in animal models. On the basis of structural properties including a slightly larger ClogP value (1.95), larger logD value (0.48) at pH 7.4, and fairly similar pKa value (8.73) compared to those of the previously optimized compound 2a, compound 20j was assumed to undergo rapid transfer to the stomach and have a moderate retention time there after single administration. Therefore, compound 20j was selected as a new promising P-CAB with moderately long duration of action. Copyright © 2017 Elsevier Ltd. All rights reserved.

Integrative clinical sequencing in the management of children and young adults with refractory or relapsed cancer

PubMed Central

Mody, Rajen J.; Wu, Yi-Mi; Lonigro, Robert J.; Cao, Xuhong; Roychowdhury, Sameek; Vats, Pankaj; Frank, Kevin M.; Prensner, John R.; Asangani, Irfan; Palanisamy, Nallasivam; Dillman, Jonathan R.; Rabah, Raja M.; Kunju, Laxmi Priya; Everett, Jessica; Raymond, Victoria M.; Ning, Yu; Su, Fengyun; Wang, Rui; Stoffel, Elena M.; Innis, Jeffrey W.; Roberts, J. Scott; Robertson, Patricia L.; Yanik, Gregory; Chamdin, Aghiad; Connelly, James A.; Choi, Sung; Harris, Andrew C.; Kitko, Carrie; Rao, Rama Jasty; Levine, John E.; Castle, Valerie P.; Hutchinson, Raymond J.; Talpaz, Moshe; Robinson, Dan R.; Chinnaiyan, Arul M.

2016-01-01

Importance Cancer is caused by a diverse array of somatic and germline genomic aberrations. Advances in genomic sequencing technologies have improved the ability to detect these molecular aberrations with greater sensitivity. However, integrating them into clinical management in an individualized manner has proven challenging. Objective To evaluate the use of integrative clinical sequencing and genetic counseling in the assessment and treatment of children and young adults with cancer. Design, Settings and Participants An observational, consecutive case series (May 2012–October 2014) of 102 children and young adults (mean age, 10.6; median age, 11.5, range: 0–22 years) with relapsed, refractory, or rare cancer at a single major academic medical center. Exposures Each participant underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing along with genetic counseling. Results were discussed in a multi-disciplinary Precision Medicine Tumor Board (PMTB) and recommendations were reported to treating physicians and families. Main Outcomes and Measures Proportion of patients with potentially actionable findings (PAF), results of clinical actions based on integrative clinical sequencing (ICS), and estimated proportion of patients or their families at risk for future cancer. PAF was defined as any genomic findings discovered during sequencing analysis that could lead to a 1) change in patient management by providing a targetable molecular aberration, 2) change in diagnosis or risk stratification or 3) provides cancer-related germline findings, which inform patients/families about a potential future risk of various cancers; Results We screened 104 patients and enrolled 102 patients of which 91 (89%) had adequate tumor tissue available to complete sequencing and only these patients were included in all subsequent calculations, including 28 (31%) with hematological malignancies and 63 (69%) with solid tumors. Overall, 42 (46%) patients had PAFs which changed patient management including, 54% (15/28) with hematological malignancies and 43% (27/63) with solid tumors. Overall, individualized actions were taken in 23 of the 91 (25%) patients and families based on actionable ICS findings, including change in treatment in 14 (15%) and genetic counseling for future cancer risk in 9 (10%) patients. 9/91 (10%) of these personalized clinical interventions resulted in ongoing partial clinical remission of 8–16 months duration or help sustain complete clinical remission of 6–21 months duration. All 9 (10%) patients and families with actionable incidental genetic findings agreed to formal genetic counseling and screening. Conclusions and Relevance In this single center case series of children and young adults with relapsed or refractory cancer, incorporation of data from integrative clinical sequencing into clinical management was feasible, revealed potentially actionable findings in 46% of patients, and was associated with change in treatment and family genetic counseling in a small proportion of patients. The lack of a control group limited our ability to judge whether better clinical outcomes were achieved compared to standard care. PMID:26325560

Optical mapping at increased illumination intensities

NASA Astrophysics Data System (ADS)

Kanaporis, Giedrius; Martišienė, Irma; Jurevičius, Jonas; Vosyliūtė, Rūta; Navalinskas, Antanas; Treinys, Rimantas; Matiukas, Arvydas; Pertsov, Arkady M.

2012-09-01

Voltage-sensitive fluorescent dyes have become a major tool in cardiac and neuro-electrophysiology. Achieving high signal-to-noise ratios requires increased illumination intensities, which may cause photobleaching and phototoxicity. The optimal range of illumination intensities varies for different dyes and must be evaluated individually. We evaluate two dyes: di-4-ANBDQBS (excitation 660 nm) and di-4-ANEPPS (excitation 532 nm) in the guinea pig heart. The light intensity varies from 0.1 to 5 mW/mm2, with the upper limit at 5 to 10 times above values reported in the literature. The duration of illumination was 60 s, which in guinea pigs corresponds to 300 beats at a normal heart rate. Within the identified duration and intensity range, neither dye shows significant photobleaching or detectable phototoxic effects. However, light absorption at higher intensities causes noticeable tissue heating, which affects the electrophysiological parameters. The most pronounced effect is a shortening of the action potential duration, which, in the case of 532-nm excitation, can reach ˜30%. At 660-nm excitation, the effect is ˜10%. These findings may have important implications for the design of optical mapping protocols in biomedical applications.

The Effect of Two Benzodiazepine Receptor Agonist Hypnotics on Sleep-Dependent Memory Consolidation

PubMed Central

Hall-Porter, Janine M.; Schweitzer, Paula K.; Eisenstein, Rhody D.; Ahmed, Hasan Ali H.; Walsh, James K.

2014-01-01

Introduction: Numerous studies have demonstrated that sleep promotes memory consolidation, but there is little research on the effect of hypnotics on sleep-dependent memory consolidation. We compared bedtime administration of zolpidem-ER 12.5 mg (6- to 8-h duration of action), middle-of-the-night administration of zaleplon 10 mg (3- to 4-h duration of action), and placebo to examine the effect of different durations of hypnotic drug exposure on memory consolidation during sleep. Methods: Twenty-two participants with no sleep complaints underwent 3 conditions in a counterbalanced crossover study: (1) zolpidem-ER 12.5 mg (bedtime dosing), (2) zaleplon 10 mg (middle-of-the-night dosing), and (3) placebo. Memory testing was conducted before and after an 8-h sleep period, using a word pair association task (WPT; declarative memory) and a finger-tapping task (FTT; procedural memory). Results: ANOVA revealed a significant condition effect for the WPT (p = 0.025) and a trend for the FTT (p = 0.067), which was significant when sex was added to the model (p = 0.014). Improvement in memory performance following sleep was lower with bedtime dosing of zolpidem-ER compared to placebo and middle-of-the-night dosing of zaleplon. There were no differences between placebo and zaleplon. Conclusions: The results suggest that in some circumstances hypnotics may have the potential to reduce the degree of sleep-dependent memory consolidation and that drug-free sleep early in the night may ameliorate this effect. Citation: Hall-Porter JM; Schweitzer PK; Eisenstein RD; Ahmed HAH; Walsh JK. The effect of two benzodiazepine receptor agonist hypnotics on sleep-dependent memory consolidation. J Clin Sleep Med 2014;10(1):27-34. PMID:24426817

Advancing Novel Anesthetics: Pharmacodynamic and Pharmacokinetic Studies of Cyclopropyl-Methoxycarbonyl Metomidate in Dogs

PubMed Central

Campagna, Jason A.; Pojasek, Kevin; Grayzel, David; Randle, John; Raines, Douglas E.

2014-01-01

Background Cyclopropyl-methoxycarbonyl metomidate (CPMM, also known as ABP-700) is a second-generation “soft” (i.e., metabolically-labile) etomidate analogue. The purpose of these studies was to characterize CPMM's pharmacology in beagle dogs in preparation for potential first in human phase 1 clinical trials. Methods CPMM's and etomidate's hypnotic activity and duration of action were assessed using loss of righting reflex and anesthesia score assays in three or four dogs. Their pharmacokinetics were defined after single bolus administration and single bolus followed by 2-h infusion. Adrenocortical recovery times after single bolus followed by 2-h infusion of CPMM, propofol, etomidate, and vehicle were measured using an adrenocorticotropic hormone stimulation test. Results Compared to etomidate, CPMM was half as potent as a hypnotic (ED50 ~ 0.8 mg/kg), more rapidly metabolized, and had a shorter duration of sedative-hypnotic action. Recovery times after CPMM administration were also independent of infusion duration. After hypnotic infusion, adrenocorticotropic hormone-stimulated plasma cortisol concentrations were 4- to 27-fold higher in dogs that received CPMM versus etomidate. Adrenocortical recovery was faster in dogs after CPMM infusion versus etomidate infusion (half-time: 215 min vs. 1623 min, respectively). Adrenocortical responsiveness assessed 90 min after CPMM infusion was not significantly different from that after propofol infusion. Conclusion Our studies in dogs confirm that CPMM has hypnotic and adrenocortical recovery profiles that are superior than those of etomidate, supporting the continued development of CPMM as a clinical sedative-hypnotic to be used as a single bolus and by continuous infusion to induce and maintain general anesthesia or procedural sedation. PMID:25170571

Calcium release and its voltage dependence in frog cut muscle fibers equilibrated with 20 mM EGTA

PubMed Central

1995-01-01

Sarcoplasmic reticulum (SR) Ca release was studied at 13-16 degrees C in cut fibers (sarcomere length, 3.4-3.9 microns) mounted in a double Vaseline-gap chamber. The amplitude and duration of the action- potential stimulated free [Ca] transient were reduced by equilibration with end-pool solutions that contained 20 mM EGTA with 1.76 mM Ca and 0.63 mM phenol red, a maneuver that appeared to markedly reduce the amount of Ca complexed by troponin. A theoretical analysis shows that, under these conditions, the increase in myoplasmic free [Ca] is expected to be restricted to within a few hundred nanometers of the SR Ca release sites and to have a time course that essentially matches that of release. Furthermore, almost all of the Ca that is released from the SR is expected to be rapidly bound by EGTA and exchanged for protons with a 1:2 stoichiometry. Consequently, the time course of SR Ca release can be estimated by scaling the delta pH signal measured with phenol red by -beta/2. The value of beta, the buffering power of myoplasm, was determined in fibers equilibrated with a combination of EGTA, phenol red, and fura-2; its mean value was 22 mM/pH unit. The Ca content of the SR (expressed as myoplasmic concentration) was estimated from the total amount of Ca released by either a train of action potentials or a depleting voltage step; its mean value was 2,685 microM in the action-potential experiments and 2,544 microM in the voltage- clamp experiments. An action potential released, on average, 0.14 of the SR Ca content with a peak rate of release of approximately 5%/ms. A second action potential, elicited 20 ms later, released only 0.6 times as much Ca (expressed as a fraction of the SR content), probably because Ca inactivation of Ca release was produced by the first action potential. During a depolarizing voltage step to 60 mV, the rate of Ca release rapidly increased to a peak value of approximately 3%/ms and then decreased to a quasi-steady level that was only 0.6 times as large; this decrease was also probably due to Ca inactivation of Ca release. SR Ca release was studied with small step depolarizations that open no more than one SR Ca channel in 7,000 and increase the value of spatially averaged myoplasmic free [Ca] by only 0.2 nM. PMID:8537818

78 FR 12336 - Draft Program Comment for Extending the Duration of Programmatic Agreements Based on the...

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2013-02-22

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Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-14

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Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-12

... significant regulatory action due to being limited in size and duration. Small Entities Under the Regulatory... impact on a substantial number of small entities. The term ``small entities'' comprises small businesses... duration. Assistance for Small Entities Under section 213(a) of the Small Business Regulatory Enforcement...

Reactive oxygen species alters the electrophysiological properties and raises [Ca2+]i in intracardiac ganglion neurons

PubMed Central

Dyavanapalli, Jhansi; Rimmer, Katrina

2010-01-01

We have investigated the effects of the reactive oxygen species (ROS) donors hydrogen peroxide (H2O2) and tert-butyl hydroperoxide (t-BHP) on the intrinsic electrophysiological characteristics: ganglionic transmission and resting [Ca2+]i in neonate and adult rat intracardiac ganglion (ICG) neurons. Intracellular recordings were made using sharp microelectrodes filled with either 0.5 M KCl or Oregon Green 488 BAPTA-1, allowing recording of electrical properties and measurement of [Ca2+]i. H2O2 and t-BHP both hyperpolarized the resting membrane potential and reduced membrane resistance. In adult ICG neurons, the hyperpolarizing action of H2O2 was reversed fully by Ba2+ and partially by tetraethylammonium, muscarine, and linopirdine. H2O2 and t-BHP reduced the action potential afterhyperpolarization (AHP) amplitude but had no impact on either overshoot or AHP duration. ROS donors evoked an increase in discharge adaptation to long depolarizing current pulses. H2O2 blocked ganglionic transmission in most ICG neurons but did not alter nicotine-evoked depolarizations. By contrast, t-BHP had no significant action on ganglionic transmission. H2O2 and t-BHP increased resting intracellular Ca2+ levels to 1.6 ( ± 0.6, n = 11, P < 0.01) and 1.6 ( ± 0.3, n = 8, P < 0.001), respectively, of control value (1.0, ∼60 nM). The ROS scavenger catalase prevented the actions of H2O2, and this protection extended beyond the period of application. Superoxide dismutase partially shielded against the action of H2O2, but this was limited to the period of application. These data demonstrate that ROS decreases the excitability and ganglionic transmission of ICG neurons, attenuating parasympathetic control of the heart. PMID:20445155

A simultaneous multichannel monophasic action potential electrode array for in vivo epicardial repolarization mapping.

PubMed

Sahakian, A V; Peterson, M S; Shkurovich, S; Hamer, M; Votapka, T; Ji, T; Swiryn, S

2001-03-01

While the recording of extracellular monophasic action potentials (MAPs) from single epicardial or endocardial sites has been performed for over a century, we are unaware of any previous successful attempt to record MAPs simultaneously from a large number of sites in vivo. We report here the design and validation of an array of MAP electrodes which records both depolarization and repolarization simultaneously at up to 16 epicardial sites in a square array on the heart in vivo. The array consists of 16 sintered Ag-AgCl electrodes mounted in a common housing with individual suspensions allowing each electrode to exert a controlled pressure on the epicardial surface. The electrodes are arranged in a square array, with each quadrant of four having an additional recessed sintered Ag-AgCl reference electrode at its center. A saline-soaked sponge establishes ionic contact between the reference electrodes and the tissue. The array was tested on six anesthetized open-chested pigs. Simultaneous diagnostic-quality MAP recordings were obtained from up to 13 out of 16 ventricular sites. Ventricular MAPs had amplitudes of 10-40 mV with uniform morphologies and stable baselines for up to 30 min. MAP duration at 90% repolarization was measured and shown to vary as expected with cycle length during sustained pacing. The relationship between MAP duration and effective refractory period was also confirmed. The ability of the array to detect local differences in repolarization was tested in two ways. Placement of the array straddling the atrioventricular (AV) junction yielded simultaneous atrial or ventricular recordings at corresponding sites during 1:1 and 2:1 AV conduction. Localized ischemia via constriction of a coronary artery branch resulted in shortening of the repolarization phase at the ischemic, but not the nonischemic, sites. In conclusion, these results indicate that the simultaneous multichannel MAP electrode array is a viable method for in vivo epicardial repolarization mapping. The array has the potential to be expanded to increase the number of sites and spatial resolution.

Spatial gradients in action potential duration created by regional magnetofection of hERG are a substrate for wavebreak and turbulent propagation in cardiomyocyte monolayers.

PubMed

Campbell, Katherine; Calvo, Conrado J; Mironov, Sergey; Herron, Todd; Berenfeld, Omer; Jalife, José

2012-12-15

Spatial dispersion of action potential duration (APD) is a substrate for the maintenance of cardiac fibrillation, but the mechanisms are poorly understood. We investigated the role played by spatial APD dispersion in fibrillatory dynamics. We used an in vitro model in which spatial gradients in the expression of ether-à-go-go-related (hERG) protein, and thus rapid delayed rectifying K(+) current (I(Kr)) density, served to generate APD dispersion, high-frequency rotor formation, wavebreak and fibrillatory conduction. A unique adenovirus-mediated magnetofection technique generated well-controlled gradients in hERG and green fluorescent protein (GFP) expression in neonatal rat ventricular myocyte monolayers. Computer simulations using a realistic neonatal rat ventricular myocyte monolayer model provided crucial insight into the underlying mechanisms. Regional hERG overexpression shortened APD and increased rotor incidence in the hERG overexpressing region. An APD profile at 75 percent repolarization with a 16.6 ± 0.72 ms gradient followed the spatial profile of hERG-GFP expression; conduction velocity was not altered. Rotors in the infected region whose maximal dominant frequency was 12.9 Hz resulted in wavebreak at the interface (border zone) between infected and non-infected regions; dominant frequency distribution was uniform when the maximal dominant frequency was <12.9 Hz or the rotors resided in the uninfected region. Regularity at the border zone was lowest when rotors resided in the infected region. In simulations, a fivefold regional increase in I(Kr) abbreviated the APD and hyperpolarized the resting potential. However, the steep APD gradient at the border zone proved to be the primary mechanism of wavebreak and fibrillatory conduction. This study provides insight at the molecular level into the mechanisms by which spatial APD dispersion contributes to wavebreak, rotor stabilization and fibrillatory conduction.

Spatial gradients in action potential duration created by regional magnetofection of hERG are a substrate for wavebreak and turbulent propagation in cardiomyocyte monolayers

PubMed Central

Campbell, Katherine; Calvo, Conrado J; Mironov, Sergey; Herron, Todd; Berenfeld, Omer; Jalife, José

2012-01-01

Spatial dispersion of action potential duration (APD) is a substrate for the maintenance of cardiac fibrillation, but the mechanisms are poorly understood. We investigated the role played by spatial APD dispersion in fibrillatory dynamics. We used an in vitro model in which spatial gradients in the expression of ether-à-go-go-related (hERG) protein, and thus rapid delayed rectifying K+ current (IKr) density, served to generate APD dispersion, high-frequency rotor formation, wavebreak and fibrillatory conduction. A unique adenovirus-mediated magnetofection technique generated well-controlled gradients in hERG and green fluorescent protein (GFP) expression in neonatal rat ventricular myocyte monolayers. Computer simulations using a realistic neonatal rat ventricular myocyte monolayer model provided crucial insight into the underlying mechanisms. Regional hERG overexpression shortened APD and increased rotor incidence in the hERG overexpressing region. An APD profile at 75 percent repolarization with a 16.6 ± 0.72 ms gradient followed the spatial profile of hERG-GFP expression; conduction velocity was not altered. Rotors in the infected region whose maximal dominant frequency was ≥12.9 Hz resulted in wavebreak at the interface (border zone) between infected and non-infected regions; dominant frequency distribution was uniform when the maximal dominant frequency was <12.9 Hz or the rotors resided in the uninfected region. Regularity at the border zone was lowest when rotors resided in the infected region. In simulations, a fivefold regional increase in IKr abbreviated the APD and hyperpolarized the resting potential. However, the steep APD gradient at the border zone proved to be the primary mechanism of wavebreak and fibrillatory conduction. This study provides insight at the molecular level into the mechanisms by which spatial APD dispersion contributes to wavebreak, rotor stabilization and fibrillatory conduction. PMID:23090949

The actions of mdivi-1, an inhibitor of mitochondrial fission, on rapidly activating delayed-rectifier K⁺ current and membrane potential in HL-1 murine atrial cardiomyocytes.

PubMed

So, Edmund Cheung; Hsing, Chung-Hsi; Liang, Chia-Hua; Wu, Sheng-Nan

2012-05-15

Mdivi-1 is an inhibitor of dynamin related protein 1- (drp1)-mediated mitochondrial fission. However, the mechanisms through which this compound interacts directly with ion currents in heart cells remain unknown. In this study, its effects on ion currents and membrane potential in murine HL-1 cardiomyocytes were investigated. In whole-cell recordings, the addition of mdivi-1 decreased the amplitude of tail current (I(tail)) for the rapidly activating delayed-rectifier K⁺ current (I(Kr)) in a concentration-dependent manner with an IC₅₀ value at 11.6 μM, a value that resembles the inhibition requirement for mitochondrial division. It shifted the activation curve of I(tail) to depolarized voltages with no change in the gating charge. However, mdivi-1 did not alter the rate of recovery from current inactivation. In cell-attached configuration, mdivi-1 inside the pipette suppressed the activity of acetylcholine-activated K⁺ channels without modifying the single-channel conductance. Mdivi-1 (30 μM) slightly depressed the peak amplitude of Na⁺ current with no change in the overall current-voltage relationship. Under current-clamp recordings, addition of mdivi-1 resulted in prolongation for the duration of action potentials (APs) and to increase the firing of spontaneous APs in HL-1 cells. Similarly, in pituitary GH₃ cells, mdivi-1 was effective in directly suppressing the amplitude of ether-à-go-go-related gene-mediated K⁺ current. Therefore, the lengthening of AP duration and increased firing of APs caused by mdivi-1 can be primarily explained by its inhibition of these K⁺ channels enriched in heart cells. The observed effects of mdivi-1 on ion currents were direct and not associated with its inhibition of mitochondrial division. Copyright © 2012 Elsevier B.V. All rights reserved.

Enhanced basal late sodium current appears to underlie the age-related prolongation of action potential duration in guinea pig ventricular myocytes.

PubMed

Song, Yejia; Belardinelli, Luiz

2017-12-14

Aging hearts have prolonged QT interval and are vulnerable to oxidative stress. Because the QT interval indirectly reflects the action potential duration (APD), we examined the hypotheses that 1) the APD of ventricular myocytes increases with age; 2) the age-related prolongation of APD is due to an enhancement of basal late Na + current (I NaL ); 3) inhibition of I NaL may protect aging hearts from arrhythmogenic effects of hydrogen peroxide (H 2 O 2 ). Experiments were performed on ventricular myocytes isolated from one-month (young) and one-year (old) guinea pigs (GPs). The APD of myocytes from old GPs was significantly longer than that from young GPs and was shortened by the I NaL inhibitors GS967 and tetrodotoxin. The magnitude of I NaL was significantly larger in myocytes from old than from young GPs. The CaMKII inhibitors KN-93 and AIP and the Na V 1.5-channel blocker MTSEA blocked the I NaL . There were no significant differences between myocytes from young and old GPs in L-type Ca 2+ current and the rapidly- and slowly-activating delayed rectifier K + currents, although the inward rectifier K + current was slightly decreased in myocytes from old GPs. H 2 O 2 induced more early afterdepolarizations in myocytes from old than from young GPs. The effect of H 2 O 2 was attenuated by GS967. The results suggest that 1) the APD of myocytes from old GPs is prolonged, 2) a CaMKII-mediated increase in Na V 1.5-channel I NaL is responsible for the prolongation of APD, and 3) Inhibition of I NaL may be beneficial for maintaining electrical stability under oxidative stress in myocytes of old GPs.

Effect of mental challenge induced by movie clips on action potential duration in normal human subjects independent of heart rate.

PubMed

Child, Nicholas; Hanson, Ben; Bishop, Martin; Rinaldi, Christopher A; Bostock, Julian; Western, David; Cooklin, Michael; O'Neil, Mark; Wright, Matthew; Razavi, Reza; Gill, Jaswinder; Taggart, Peter

2014-06-01

Mental stress and emotion have long been associated with ventricular arrhythmias and sudden death in animal models and humans. The effect of mental challenge on ventricular action potential duration (APD) in conscious healthy humans has not been reported. Activation recovery intervals measured from unipolar electrograms as a surrogate for APD (n=19) were recorded from right and left ventricular endocardium during steady-state pacing, whilst subjects watched an emotionally charged film clip. To assess the possible modulating role of altered respiration on APD, the subjects then repeated the same breathing pattern they had during the stress, but without the movie clip. Hemodynamic parameters (mean, systolic, and diastolic blood pressure, and rate of pressure increase) and respiration rate increased during the stressful part of the film clip (P=0.001). APD decreased during the stressful parts of the film clip, for example, for global right ventricular activation recovery interval at end of film clip 193.8 ms (SD, 14) versus 198.0 ms (SD, 13) during the matched breathing control (end film left ventricle 199.8 ms [SD, 16] versus control 201.6 ms [SD, 15]; P=0.004). Respiration rate increased during the stressful part of the film clip (by 2 breaths per minute) and was well matched in the respective control period without any hemodynamic or activation recovery interval changes. Our results document for the first time direct recordings of the effect of a mental challenge protocol on ventricular APD in conscious humans. The effect of mental challenge on APD was not secondary to emotionally induced altered respiration or heart rate. © 2014 American Heart Association, Inc.

Adrenergic Stress Protection of Human iPS Cell-Derived Cardiomyocytes by Fast Kv7.1 Recycling

PubMed Central

Piccini, Ilaria; Fehrmann, Edda; Frank, Stefan; Müller, Frank U.; Greber, Boris; Seebohm, Guiscard

2017-01-01

The fight-or-flight response (FFR), a physiological acute stress reaction, involves positive chronotropic and inotropic effects on heart muscle cells mediated through β-adrenoceptor activation. Increased systolic calcium is required to enable stronger heart contractions whereas elevated potassium currents are to limit the duration of the action potentials and prevent arrhythmia. The latter effect is accomplished by an increased functional activity of the Kv7.1 channel encoded by KCNQ1. Current knowledge, however, does not sufficiently explain the full extent of rapid Kv7.1 activation and may hence be incomplete. Using inducible genetic KCNQ1 complementation in KCNQ1-deficient human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we here reinvestigate the functional role of Kv7.1 in adapting human CMs to adrenergic stress. Under baseline conditions, Kv7.1 was barely detectable at the plasma membrane of hiPSC-CMs, yet it fully protected these from adrenergic stress-induced beat-to-beat variability of repolarization and torsade des pointes-like arrhythmia. Furthermore, isoprenaline treatment increased field potential durations specifically in KCNQ1-deficient CMs to cause these adverse macroscopic effects. Mechanistically, we find that the protective action by Kv7.1 resides in a rapid translocation of channel proteins from intracellular stores to the plasma membrane, induced by adrenergic signaling. Gene silencing experiments targeting RAB GTPases, mediators of intracellular vesicle trafficking, showed that fast Kv7.1 recycling under acute stress conditions is RAB4A-dependent.Our data reveal a key mechanism underlying the rapid adaptation of human cardiomyocytes to adrenergic stress. These findings moreover aid to the understanding of disease pathology in long QT syndrome and bear important implications for safety pharmacological screening. PMID:28959214

Dominant frequency increase rate predicts transition from paroxysmal to long-term persistent atrial fibrillation.

PubMed

Martins, Raphael P; Kaur, Kuljeet; Hwang, Elliot; Ramirez, Rafael J; Willis, B Cicero; Filgueiras-Rama, David; Ennis, Steven R; Takemoto, Yoshio; Ponce-Balbuena, Daniela; Zarzoso, Manuel; O'Connell, Ryan P; Musa, Hassan; Guerrero-Serna, Guadalupe; Avula, Uma Mahesh R; Swartz, Michael F; Bhushal, Sandesh; Deo, Makarand; Pandit, Sandeep V; Berenfeld, Omer; Jalife, José

2014-04-08

Little is known about the mechanisms underlying the transition from paroxysmal to persistent atrial fibrillation (AF). In an ovine model of long-standing persistent AF we tested the hypothesis that the rate of electric and structural remodeling, assessed by dominant frequency (DF) changes, determines the time at which AF becomes persistent. Self-sustained AF was induced by atrial tachypacing. Seven sheep were euthanized 11.5±2.3 days after the transition to persistent AF and without reversal to sinus rhythm; 7 sheep were euthanized after 341.3±16.7 days of long-standing persistent AF. Seven sham-operated animals were in sinus rhythm for 1 year. DF was monitored continuously in each group. Real-time polymerase chain reaction, Western blotting, patch clamping, and histological analyses were used to determine the changes in functional ion channel expression and structural remodeling. Atrial dilatation, mitral valve regurgitation, myocyte hypertrophy, and atrial fibrosis occurred progressively and became statistically significant after the transition to persistent AF, with no evidence for left ventricular dysfunction. DF increased progressively during the paroxysmal-to-persistent AF transition and stabilized when AF became persistent. Importantly, the rate of DF increase correlated strongly with the time to persistent AF. Significant action potential duration abbreviation, secondary to functional ion channel protein expression changes (CaV1.2, NaV1.5, and KV4.2 decrease; Kir2.3 increase), was already present at the transition and persisted for 1 year of follow up. In the sheep model of long-standing persistent AF, the rate of DF increase predicts the time at which AF stabilizes and becomes persistent, reflecting changes in action potential duration and densities of sodium, L-type calcium, and inward rectifier currents.

Influence of limb temperature on cutaneous silent periods.

PubMed

Kofler, Markus; Valls-Solé, Josep; Vasko, Peter; Boček, Václav; Štetkárová, Ivana

2014-09-01

The cutaneous silent period (CSP) is a spinal inhibitory reflex mediated by small-diameter afferents (A-delta fibers) and large-diameter efferents (alpha motoneurons). The effect of limb temperature on CSPs has so far not been assessed. In 27 healthy volunteers (11 males; age 22-58 years) we recorded median nerve motor and sensory action potentials, median nerve F-wave and CSPs induced by noxious digit II stimulation in thenar muscles in a baseline condition at room temperature, and after randomly submersing the forearm in 42 °C warm or 15 °C cold water for 20 min each. In cold limbs, distal and proximal motor and sensory latencies as well as F-wave latencies were prolonged. Motor and sensory nerve conduction velocities were reduced. Compound motor and sensory nerve action potential amplitudes did not differ significantly from baseline. CSP onset and end latencies were more delayed than distal and proximal median nerve motor and sensory latencies, whereas CSP duration was not affected. In warm limbs, opposite but smaller changes were seen in nerve conduction studies and CSPs. The observed CSP shift "en bloc" towards longer latencies without affecting CSP duration during limb cooling concurs with slower conduction velocity in both afferent and efferent fibers. Disparate conduction slowing in afferents and efferents, however, suggests that nociceptive EMG suppression is mediated by fibers of different size in the afferent than in the efferent arm, indirectly supporting the contribution of A-delta fibers as the main afferent input. Limb temperature should be taken into account when testing CSPs in the clinical setting, as different limb temperatures affect CSP latencies more than large-diameter fiber conduction function. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Role of suppression of the inward rectifier current in terminal action potential repolarization in the failing heart.

PubMed

Klein, Michael G; Shou, Matie; Stohlman, Jayna; Solhjoo, Soroosh; Haigney, Myles; Tidwell, Richard R; Goldstein, Robert E; Flagg, Thomas P; Haigney, Mark C

2017-08-01

The failing heart exhibits an increased arrhythmia susceptibility that is often attributed to action potential (AP) prolongation due to significant ion channel remodeling. The inwardly rectifying K + current (I K1 ) has been reported to be reduced, but its contribution to shaping the AP waveform and cell excitability in the failing heart remains unclear. The purpose of this study was to define the effect of I K1 suppression on the cardiac AP and excitability in the normal and failing hearts. We used electrophysiological and pharmacological approaches to investigate I K1 function in a swine tachy-pacing model of heart failure (HF). Terminal repolarization of the AP (TRAP; the time constant of the exponential fit to terminal repolarization) was markedly prolonged in both myocytes and arterially perfused wedges from animals with HF. TRAP was increased by 54.1% in HF myocytes (P < .001) and 26.2% in HF wedges (P = .014). The increase in TRAP was recapitulated by the potent and specific I K1 inhibitor, PA-6 (pentamidine analog 6), indicating that I K1 is the primary determinant of the final phase of repolarization. Moreover, we find that I K1 suppression reduced the ratio of effective refractory period to AP duration at 90% of repolarization, permitting re-excitation before full repolarization, reduction of AP upstroke velocity, and likely promotion of slow conduction. Using an objective measure of terminal repolarization, we conclude that I K1 is the major determinant of the terminal repolarization time course. Moreover, suppression of I K1 prolongs repolarization and reduces postrepolarization refractoriness without marked effects on the overall AP duration. Collectively, these findings demonstrate how I K1 suppression may contribute to arrhythmogenesis in the failing heart. Published by Elsevier Inc.

Adrenergic Stress Protection of Human iPS Cell-Derived Cardiomyocytes by Fast Kv7.1 Recycling.

PubMed

Piccini, Ilaria; Fehrmann, Edda; Frank, Stefan; Müller, Frank U; Greber, Boris; Seebohm, Guiscard

2017-01-01

The fight-or-flight response (FFR), a physiological acute stress reaction, involves positive chronotropic and inotropic effects on heart muscle cells mediated through β-adrenoceptor activation. Increased systolic calcium is required to enable stronger heart contractions whereas elevated potassium currents are to limit the duration of the action potentials and prevent arrhythmia. The latter effect is accomplished by an increased functional activity of the K v 7.1 channel encoded by KCNQ1 . Current knowledge, however, does not sufficiently explain the full extent of rapid K v 7.1 activation and may hence be incomplete. Using inducible genetic KCNQ1 complementation in KCNQ1 -deficient human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we here reinvestigate the functional role of K v 7.1 in adapting human CMs to adrenergic stress. Under baseline conditions, K v 7.1 was barely detectable at the plasma membrane of hiPSC-CMs, yet it fully protected these from adrenergic stress-induced beat-to-beat variability of repolarization and torsade des pointes -like arrhythmia. Furthermore, isoprenaline treatment increased field potential durations specifically in KCNQ1-deficient CMs to cause these adverse macroscopic effects. Mechanistically, we find that the protective action by K v 7.1 resides in a rapid translocation of channel proteins from intracellular stores to the plasma membrane, induced by adrenergic signaling. Gene silencing experiments targeting RAB GTPases, mediators of intracellular vesicle trafficking, showed that fast K v 7.1 recycling under acute stress conditions is RAB4A-dependent.Our data reveal a key mechanism underlying the rapid adaptation of human cardiomyocytes to adrenergic stress. These findings moreover aid to the understanding of disease pathology in long QT syndrome and bear important implications for safety pharmacological screening.

Developing novel anti-fibrotic therapeutics to modulate post-surgical wound healing in glaucoma: big potential for small molecules

PubMed Central

Yu-Wai-Man, Cynthia; Khaw, Peng Tee

2015-01-01

Ocular fibrosis leads to significant visual impairment and blindness in millions of people worldwide, and is one of the largest areas of unmet need in clinical ophthalmology. The antimetabolites, mitomycin C and 5-fluorouracil, are the current gold standards used primarily to prevent fibrosis after glaucoma surgery, but have potentially blinding complications like tissue damage, breakdown and infection. This review thus focuses on the development of new classes of small molecule therapeutics to prevent post-surgical fibrosis in the eye, especially in the context of glaucoma filtration surgery. We discuss recent advances and innovations in ophthalmic wound healing research, including antibodies, RNAi, gene therapy, nanoparticles, liposomes, dendrimers, proteoglycans and small molecule inhibitors. We also review the challenges involved in terms of drug delivery, duration of action and potential toxicity of new anti-fibrotic agents in the eye. PMID:25983855

Specific Features of the Response of Cerium to Pulsed Actions

NASA Astrophysics Data System (ADS)

Atroshenko, S. A.; Zubareva, A. N.; Morozov, V. A.; Savenkov, G. G.; Utkin, A. V.

2018-02-01

Experimental studies of cerium at high rates and nanosecond durations of action have been performed. The isomorphic phase transition was studied upon shock compression. The spall strength of cerium has been determined. Cerium demonstrates anomalous compressibility upon dynamic loading. Stress waves dampen under action of a high-current electron beam due to the energy dissipation during fragmentation and twinning.

Bioactive Compounds and Their Neuroprotective Effects in Diabetic Complications

PubMed Central

Oh, Yoon Sin

2016-01-01

Hyperglycemia, hyperlipidemia and impaired insulin signaling during the development of diabetes can cause diabetic complications, such as diabetic neuropathy, resulting in significant morbidity and mortality. Although various therapeutics are available for the treatment of diabetic neuropathy, no absolute cure exists, and additional research is necessary to comprehensively understand the underlying pathophysiological pathways. A number of studies have demonstrated the potential health benefits of bioactive compounds, i.e., flavonoids and vitamins, which may be effective as supplementary treatments for diabetes and its complications. In this review, we highlight the most recent reports about the mechanisms of action of bioactive compounds (flavonoids and vitamins) possessing potential neuroprotective properties in diabetic conditions. Additional clinical studies are required to determine the appropriate dose and duration of bioactive compound supplementation for neuroprotection in diabetic patients. PMID:27483315

Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence.

PubMed

Rohleder, Cathrin; Müller, Juliane K; Lange, Bettina; Leweke, F M

2016-01-01

There is urgent need for the development of mechanistically different and less side-effect prone antipsychotic compounds. The endocannabinoid system has been suggested to represent a potential new target in this indication. While the chronic use of cannabis itself has been considered a risk factor contributing to the development of schizophrenia, triggered by the phytocannabinoid delta-9-tetrahydrocannabinol (Δ 9 -THC), cannabidiol, the second most important phytocannabinoid, appears to have no psychotomimetic potential. Although, results from animal studies are inconsistent to a certain extent and seem to depend on behavioral paradigms, treatment duration and experimental conditions applied, cannabidiol has shown antipsychotic properties in both rodents and rhesus monkeys. After some individual treatment attempts, the first randomized, double-blind controlled clinical trial demonstrated that in acute schizophrenia cannabidiol exerts antipsychotic properties comparable to the antipsychotic drug amisulpride while being accompanied by a superior, placebo-like side effect profile. As the clinical improvement by cannabidiol was significantly associated with elevated anandamide levels, it appears likely that its antipsychotic action is based on mechanisms associated with increased anandamide concentrations. Although, a plethora of mechanisms of action has been suggested, their potential relevance for the antipsychotic effects of cannabidiol still needs to be investigated. The clarification of these mechanisms as well as the establishment of cannabidiol's antipsychotic efficacy and its hopefully benign side-effect profile remains the subject of a number of previously started clinical trials.

Spatial correlation of action potential duration and diastolic dysfunction in transgenic and drug-induced LQT2 rabbits.

PubMed

Odening, Katja E; Jung, Bernd A; Lang, Corinna N; Cabrera Lozoya, Rocio; Ziupa, David; Menza, Marius; Relan, Jatin; Franke, Gerlind; Perez Feliz, Stefanie; Koren, Gideon; Zehender, Manfred; Bode, Christoph; Brunner, Michael; Sermesant, Maxime; Föll, Daniela

2013-10-01

Enhanced dispersion of action potential duration (APD) is a major contributor to long QT syndrome (LQTS)-related arrhythmias. To investigate spatial correlations of regional heterogeneities in cardiac repolarization and mechanical function in LQTS. Female transgenic LQTS type 2 (LQT2; n = 11) and wild-type littermate control (LMC) rabbits (n = 9 without E4031 and n = 10 with E4031) were subjected to phase contrast magnetic resonance imaging to assess regional myocardial velocities. In the same rabbits' hearts, monophasic APDs were assessed in corresponding segments. In LQT2 and E4031-treated rabbits, APD was longer in all left ventricular segments (P < .01) and APD dispersion was greater than that in LMC rabbits (P < .01). In diastole, peak radial velocities (Vr) were reduced in LQT2 and E4031-treated compared to LMC rabbits in LV base and mid (LQT2: -3.36 ± 0.4 cm/s, P < .01; E4031-treated: -3.24 ± 0.6 cm/s, P < .0001; LMC: -4.42 ± 0.5 cm/s), indicating an impaired diastolic function. Regionally heterogeneous diastolic Vr correlated with APD (LQT2: correlation coefficient [CC] 0.38, P = .01; E4031-treated: CC 0.42, P < .05). Time-to-diastolic peak Vr were prolonged in LQT2 rabbits (LQT2: 196.8 ± 2.9 ms, P < .001; E4031-treated: 199.5 ± 2.2 ms, P < .0001, LMC 183.1 ± 1.5), indicating a prolonged contraction duration. Moreover, in transgenic LQT2 rabbits, diastolic time-to-diastolic peak Vr correlated with APD (CC 0.47, P = .001). In systole, peak Vr were reduced in LQT2 and E4031-treated rabbits (P < .01) but longitudinal velocities or ejection fraction did not differ. Finally, random forest machine learning algorithms enabled a differentiation between LQT2, E4031-treated, and LMC rabbits solely based on "mechanical" magnetic resonance imaging data. The prolongation of APD led to impaired diastolic and systolic function in transgenic and drug-induced LQT2 rabbits. APD correlated with regional diastolic dysfunction, indicating that LQTS is not purely an electrical but an electromechanical disorder. © 2013 Heart Rhythm Society. All rights reserved.

Effects of Nicotinamide Adenine Dinucleotide (NAD(+)) and Diadenosine Tetraphosphate (Ap4A) on Electrical Activity of Working and Pacemaker Atrial Myocardium in Guinea Pigs.

PubMed

Pustovit, K B; Abramochkin, D V

2016-04-01

Effects of nucleotide polyphosphate compounds (nicotinamide adenine dinucleotide, NAD(+); diadenosine tetraphosphate, Ap4A) on the confi guration of action potentials were studied in isolated preparations of guinea pig sinoatrial node and right atrial appendage (auricle). In the working myocardium, NAD(+) and Ap4A in concentrations of 10(-5) and 10(-4) M had no effect on resting potential, but significantly reduced the duration of action potentials; the most pronounced decrease was found at 25% repolarization. In the primary pacemaker of the sinoatrial node, both concentrations of NAD(+) and Ap4A induced hyperpolarization and reduction in the rate of slow diastolic depolarization, but significant slowing of the sinus rhythm was produced by these substances only in the concentration of 10(-4) M. Moreover, AP shortening and marked acceleration of AP upstroke were observed in the pacemaker myocardium after application of polyphosphates. Comparative analysis of the effects of NAD(+) and Ap4A in the working and pacemaker myocardium drove us to a hypothesis on inhibitory effects of these substances on L-type calcium current accompanied by stimulation of one or several potassium currents, which induce enhancement of repolarization and hyperpolarization of membranes probably mediated by the activation of purine receptors.

Prediction of Human Activity by Discovering Temporal Sequence Patterns.

PubMed

Li, Kang; Fu, Yun

2014-08-01

Early prediction of ongoing human activity has become more valuable in a large variety of time-critical applications. To build an effective representation for prediction, human activities can be characterized by a complex temporal composition of constituent simple actions and interacting objects. Different from early detection on short-duration simple actions, we propose a novel framework for long -duration complex activity prediction by discovering three key aspects of activity: Causality, Context-cue, and Predictability. The major contributions of our work include: (1) a general framework is proposed to systematically address the problem of complex activity prediction by mining temporal sequence patterns; (2) probabilistic suffix tree (PST) is introduced to model causal relationships between constituent actions, where both large and small order Markov dependencies between action units are captured; (3) the context-cue, especially interactive objects information, is modeled through sequential pattern mining (SPM), where a series of action and object co-occurrence are encoded as a complex symbolic sequence; (4) we also present a predictive accumulative function (PAF) to depict the predictability of each kind of activity. The effectiveness of our approach is evaluated on two experimental scenarios with two data sets for each: action-only prediction and context-aware prediction. Our method achieves superior performance for predicting global activity classes and local action units.

Preclinical pharmacology of midazolam.

PubMed

Pieri, L

1983-01-01

Midazolam, a new imidazobenzodiazepine, forms salts that are stable in water solution, and has an overall pharmacological potency similar to that of diazepam but a much shorter duration of action. It produces all the characteristic effects of the benzodiazepine class. Its metabolites account for only a negligible part, if any, of its pharmacological effects observed in the mouse. The time course of its anticonvulsant activity, studied with different experimental protocols and by different routes of administration, revealed an almost immediate onset of action. Midazolam was slightly more potent, and its duration of action was shorter than diazepam, in enhancing presynaptic inhibition in the spinal cord of cats and in depressing spontaneous activity of cerebellar Purkinje cells in the rat. Midazolam decreased spontaneous multiunit activity (MUA) in different nuclei of the brain in 'encéphale isolé' rats. This depression was reversed by Ro 15-1788, a recently discovered selective benzodiazepine antagonist. Midazolam and diazepam decreased the cyclic GMP level in the cerebellum of rats with about the same potency; the effect of midazolam was of much shorter duration than that of diazepam. Midazolam had one-third the potency of diazepam in displacing 3H-flunitrazepam in mouse brain in vivo, and also in this case the effect of midazolam was of brief duration, as compared with diazepam. Midazolam in therapeutic doses was virtually ineffective in the cardiovascular system of conscious dogs after p.o. or i.v. administration. No direct effects of the drug on autonomic functions were found. The animal data suggest the usefulness of midazolam as an oral sleep-inducer, as an agent for i.v. induction of anaesthesia and as an i.v. or i.m. anticonvulsant in status epilepticus or tetanus, because of its rapid onset of action and its excellent local tolerance as water-soluble injection form.

Preparing a prescription drug monitoring program data set for research purposes.

PubMed

O'Kane, Nicole; Hallvik, Sara E; Marino, Miguel; Van Otterloo, Joshua; Hildebran, Christi; Leichtling, Gillian; Deyo, Richard A

2016-09-01

To develop a complete and consistent prescription drug monitoring program (PDMP) data set for use by drug safety researchers in evaluating patterns of high-risk use and potential abuse of scheduled drugs. Using publically available data references from the US Food and Drug Administration and the Centers for Disease Control and Prevention, we developed a strategic methodology to assign drug categories based on pharmaceutical class for the majority of prescriptions in the PDMP data set. We augmented data elements required to calculate morphine milligram equivalents and assigned duration of action (short-acting or long acting) properties for a majority of opioids in the data set. About 10% of prescriptions in the PDMP data set did not have a vendor-assigned drug category, and 20% of opioid prescriptions were missing data needed to calculate risk metrics. Using inclusive methods, 19 133 167 (>99.9%) of prescriptions in the PDMP data set were assigned a drug category. For the opioid category, augmenting data elements resulted in 10 760 669 (99.8%) having required values to calculate morphine milligram equivalents and evaluate duration of action properties. Drug safety researchers who require a complete and consistent PDMP data set can use the methods described here to ensure that prescriptions of interest are assigned consistent drug categories and complete opioid risk variable values. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

An Investigation of the Mechanics and Sticking Region of a One-Repetition Maximum Close-Grip Bench Press versus the Traditional Bench Press

PubMed Central

Lockie, Robert G.; Callaghan, Samuel J.; Moreno, Matthew R.; Risso, Fabrice G.; Liu, Tricia M.; Stage, Alyssa A.; Birmingham-Babauta, Samantha A.; Stokes, John J.; Giuliano, Dominic V.; Lazar, Adrina; Davis, DeShaun L.; Orjalo, Ashley J.

2017-01-01

The close-grip bench press (CGBP) is a variation of the traditional bench press (TBP) that uses a narrower grip (~95% of biacromial distance (BAD)) and has potential application for athletes performing explosive arm actions from positions where the hands are held close to the torso. Limited research has investigated CGBP mechanics compared to the TBP. Twenty-seven resistance-trained individuals completed a one-repetition maximum TBP and CGBP. The TBP was performed with the preferred grip; the CGBP with a grip width of 95% BAD. A linear position transducer measured lift distance and duration; peak and mean power, velocity, and force; distance and time when peak power occurred; and work. Pre-sticking region (PrSR), sticking region, and post-sticking region distance and duration for each lift was measured. A repeated measures ANOVA was used to derive differences between TBP and CGBP mechanics (p < 0.01); effect sizes (d) were also calculated. A greater load was lifted in the TBP, thus mean force was greater (d = 0.16–0.17). Peak power and velocity were higher in the CGBP, which had a longer PrSR distance (d = 0.49–1.32). The CGBP could emphasize power for athletes that initiate explosive upper-body actions with the hands positioned close to the torso.

Apomorphine and piribedil in rats: biochemical and pharmacologic studies.

PubMed

Butterworth, R F; Poignant, J C; Barbeau, A

1975-01-01

We studied the biochemical and pharmacologic modes of action of piribedil and apomorphine in the rat. Although both drugs have many points in common, they are also different in many of their manifestations. Apomorphine causes high-intensity, short-duration stereotyped behavior; it is distributed within the brain in uneven fashion, the striatum being the area of lowest concentration as measured by fluorometry. Direct stereotactic injection within the dopaminergic mesolimbic system, and particularly the tuberculum olfactorium, produced constant intense responses. All effects of apomorphine can be blocked by pimozide, but propanolol, a beta blocker, only reduces aggression and ferocity, leaving stereotyped behaviors intact. Finally, L-5-HTP tends to reduce aggression, ferocity, and to a lesser extent stereotypy; MIF or piribedil, as well as reserpine, potentiates the stereotyped behaviors induced by apomorphine, whereas L-DOPA usually decreases them. Piribedil, on the other hand, causes low-intensity, long-duration stereotyped behavior. It is distributed within the brain almost uniformly. Most effects of piribedil can be blocked by pimozide, but propanolol blocks only aggression and ferocity, leaving stereotyped behaviors intact. On the other hand, clonidine, an alpha-receptor agonist, blocks stereotyped behaviors induced by piribedil but markedly increases aggression, ferocity, and motor activity. L-5-HTP and L-DOPA have little effect on piribedil-induced manifestations. Reserpine decreases piribedil stereotypy. The main metabolite of piribedil, S 584, had no clear-cut pharmacologic action in our hands at the dosage used. It is concluded that both apomorphine and piribedil produce stereotyped behavior by modifying the physiologic balance between mesolimbic and nigrostriatal dopaminergic systems. The other actions of apomorphine and piribedil upon aggression, ferocity, and motor activity are not always in parallel and depend probably on the fact that piribedil is less specific, affecting also noradrenergic, serotonergic, histaminergic, and/or cholinergic circuits. The usefulness of piribedil against some forms of human tremor and its low-intensity antiakinetic action probably result from this pattern of pharmacologic activity.

Examining age-related movement representations for sequential (fine-motor) finger movements.

PubMed

Gabbard, Carl; Caçola, Priscila; Bobbio, Tatiana

2011-12-01

Theory suggests that imagined and executed movement planning relies on internal models for action. Using a chronometry paradigm to compare the movement duration of imagined and executed movements, we tested children aged 7-11 years and adults on their ability to perform sequential finger movements. Underscoring this tactic was our desire to gain a better understanding of the age-related ability to create internal models for action requiring fine-motor movements. The task required number recognition and ordering and was presented in three levels of complexity. Results for movement duration indicated that 7-year-olds and adults were different from the other groups with no statistical distinction between 9- and 11-year-olds. Correlation analysis indicated a significant relationship between imagined and executed actions. These results are the first to document the increasing convergence between imagined and executed movements in the context of fine-motor behavior; a finding that adds to our understanding of action representation in children. Copyright © 2011 Elsevier Inc. All rights reserved.

Aging in movement representations for sequential finger movements: a comparison between young-, middle-aged, and older adults.

PubMed

Caçola, Priscila; Roberson, Jerroed; Gabbard, Carl

2013-06-01

Studies show that as we enter older adulthood (>64years), our ability to mentally represent action in the form of using motor imagery declines. Using a chronometry paradigm to compare the movement duration of imagined and executed movements, we tested young-, middle-aged, and older adults on their ability to perform sequential finger (fine-motor) movements. The task required number recognition and ordering and was presented in three levels of complexity. Results for movement duration indicated no differences between young- and middle-aged adults, however both performed faster than the older group. In regard to the association between imagined and executed actions, correlation analyses indicated that values for all groups were positive and moderate (r's .80,.76,.70). In summary, whereas the older adults were significantly slower in processing actions than their younger counterparts, the ability to mentally represent their actions was similar. Copyright © 2013 Elsevier Inc. All rights reserved.

FURTHER STUDY OF SOMA, DENDRITE, AND AXON EXCITATION IN SINGLE NEURONS

PubMed Central

Eyzaguirre, Carlos; Kuffler, Stephen W.

1955-01-01

The present investigation continues a previous study in which the soma-dendrite system of sensory neurons was excited by stretch deformation of the peripheral dendrite portions. Recording was done with intracellular leads which were inserted into the cell soma while the neuron was activated orthodromically or antidromically. The analysis was also extended to axon conduction. Crayfish, Procambarus alleni (Faxon) and Orconectes virilis (Hagen), were used. 1. The size and time course of action potentials recorded from the soma-dendrite complex vary greatly with the level of the cell's membrane potential. The latter can be changed over a wide range by stretch deformation which sets up a "generator potential" in the distal portions of the dendrites. If a cell is at its resting unstretched equilibrium potential, antidromic stimulation through the axon causes an impulse which normally overshoots the resting potential and decays into an afternegativity of 15 to 20 msec. duration. The postspike negativity is not followed by an appreciable hyperpolarization (positive) phase. If the membrane potential is reduced to a new steady level a postspike positivity appears and increases linearly over a depolarization range of 12 to 20 mv. in various cells. At those levels the firing threshold of the cell for orthodromic discharges is generally reached. 2. The safety factor for conduction between axon and cell soma is reduced under three unrelated conditions, (a) During the recovery period (2 to 3 msec.) immediately following an impulse which has conducted fully over the cell soma, a second impulse may be delayed, may invade the soma partially, or may be blocked completely. (b) If progressive depolarization is produced by stretch, it leads to a reduction of impulse height and eventually to complete block of antidromic soma invasion, resembling cathodal block, (c) In some cells, when the normal membrane potential is within several millivolts of the relaxed resting state, an antidromic impulse may be blocked and may set up within the soma a local potential only. The local potential can sum with a second one or it may sum with potential changes set up in the dendrites, leading to complete invasion of the soma. Such antidromic invasion block can always be relieved by appropriate stretch which shifts the membrane potential out of the "blocking range" nearer to the soma firing level. During the afterpositivity of an impulse in a stretched cell the membrane potential may fall below or near the blocking range. During that period another impulse may be delayed or blocked. 3. Information regarding activity and conduction in dendrites has been obtained indirectly, mainly by analyzing the generator action under various conditions of stretch. The following conclusions have been reached: The large dendrite branches have similar properties to the cell body from which they arise and carry the same kind of impulses. In the finer distal filaments of even lightly depolarized dendrites, however, no axon type all-or-none conduction occurs since the generator potential persists to a varying degree during antidromic invasion of the cell. With the membrane potential at its resting level the dendrite terminals contribute to the prolonged impulse afternegativity of the soma. 4. Action potentials in impaled axons and in cell bodies have been compared. It is thought that normally the over-all duration of axon impulses is shorter. Local activity during reduction of the safety margin for conduction was studied. 5. An analysis was made of high frequency grouped discharges which occasionally arise in cells. They differ in many essential aspects from the regular discharges set up by the generator action. It is proposed that grouped discharges occur only when invasion of dendrites is not synchronous, due to a delay in excitation spread between soma and dendrites. Each impulse in a group is assumed to be caused by an impulse in at least one of the large dendrite branches. Depolarization of dendrites abolishes the grouped activity by facilitating invasion of the large dendrite branches. PMID:13252238

Persistent modification of Na{sub v}1.9 following chronic exposure to insecticides and pyridostigmine bromide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nutter, Thomas J., E-mail: tnutter@dental.ufl.edu; Cooper, Brian Y., E-mail: bcooper@dental.ufl.edu

Many veterans of the 1991 Gulf War (GW) returned from that conflict with a widespread chronic pain affecting deep tissues. Recently, we have shown that a 60 day exposure to the insecticides permethrin, chlorpyrifos, and pyridostigmine bromide (NTPB) had little influence on nociceptor action potential forming Na{sub v}1.8, but increased K{sub v}7 mediated inhibitory currents 8 weeks after treatment. Using the same exposure regimen, we used whole cell patch methods to examine whether the influences of NTPB could be observed on Na{sub v}1.9 expressed in muscle and vascular nociceptors. During a 60 day exposure to NTPB, rats exhibited lowered musclemore » pain thresholds and increased rest periods, but these measures subsequently returned to normal levels. Eight and 12 weeks after treatments ceased, DRG neurons were excised from the sensory ganglia. Whole cell patch studies revealed little change in voltage dependent activation and deactivation of Na{sub v}1.9, but significant increases in the amplitude of Na{sub v}1.9 were observed 8 weeks after exposure. Cellular studies, at the 8 week delay, revealed that NTPB also significantly prolonged action potential duration and afterhyperpolarization (22 °C). Acute application of permethrin (10 μM) also increased the amplitude of Na{sub v}1.9 in skin, muscle and vascular nociceptors. In conclusion, chronic exposure to Gulf War agents produced long term changes in the amplitude of Na{sub v}1.9 expressed in muscle and vascular nociceptors. The reported increases in K{sub v}7 amplitude may have been an adaptive response to increased Na{sub v}1.9, and effectively suppressed behavioral pain measures in the post treatment period. Factors that alter the balance between Na{sub v}1.9 and K{sub v}7 could release spontaneous discharge and produce chronic deep tissue pain. - Highlights: • Rats were treated 60 days with permethrin, chlorpyrifos and pyridostigmine bromide. • 8 weeks after treatments, Nav1.9 activation and deactivation were unchanged. • The amplitude and conductance of Nav1.9 were increased 8 weeks following exposure. • Nociceptors exhibit increased action potential duration and afterhyperpolarization. • Acute permethrin altered activation physiology and increased the amplitude of Nav1.9.« less

[Aging-related ionic remodeling of L-type voltage dependent calcium channel in left atria of canine].

PubMed

Zhou, Xian-hui; Zhang, Jian; Gan, Tian-yi; Xu, Guo-jun; Tang, Bao-peng

2012-04-01

To investigate aging-related ionic remodeling of L-type voltage dependent calcium channel (LVDCC) in left atria of canine. Seven adult (2.0 - 2.5 years) and 10 aged (> 8 years) dogs were used. The current of LVDCC was recorded by patch clamp technique in the whole cell mode. The action potential duration (APD(90)), amplitude of action potential plateau (APA), I(Ca-L) peak current density of LVDCC were recorded. The mRNA and protein expressions of α1c subunit (Ca(V1.2)), sarcoplasmic reticulum Ca(2+)-ATPase (SECRA(2)), Calpain-I, ryanodine receptor (RYR(2)) were detected by quantitative RT-PCR and Western blot, respectively. I(Ca-L) peak current density [(-8.11 ± 0.54) pA/pF vs. (-14.04 ± 0.82) pA/pF, P < 0.05] was significantly reduced and action potential duration to 90% repolarization (APD(90)) significantly prolonged [(340.5 ± 10.1) ms vs. (320.0 ± 7.9) ms, P < 0.05] in aged group than in adult group. The mRNA gene expression level of Ca(V1.2) was significantly lower (0.90 ± 0.35 vs. 2.38 ± 0.40, P < 0.05) while mRNA expression of RYR(2) was significantly higher (4.39 ± 4.68 vs. 1.49 ± 1.69, P < 0.05) in the aged dogs than in the adult dogs. mRNA expression of SECRA(2) and Calpain-I was similar between the two groups. Similarly, the protein expression level of Ca(V1.2) was significantly lower (0.13 ± 0.10 vs. 0.29 ± 0.12, P < 0.05) while the protein expression level of RYR(2) was significantly higher (0.18 ± 0.21 vs. 0.08 ± 0.36, P < 0.05) in the aged dogs than in the adult dogs. Again, protein expression of SECRA(2), PLN(1) and Calpain-I was similar between the two groups. These data suggest that aging could induce mRNA and protein expression changes of Ca(V1.2) and RYR(2) of LVDCC which might serve as the molecular basis of I(Ca-L) remodeling in aged dogs and might be linked to the increased likelihood of developing atrial fibrillation (AF) in aged dogs.

Kinematic cues in perceptual weight judgement and their origins in box lifting

PubMed Central

Hamilton, A.; Joyce, D. W.; Flanagan, R.; Frith, C. D.; Wolpert, D. M.

2009-01-01

When accepting a parcel from another person, we are able to use information about that person’s movement to estimate in advance the weight of the parcel, that is, to judge its weight from observed action. Perceptual weight judgment provides a powerful method to study our interpretation of other people’s actions, but it is not known what sources of information are used in judging weight. We have manipulated full form videos to obtain precise control of the perceived kinematics of a box lifting action, and use this technique to explore the kinematic cues that affect weight judgment. We find that observers rely most on the duration of the lifting movement to judge weight, and make less use of the durations of the grasp phase, when the box is first gripped, or the place phase, when the box is put down. These findings can be compared to the kinematics of natural box lifting behaviour, where we find that the duration of the grasp component is the best predictor of true box weight. The lack of accord between the optimal cues predicted by the natural behaviour and the cues actually used in the perceptual task has implications for our understanding of action observation in terms of a motor simulation. The differences between perceptual and motor behaviour are evidence against a strong version of the motor simulation hypothesis. PMID:16311765

Predicting lethal entanglements as a consequence of drag from fishing gear.

PubMed

van der Hoop, Julie M; Corkeron, Peter; Henry, Allison G; Knowlton, Amy R; Moore, Michael J

2017-02-15

Large whales are frequently entangled in fishing gear and sometimes swim while carrying gear for days to years. Entangled whales are subject to additional drag forces requiring increased thrust power and energy expenditure over time. To classify entanglement cases and aid potential disentanglement efforts, it is useful to know how long an entangled whale might survive, given the unique configurations of the gear they are towing. This study establishes an approach to predict drag forces on fishing gear that entangles whales, and applies this method to ten North Atlantic right whale cases to estimate the resulting increase in energy expenditure and the critical entanglement duration that could lead to death. Estimated gear drag ranged 11-275N. Most entanglements were resolved before critical entanglement durations (mean±SD 216±260days) were reached. These estimates can assist real-time development of disentanglement action plans and U.S. Federal Serious Injury assessments required for protected species. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mechanism for Amplitude Alternans in Electrocardiograms and the Initiation of Spatiotemporal Chaos

NASA Astrophysics Data System (ADS)

Chen, Diandian Diana; Gray, Richard A.; Uzelac, Ilija; Herndon, Conner; Fenton, Flavio H.

2017-04-01

It is widely believed that one major life-threatening transition to chaotic fibrillation occurs via spiral-wave breakup that is preceded by spatiotemporal dispersion of refractoriness due to alternations in the duration of the cardiac action potential (AP). However, recent clinical and experimental evidence suggests that other characteristics of the AP may contribute to, and perhaps drive, this dangerous dynamical instability. To identify the relative roles of AP characteristics, we performed experiments in rabbit hearts under conditions to minimize AP duration dynamics which unmasked pronounced AP amplitude alternans just before the onset of fibrillation. We used a simplified ionic cell model to derive a return map and a stability condition that elucidates a novel underlying mechanism for AP alternans and spiral breakup. We found that inactivation of the sodium current is key to developing amplitude alternans and is directly connected to conduction block and initiation of arrhythmias. Simulations in 2D where AP amplitude alternation led to turbulence confirm our hypothesis.

The effect of electrical stimulation on corticospinal excitability is dependent on application duration: a same subject pre-post test design.

PubMed

Andrews, Rebecca K; Schabrun, Siobhan M; Ridding, Michael C; Galea, Mary P; Hodges, Paul W; Chipchase, Lucinda S

2013-06-10

In humans, corticospinal excitability is known to increase following motor electrical stimulation (ES) designed to mimic a voluntary contraction. However, whether the effect is equivalent with different application durations and whether similar effects are apparent for short and long applications is unknown. The aim of this study was to investigate whether the duration of peripheral motor ES influenced its effect on corticospinal excitability. The excitability of the corticomotor pathway to abductor pollicis brevis (APB) was measured in fourteen health subjects using transcranial magnetic stimulation before, immediately after and 10 minutes after three different durations (20-, 40-, 60-min) of motor ES (30Hz, ramped). This intervention was designed to mimic a voluntary contraction in APB. To control for effects of motor ES on the peripheral elements (muscle fibre, membrane, neuromuscular junction), maximum compound muscle actions potentials (M-waves) were also recorded at each time point. Results were analysed using a repeated measures analysis of variance. Peripheral excitability was reduced following all three motor ES interventions. Conversely, corticospinal excitability was increased immediately following 20- and 40-min applications of motor ES and this increase was maintained at least 20-min following the intervention. A 60-min application of motor ES did not alter corticospinal excitability. A 20-min application of motor ES that is designed to mimic voluntary muscle contraction is as effective as that applied for 40-min when the aim of the intervention is to increase corticospinal excitability. Longer motor ES durations of 60-min do not influence corticospinal excitability, possibly as a result of homeostatic plasticity mechanisms.

Novel Exenatide Analogs with Peptidic Albumin Binding Domains: Potent Anti-Diabetic Agents with Extended Duration of Action

PubMed Central

Levy, Odile E.; Jodka, Carolyn M.; Ren, Shijun Steven; Mamedova, Lala; Sharma, Abhinandini; Samant, Manoj; D’Souza, Lawrence J.; Soares, Christopher J.; Yuskin, Diane R.; Jin, Li Jenny; Parkes, David G.; Tatarkiewicz, Krystyna; Ghosh, Soumitra S.

2014-01-01

The design, synthesis and pharmacology of novel long-acting exenatide analogs for the treatment of metabolic diseases are described. These molecules display enhanced pharmacokinetic profile and potent glucoregulatory and weight lowering actions compared to native exenatide. [Leu14]exenatide-ABD is an 88 residue peptide amide incorporating an Albumin Binding Domain (ABD) scaffold. [Leu14]exenatide-ABP is a 53 residue peptide incorporating a short Albumin Binding Peptide (ABP). [Leu14]exenatide-ABD and [Leu14]exenatide-ABP exhibited nanomolar functional GLP-1 receptor potency and were metabolically stable in vitro in human plasma and in a pancreatic digestive enzyme mixture. Both molecules displayed picomolar and nanomolar binding association with albumin across multiple species and circulating half lives of 16 and 11 hours, respectively, post a single IV dose in rats. Unlike exenatide, both molecules elicited robust glucose lowering when injected 1 day prior to an oral glucose tolerance test, indicative of their extended duration of action. [Leu14]exenatide-ABD was compared to exenatide in a Lep ob/ob mouse model of diabetes. Twice-weekly subcutaneously dosed [Leu14]exenatide-ABD displayed superior glucose lowering and weight loss in diabetic mice when compared to continuously infused exenatide at the same total weekly dose. A single oral administration of each molecule via an enteric coated capsule to cynomolgus monkeys showed superior pharmacokinetics for [Leu14]exenatide-ABD as compared to [Leu14]exenatide-ABP with detectable exposure longer than 14 days. These studies support the potential use of these novel long acting exenatide analogs with different routes of administration for the treatment of type 2 diabetes. PMID:24503632

In vitro assessment of induced phrenic nerve cryothermal injury.

PubMed

Goff, Ryan P; Bersie, Stephanie M; Iaizzo, Paul A

2014-10-01

Phrenic nerve injury, both left and right, is considered a significant complication of cryoballoon ablation for treatment of drug-refractory atrial fibrillation, and functional recovery of the phrenic nerve can take anywhere from hours to months. The purpose of this study was to focus on short periods of cooling to determine the minimal amount of cooling that may terminate nerve function related to cryo ablation. Left and/or right phrenic nerves were dissected from the pericardium and connective tissue of swine (n = 35 preparations). Nerves were placed in a recording chamber modified with a thermocouple array. This apparatus was placed in a digital water bath to maintain an internal chamber temperature of 37°C. Nerves were stimulated proximally with a 1-V, 0.1-ms square wave. Bipolar compound action potentials were recorded proximal and distal to the site of ablation both before and after ablation, then analyzed to determine changes in latency, amplitude, and duration. Temperatures were recorded at a rate of 5 Hz, and maximum cooling rates were calculated. Phrenic nerves were found to elicit compound action potentials upon stimulation for periods up to 4 hours minimum. Average conduction velocity was 56.7 ± 14.7 m/s preablation and 49.8 ± 16.6 m/s postablation (P = .17). Cooling to mild subzero temperatures ceased production of action potentials for >1 hour. Taking into account the data presented here, previous publications, and a conservative stance, during cryotherapy applications, cooling of the nerve to below 4°C should be avoided whenever possible. Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Characterization of adenosine receptors in guinea-pig isolated left atria.

PubMed Central

Jahnel, U.; Nawrath, H.

1989-01-01

1. The effects of purinergic stimulation on action potential, force of contraction, 86Rb efflux and 45Ca uptake were investigated in guinea-pig left atria. 2. Adenosine exerted a negative inotropic effect which was antagonized by adenosine deaminase but enhanced by dipyridamole. 3. The negative inotropic effect of adenosine was mimicked by 5'-(N-ethyl)-carboxamido-adenosine (NECA) and the isomers of N6-(phenyl-isopropyl)-adenosine, R-PIA and S-PIA. NECA and R-PIA were about 100 times more potent than adenosine, whereas R-PIA was about 100 times more potent than S-PIA. 4. The inotropic effects of adenosine (in the presence of dipyridamole), NECA, R-PIA and S-PIA were competitively antagonized either by theophylline (pA2 about 4.5) or 8-phenyltheophylline (pA2 about 6.3). 5. NECA and R-PIA shortened the action potential duration and increased the rate constant of the efflux of 86Rb in a concentration-dependent manner with no differences in potency; the effects were competitively antagonized by 8-phenyltheophylline. 6. Barium ions reduced the efflux of 86Rb under control conditions and antagonized the increase induced by NECA and R-PIA. 7. NECA and R-PIA significantly reduced 45Ca uptake in beating preparations. 8. It is concluded that adenosine, NECA and R-PIA activate a common receptor population (P1 or A3) on the outside of the cell membrane of atrial heart muscle to increase the potassium conductance and to reduce the action potential and, thereby, calcium influx and force of contraction. PMID:2790380

Towards the construction of a Drought Early Warning System in México

NASA Astrophysics Data System (ADS)

Neri, C.; Magaña, V. O.

2011-12-01

Droughts in Mexico are related to severe impacts in agricultural and livestock activities, water management and with the occurrence of wildfire. Droughts are recurrent, on time scales from years to decades. The impacts however, depend on the vulnerability. The negative impacts may be reduced by studying and monitoring the dynamical evolution of meteorological drought, and by identifying the factors that result in vulnerability, in the context of risk management. Considering the analysis of the vulnerability in the northern of Mexico, a semiarid region highly vulnerable to drought, a Drought Early Warning System was created based on the use of climate information. The first step was to identify the capacity to provide useful climate information to develop prevention actions. Results confirm that the drought in northern Mexico is a well-diagnosed phenomenon from the point of view of impacts in various sectors. However, the use of climate information is still very limited resulting in response to mitigate drought impacts rather than preparing for drought. Part of the problem is the limited capacity to interpret probabilistic forecasts to define actions. Therefore, a key element in a Drought Early Warning System is the development of reliable climate information and the use of indicators to determine of the onset, maximum intensity and duration of the event. The occurrence and severity of drought may be estimated using climate diagnosis and forecast. A preventive response to drought may be defined if the severity and duration surpass a threshold value after which a decision action should be made. In order to establish the relevance of indicators for drought risk management, retroactive analyses have been developed considering the case of northwestern Mexico. After a vulnerability analysis that considers the institutional capacity to make use of climate information, a Drought Early warning System has been designed that considers a number of actions that may be put forward in order to reduce the impacts of such climatic hazard. The potential impact of such system is examined considering a number of actions that may be implemented in the water, agricultural and cattle ranching sectors. We conclude that there are great opportunities to reduce the negative impacts of drought if climate information is used.

Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication

PubMed Central

2012-01-01

A series of CCR5 antagonists representing the thiophene-3-yl-methyl ureas were designed that met the pharmacological criteria for HIV-1 inhibition and mitigated a human ether-a-go-go related gene (hERG) inhibition liability. Reducing lipophilicity was the main design criteria used to identify compounds that did not inhibit the hERG channel, but subtle structural modifications were also important. Interestingly, within this series, compounds with low hERG inhibition prolonged the action potential duration (APD) in dog Purkinje fibers, suggesting a mixed effect on cardiac ion channels. PMID:24900457

A preliminary evaluation of bardoxolone methyl for the treatment of diabetic nephropathy.

PubMed

Thomas, Merlin

2012-08-01

The coordinated activation of Nrf-2-dependent signaling pathway is currently being investigated in a range of chronic diseases. Bardoxolone methyl is a potent, orally bioavailable Nrf-2 agonist. In a recent 52-week study, treatment with bardoxolone methyl improved renal function in patients with chronic kidney disease (CKD) and type 2 diabetes. This improvement was sustained for the duration of the treatment. Such agonists potentially offer new options for the complex management of renal impairment. A literature search was performed to analyze the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of bardoxolone methyl in both healthy volunteers and patients. Updated information about bardoxolone methyl, either after single administration or after chronic administration is also included. A special focus has been put on the putative mechanisms of action and potential toxicity profiles as well as an ongoing trials in patients with CKD and type 2 diabetes. The development of an agent that leads to sustained improvement in renal function comes as a welcome relief to the millions of individuals with diabetes and CKD. However, much remains to be established regarding its actions in a complex and pleiotropic signalling cascade. Other triterpenoids with different PK/PD profiles are currently under development.

Electrophysiological changes correlated with temperature increases induced by high-intensity focused ultrasound ablation.

PubMed

Wu, Ziqi; Kumon, Ronald E; Laughner, Jacob I; Efimov, Igor R; Deng, Cheri X

2015-02-01

To gain better understanding of the detailed mechanisms of high-intensity focused ultrasound (HIFU) ablation for cardiac arrhythmias, we investigated how the cellular electrophysiological (EP) changes were correlated with temperature increases and thermal dose (cumulative equivalent minutes [CEM43]) during HIFU application using Langendorff-perfused rabbit hearts. Employing voltage-sensitive dye di-4-ANEPPS, we measured the EP and temperature during HIFU using simultaneous optical mapping and infrared imaging. Both action potential amplitude (APA) and action potential duration at 50% repolarization (APD50) decreased with temperature increases, and APD50 was more thermally sensitive than APA. EP and tissue changes were irreversible when HIFU-induced temperature increased above 52.3 ± 1.4°C and log10(CEM43) above 2.16 ± 0.51 (n = 5), but were reversible when temperature was below 50.1 ± 0.8°C and log10(CEM43) below -0.9 ± 0.3 (n = 9). EP and temperature/thermal dose changes were spatially correlated with HIFU-induced tissue necrosis surrounded by a transition zone. Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Reduced intrinsic heart rate is associated with reduced arrhythmic susceptibility in guinea-pig heart.

PubMed

Osadchii, Oleg E

2014-12-01

In the clinical setting, patients with slower resting heart rate are less prone to cardiovascular death compared with those with elevated heart rate. However, electrophysiological adaptations associated with reduced cardiac rhythm have not been thoroughly explored. In this study, relationships between intrinsic heart rate and arrhythmic susceptibility were examined by assessments of action potential duration (APD) rate adaptation and inducibility of repolarization alternans in sinoatrial node (SAN)-driven and atrioventricular (AV)-blocked guinea-pig hearts perfused with Langendorff apparatus. Electrocardiograms, epicardial monophasic action potentials, and effective refractory periods (ERP) were assessed in normokalemic and hypokalemic conditions. Slower basal heart rate in AV-blocked hearts was associated with prolonged ventricular repolarization during spontaneous beating, and with attenuated APD shortening at increased cardiac activation rates during dynamic pacing, when compared with SAN-driven hearts. During hypokalemic perfusion, the inducibility of repolarization alternans and tachyarrhythmia by rapid pacing was found to be lower in AV-blocked hearts. This difference was ascribed to prolonged ERP in the setting of reduced basal heart rate, which prevented ventricular capture at critically short pacing intervals required to induce arrhythmia. Reduced basal heart rate is associated with electrophysiological changes that prevent electrical instability upon an abrupt cardiac acceleration.

Curvature effects on activation speed and repolarization in an ionic model of cardiac myocytes

NASA Astrophysics Data System (ADS)

Comtois, P.; Vinet, A.

1999-10-01

Reentry is a major mechanism underlying the initiation and perpetuation of many cardiac arrhythmias 12345. Stimulated ventricular myocytes give action potential characterized by a fast upstroke, a long-lasting plateau, and a late repolarization phase. The plateau phase determines the action potential duration (APD) during which the system remains refractory, a property essential to the synchronization of the heart cycle. The APD varies much with prematurity and this change has been shown to be the main determinant of the dynamics in models of paced cells and cable, and during reentry in the one-dimensional loop. Curvature has also been shown to be an important factor for propagation in experimental and theoretical cardiac extended tissue. The objective of this paper is to combine both curvature and prematurity effects in a kinematical model of propagation in cardiac tissue. First, an approximation of the ionic model is used to obtain the effects of curvature and prematurity on the speed of propagation, the APD, and the absolute refractory period. Two versions of the ionic model are studied that differ in their rate of excitability recovery. The functions are used in a kinematical model describing the propagation of period-1 solutions around an annulus.

Laser-Induced Modification Of Energy Bands Of Transparent Solids

NASA Astrophysics Data System (ADS)

Gruzdev, Vitaly

2010-10-01

Laser-induced variations of electron energy bands of transparent solids significantly affect the initial stages of laser-induced ablation (LIA) influencing rates of ionization and light absorption by conduction-band electrons. We analyze fast variations with characteristic duration in femto-second time domain that include: 1) switching electron functions from bonding to anti-bonding configuration due to laser-induced ionization; 2) laser-driven oscillations of electrons in quasi-momentum space; and 3) direct distortion of the inter-atomic potential by electric field of laser radiation. Among those effects, the latter two have zero delay and reversibly modify band structure taking place from the beginning of laser action. They are of special interest due to their strong influence on the initial stage and threshold of laser ablation. The oscillations modify the electron-energy bands by adding pondermotive potential. The direct action of radiation's electric field leads to high-frequency Franz-Keldysh effect (FKE) spreading the allowed electron states into the forbidden-energy bands. FKE provides decrease of the effective band gap while the electron oscillations lead either to monotonous increase or oscillatory variations of the gap. We analyze the competition between those two opposite trends and their role in initiating LIA.

Electroneurographic findings in patients with solvent induced central nervous system dysfunction.

PubMed Central

Orbaek, P; Rosén, I; Svensson, K

1988-01-01

The function of the peripheral nervous system was examined in a group of 32 men aged 30-65 (mean 49) with diagnosed solvent induced chronic toxic encephalopathy. The subjects were examined at the time of diagnosis and 26 were re-examined after a follow up period of 22-72 months (mean 40) and compared with a group of 50 unexposed male workers aged 27-64 (mean 42) with appropriate adjustment for age. All subjects were carefully scrutinised for alcohol abuse and other neurological diseases. The results of motor fibre neurography disclosed no difference between the groups. Nevertheless, a significant decrease in motor conduction velocity was found in the patients at follow up. Sensory fibre neurography showed signs of slight axonal degeneration with significantly decreased sensory nerve action potential amplitudes in the median and sural nerves; these amplitudes increased during follow up. The duration of sensory nerve action potentials was longer in the exposed group for the median and the sural nerves. The percentage of late components was significantly higher in the median nerve. The warm-cold sensitivity in the exposed group also indicated a slight sensory dysfunction with statistically significant wider detection limits. PMID:2840109

Effect of a muscle relaxant, chlorphenesin carbamate, on the spinal neurons of rats.

PubMed

Kurachi, M; Aihara, H

1984-09-01

The effects of chlorphenesin carbamate (CPC) and mephenesin on spinal neurons were investigated in spinal rats. CPC (50 mg/kg i.v.) inhibited the mono-(MSR) and poly-synaptic reflex (PSR), the latter being more susceptible than the former to CPC depression. Mephenesin also inhibited MSR and PSR, though the effects were short in duration. CPC had no effect on the dorsal root potential evoked by the stimulation of the dorsal root, while mephenesin reduced the dorsal root-dorsal root reflex. The excitability of motoneuron was reduced by the administration of CPC or mephenesin. The excitability of primary afferent terminal was unchanged by CPC, while it was inhibited by mephenesin. Neither CPC nor mephenesin influenced the field potential evoked by the dorsal root stimulation. Both CPC and mephenesin had no effect on the synaptic recovery. These results suggest that both CPC and mephenesin inhibit the firing of motoneurons by stabilizing the neuronal membrane, while mephenesin additionally suppresses the dorsal root reflex and the excitability of the primary afferent terminal. These inhibitory actions of CPC on spinal activities may contribute, at least partly, to its muscle relaxing action.

ParamAP: Standardized Parameterization of Sinoatrial Node Myocyte Action Potentials.

PubMed

Rickert, Christian; Proenza, Catherine

2017-08-22

Sinoatrial node myocytes act as cardiac pacemaker cells by generating spontaneous action potentials (APs). Much information is encoded in sinoatrial AP waveforms, but both the analysis and the comparison of AP parameters between studies is hindered by the lack of standardized parameter definitions and the absence of automated analysis tools. Here we introduce ParamAP, a standalone cross-platform computational tool that uses a template-free detection algorithm to automatically identify and parameterize APs from text input files. ParamAP employs a graphic user interface with automatic and user-customizable input modes, and it outputs data files in text and PDF formats. ParamAP returns a total of 16 AP waveform parameters including time intervals such as the AP duration, membrane potentials such as the maximum diastolic potential, and rates of change of the membrane potential such as the diastolic depolarization rate. ParamAP provides a robust AP detection algorithm in combination with a standardized AP parameter analysis over a wide range of AP waveforms and firing rates, owing in part to the use of an iterative algorithm for the determination of the threshold potential and the diastolic depolarization rate that is independent of the maximum upstroke velocity, a parameter that can vary significantly among sinoatrial APs. Because ParamAP is implemented in Python 3, it is also highly customizable and extensible. In conclusion, ParamAP is a powerful computational tool that facilitates quantitative analysis and enables comparison of sinoatrial APs by standardizing parameter definitions and providing an automated work flow. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

40 CFR 63.1367 - Recordkeeping requirements.

Code of Federal Regulations, 2012 CFR

2012-07-01

..., and malfunction and a program for corrective action for a malfunctioning process, air pollution... duration of each malfunction of the process operations or of air pollution control equipment used to comply... explanation of the cause of the alarm and the corrective action taken. (6) The owner or operator of an...

Poisson process stimulation of an excitable membrane cable model.

PubMed Central

Goldfinger, M D

1986-01-01

The convergence of multiple inputs within a single-neuronal substrate is a common design feature of both peripheral and central nervous systems. Typically, the result of such convergence impinges upon an intracellularly contiguous axon, where it is encoded into a train of action potentials. The simplest representation of the result of convergence of multiple inputs is a Poisson process; a general representation of axonal excitability is the Hodgkin-Huxley/cable theory formalism. The present work addressed multiple input convergence upon an axon by applying Poisson process stimulation to the Hodgkin-Huxley axonal cable. The results showed that both absolute and relative refractory periods yielded in the axonal output a random but non-Poisson process. While smaller amplitude stimuli elicited a type of short-interval conditioning, larger amplitude stimuli elicited impulse trains approaching Poisson criteria except for the effects of refractoriness. These results were obtained for stimulus trains consisting of pulses of constant amplitude and constant or variable durations. By contrast, with or without stimulus pulse shape variability, the post-impulse conditional probability for impulse initiation in the steady-state was a Poisson-like process. For stimulus variability consisting of randomly smaller amplitudes or randomly longer durations, mean impulse frequency was attenuated or potentiated, respectively. Limitations and implications of these computations are discussed. PMID:3730505

Optical stimulation of the hearing and deaf cochlea under thermal and stress confinement condition

NASA Astrophysics Data System (ADS)

Schultz, M.; Baumhoff, P.; Kallweit, N.; Sato, M.; Krüger, A.; Ripken, T.; Lenarz, T.; Kral, A.

2014-03-01

There is a controversy, to which extend cochlear stimulation with near infrared laser pulses at a wavelength of 1860 nm is based on optoacoustic stimulation of intact hair cells or -in contrast- is based on direct stimulation of the nerve cells in absence of functional hair cells. Thermal and stress confinement conditions apply, because of the pulse duration range (5 ns, 10 μs-20 ms) of the two lasers used. The dependency of the signal characteristics on pulse peak power and pulse duration was investigated in this study. The compound action potential (CAP) was measured during stimulation of the cochlea of four anaesthetized guinea pigs, which were hearing at first and afterwards acutely deafened using intracochlear neomycin-rinsing. For comparison hydrophone measurements in a water tank were performed to investigate the optoacoustic signals at different laser interaction regimes. With rising pulse peak power CAPs of the hearing animals showed first a threshold, then a positively correlated and finally a saturating dependency. CAPs also showed distinct responses at laser onset and offset separated with the pulse duration. At pulse durations shorter than physiological response times the signals merged. Basically the same signal characteristics were observed in the optoacoustic hydrophone measurements, scaled with the sensitivity and response time of the hydrophone. Taking together the qualitative correspondence in the signal response and the absence of any CAPs in deafened animals our results speak in favor of an optoacoustic stimulation of intact hair cells rather than a direct stimulation of nerve cells.

Inhibition of potassium currents is involved in antiarrhythmic effect of moderate ethanol on atrial fibrillation.

PubMed

Yang, Baode; Li, Chenxing; Sun, Junyi; Wang, Xinghui; Liu, Xinling; Yang, Chun; Chen, Lina; Zhou, Jun; Hu, Hao

2017-05-01

Excessive consumption of alcohol is a well-established risk factor of atrial fibrillation (AF). However, the effects of moderate alcohol drinking remain to be elucidated. This study was designed to determine the effects of moderate ethanol ingestion on atrial fibrillation and the electrophysiological mechanisms. In acetylcholine-induced canine and mouse AF models, the moderate ethanol prevented the generation and persistence of AF through prolonging the latent period of AF and shortening the duration of AF. The action potential duration (APD) was remarkably prolonged under the concentration range of 12.5-50.0mM ethanol in guinea pig atrial myocytes. Ultra-rapid delayed rectified potassium currents (I Kv1.5 ) were markedly inhibited by 12.5-50.0mM ethanol in a concentration-dependent manner. Ethanol with 50.0mM could inhibit rapid delayed rectifier potassium currents (I hERG ). Ethanol under 6.25-50.0mM did not affect on inward rectifier potassium currents (I Kir2.1 ). Collectively, the present study provided an evidence that moderate ethanol intake can prolong the APD of atrial myocytes by inhibition of I Kv1.5 and I hERG , which contributed to preventing the development and duration of AF. Copyright © 2017 Elsevier Inc. All rights reserved.

Essential oil of Croton zehntneri and its main constituent anethole block excitability of rat peripheral nerve.

PubMed

da Silva-Alves, Kerly Shamyra; Ferreira-da-Silva, Francisco Walber; Coelho-de-Souza, Andrelina Noronha; Albuquerque, Aline Alice Cavalcante; do Vale, Otoni Cardoso; Leal-Cardoso, José Henrique

2015-03-01

Croton zehntneri is an aromatic plant native to Northeast Brazil and employed by local people to treat various diseases. The leaves of this plant have a rich content of essential oil. The essential oil of C. zehntneri samples, with anethole as the major constituent and anethole itself, have been reported to have several pharmacological activities such as antispasmodic, cardiovascular, and gastroprotective effects and inducing the blockade of neuromuscular transmission and antinociception. Since several works have demonstrated that essential oils and their constituents block cell excitability and in view of the multiple effects of C. zehntneri essential oil and anethole on biological tissues, we undertook this investigation aiming to characterize and compare the effects of this essential oil and its major constituent on nerve excitability. Sciatic nerves of Wistar rats were used. They were mounted in a moist chamber, and evoked compound action potentials were recorded. Nerves were exposed in vitro to the essential oil of C. zehntneri and anethole (0.1-1 mg/mL) up to 180 min, and alterations in excitability (rheobase and chronaxie) and conductibility (peak-to-peak amplitude and conduction velocity) parameters of the compound action potentials were evaluated. The essential oil of C. zehntneri and anethole blocked, in a concentration-dependent manner with similar pharmacological potencies (IC50: 0.32 ± 0.07 and 0.22 ± 0.11 mg/mL, respectively), rat sciatic nerve compound action potentials. Strength-duration curves for both agents were shifted upward and to the right compared to the control curve, and the rheobase and chronaxie were increased following essential oil and anethole exposure. The time courses of the essential oil of C. zehntneri and anethole effects on peak-to-peak amplitude of compound action potentials followed an exponential decay and reached a steady state. The essential oil of C. zehntneri and anethole caused a similar reduction in conduction velocities of the compound action potential waves investigated. In conclusion, we demonstrated here that the essential oil of C. zehntneri blocks neuronal excitability and that this effect, which can be predominantly attributable to its major constituent, anethole, is important since these agents have several pharmacological effects likely related to the alteration of excitability. This finding is relevant due to the use of essential oils in aromatherapy and the low acute toxicity of this agent, which exhibits other effects of potential therapeutic usefulness. Georg Thieme Verlag KG Stuttgart · New York.

Intramural activation and repolarization sequences in canine ventricles. Experimental and simulation studies.

PubMed

Taccardi, Bruno; Punske, Bonnie B; Sachse, Frank; Tricoche, Xavier; Colli-Franzone, Piero; Pavarino, Luca F; Zabawa, Christine

2005-10-01

There are no published data showing the three-dimensional sequence of repolarization and the associated potential fields in the ventricles. Knowledge of the sequence of repolarization has medical relevance because high spatial dispersion of recovery times and action potential durations favors cardiac arrhythmias. In this study we describe measured and simulated 3-D excitation and recovery sequences and activation-recovery intervals (ARIs) (measured) or action potential durations (APDs) (simulated) in the ventricular walls. We recorded from 600 to 1400 unipolar electrograms from canine ventricular walls during atrial and ventricular pacing at 350-450 ms cycle length. Measured excitation and recovery times and ARIs were displayed as 2-D maps in transmural planes or 3-D maps in the volume explored, using specially developed software. Excitation and recovery sequences and APD distributions were also simulated in parallelepipedal slabs using anisotropic monodomain or bidomain models based on the Lou-Rudy version 1 model with homogeneous membrane properties. Simulations showed that in the presence of homogeneous membrane properties, the sequence of repolarization was similar but not identical to the excitation sequence. In a transmural plane perpendicular to epicardial fiber direction, both activation and recovery pathways starting from an epicardial pacing site returned toward the epicardium at a few cm distance from the pacing site. However, APDs were not constant, but had a dispersion of approximately 14 ms in the simulated domain. The maximum APD value was near the pacing site and two minima appeared along a line perpendicular to fiber directions, passing through the pacing site. Electrical measurements in dog ventricles showed that, for short cycle lengths, both excitation and recovery pathways, starting from an epicardial pacing site, returned toward the epicardium. For slower pacing rates, pathways of recovery departed from the pathway of excitation. Highest ARI values were observed near the pacing site in part of the experiments. In addition, maps of activation-recovery intervals showed mid-myocardial clusters with activation-recovery intervals that were slightly longer than ARIs closer to the epi- or endocardium, suggesting the presence of M cells in those areas. Transmural dispersion of measured ARIs was on the order of 20-25 ms. Potential distributions during recovery were less affected by myocardial anisotropy than were excitation potentials.

Extended Duration Vascular Endothelial Growth Factor Inhibition in the Eye: Failures, Successes, and Future Possibilities.

PubMed

Stewart, Michael W

2018-01-27

Vascular endothelial growth factor (VEGF) plays a pivotal role in the development of neovascularization and edema from several common chorioretinal vascular conditions. The intravitreally injected drugs (aflibercept, bevacizumab, conbercept, pegaptanib, and ranibizumab) used to treat these conditions improve the visual acuity and macular morphology in most patients. Monthly or bimonthly injections were administered in the phase III pivotal trials but physicians usually individualize therapy with pro re nata (PRN) or treat and extend regimens. Despite these lower frequency treatment regimens, frequent injections and clinic visits are still needed to produce satisfactory outcomes. Newly developed drugs and refillable reservoirs with favorable pharmacokinetic profiles may extend durations of action and require fewer office visits. However, we have learned from previous experiences that the longer durations of action seen in strategically designed phase III trials often do not translate to less frequent injections in real-life clinical practice. Unfortunately, long-acting therapies that produce soluble VEGF receptors (encapsulated cell technology and adenovirus injected DNA) have failed in phase II trials. The development of longer duration therapies remains a difficult and frustrating process, and frequent drug injections are likely to remain the standard-of-care for years to come.

Block of the delayed rectifier current (IK) by the 5-HT3 antagonists ondansetron and granisetron in feline ventricular myocytes.

PubMed Central

de Lorenzi, F G; Bridal, T R; Spinelli, W

1994-01-01

1. We investigated the effects of two 5-HT3 antagonists, ondansetron and granisetron, on the action potential duration (APD) and the delayed rectifier current (IK) of feline isolated ventricular myocytes. Whole-cell current and action potential recordings were performed at 37 degrees C with the patch clamp technique. 2. Ondansetron and granisetron blocked IK with a KD of 1.7 +/- 1.0 and 4.3 +/- 1.7 microM, respectively. At a higher concentration (30 microM), both drugs blocked the inward rectifier (IKl). 3. The block of IK was dependent on channel activation. Both drugs slowed the decay of IK tail currents and produced a crossover with the pre-drug current trace. These results are consistent with block and unblock from the open state of the channel. 4. Granisetron showed an intrinsic voltage-dependence as the block increased with depolarization. The equivalent voltage-dependency of block (delta) was 0.10 +/- 0.04, suggesting that granisetron blocks from the intracellular side at a binding site located 10% across the transmembrane electrical field. 5. Ondansetron (1 microM) and granisetron (3 microM) prolonged APD by about 30% at 0.5 Hz. The prolongation of APD by ondansetron was abolished at faster frequencies (3 Hz) showing reverse rate dependence. 6. In conclusion, the 5-HT3 antagonists, ondansetron and granisetron, are open state blockers of the ventricular delayed rectifier and show a clear class III action. PMID:7834204

The role of exercise in migraine treatment.

PubMed

Koseoglu, E; Yetkin, M F; Ugur, F; Bilgen, M

2015-09-01

This review aims to provide a comprehensive overview of the literature on the use of exercise for migraine treatment with regard to its efficacy, mechanism of action and role in practice. Many randomized studies have reported the efficacy of prophylactic treatment of migrane with medications such as beta blockers or antiepileptic drugs. Studies on alternative approaches, like aerobic exercise and biofeedback, are however limited but also considered to be effective. Scientific databases were searched with keywords "exercise" and "migraine". The resulting publications were gathered, examined and discussed throughly. Past studies had limitations and were few in number, but more recent randomized controlled studies have concretely provided level of evidence about the effectiveness of exercise in prophylactic treatment of migraine. Core properties of exercise like intensity, duration, frequency, type and warming up period are required to be monitored while treating migraine to increase the beneficial effects and, also to prevent injuries and side effects which may include exertional headache. Isometric neck exercise is helpful when the migraine is accompanied by neck pain. Patient population with low beta endorphin level in blood, high physical fitness and high motivation receives significant benefits from the exercise treatment. The action of exercise on migraine is in general related to neurochemical factors, psychological states and increase in cardivascular and cerebrovascular fitness. Considering its effectiveness and minimal side effects, migraine patients should often be encouraged to practice physical exercise with intensity, frequency and duration that should be carefully instituted to achieve the most beneficial outcome while preventing potential injuries and side effects.

Chronic valproic acid treatment triggers increased neuropeptide y expression and signaling in rat nucleus reticularis thalami.

PubMed

Brill, Julia; Lee, Michelle; Zhao, Sheng; Fernald, Russell D; Huguenard, John R

2006-06-21

Valproate (VPA) can suppress absence and other seizures, but its precise mechanisms of action are not completely understood. We investigated whether VPA influences the expression of neuropeptide Y (NPY), an endogenous anticonvulsant. Chronic VPA administration to young rats (300-600 mg.kg(-1).d(-1) in divided doses over 4 d) resulted in a 30-50% increase in NPY mRNA and protein expression in the nucleus reticularis thalami (nRt) and hippocampus, but not in the neocortex, as shown by real-time PCR, radioimmunoassay, and immunohistochemistry. No increased expression was observed after a single acute dose of VPA. Chronic treatment with the pharmacologically inactive VPA analog octanoic acid did not elicit changes in NPY expression. No significant expression changes could be shown for the mRNAs of the Y1 receptor or of the neuropeptides somatostatin, vasoactive intestinal polypeptide, and choleocystokinin. Fewer synchronous spontaneous epileptiform oscillations were recorded in thalamic slices from VPA-treated animals, and oscillation duration as well as the period of spontaneous and evoked oscillations were decreased. Application of the Y1 receptor inhibitor N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-D-arginine-amide (BIBP3226) enhanced thalamic oscillations, indicating that NPY is released during those oscillations and acts to downregulate oscillatory strength. Chronic VPA treatment significantly potentiated the effect of BIBP3226 on oscillation duration but not on oscillation period. These results demonstrate a novel mechanism for the antiepileptic actions of chronic VPA therapy.

Electrophysiological effects of protopine in cardiac myocytes: inhibition of multiple cation channel currents.

PubMed

Song, L S; Ren, G J; Chen, Z L; Chen, Z H; Zhou, Z N; Cheng, H

2000-03-01

Protopine (Pro) from Corydalis tubers has been shown to have multiple actions on cardiovascular system, including anti-arrhythmic, anti-hypertensive and negative inotropic effects. Although it was thought that Pro exerts its actions through blocking Ca(2+) currents, the electrophysiological profile of Pro is unclear. The aim of this study is to elucidate the ionic mechanisms of Pro effects in the heart. In single isolated ventricular myocytes from guinea-pig, extracellular application of Pro markedly and reversibly abbreviates action potential duration, and decreases the rate of upstroke (dV/dt)(max), amplitude and overshoot of action potential in a dose-dependent manner. Additionally, it produces a slight, but significant hyperpolarization of the resting membrane potential. Pro at 25, 50 and 100 microM reduces L-type Ca(2+) current (I(Ca,L)) amplitude to 89.1, 61.9 and 45.8% of control, respectively, and significantly slows the decay kinetics of I(Ca,L) at higher concentration. The steady state inactivation of I(Ca,L) is shifted negatively by 5.9 - 7.0 mV (at 50 - 100 microM Pro), whereas the voltage-dependent activation of I(Ca,L) remains unchanged. In contrast, Pro at 100 microM has no evident effects on T-type Ca(2+) current (I(Ca,T)). In the presence of Pro, both the inward rectifier (I(K1)) and delayed rectifier (I(K)) potassium currents are variably inhibited, depending on Pro concentrations. Sodium current (I(Na)), recorded in low [Na(+)](o) (40 mM) solution, is more potently suppressed by Pro. At 25 microM, Pro significantly attenuated I(Na) at most of the test voltages (-60 approximately +40 mV, with a 53% reduction at -30 mV. Thus, Pro is not a selective Ca(2+) channel antagonist. Rather, it acts as a promiscuous inhibitor of cation channel currents including I(Ca,L), I(K), I(K1) as well as I(Na). These findings may provide some mechanistic explanations for the therapeutic actions of Pro in the heart.

Electrophysiological effects of protopine in cardiac myocytes: inhibition of multiple cation channel currents

PubMed Central

Song, Long-Sheng; Ren, Guo-Jun; Chen, Zhao-Luan; Chen, Zhi-He; Zhou, Zhao-Nian; Cheng, Heping

2000-01-01

Protopine (Pro) from Corydalis tubers has been shown to have multiple actions on cardiovascular system, including anti-arrhythmic, anti-hypertensive and negative inotropic effects. Although it was thought that Pro exerts its actions through blocking Ca2+ currents, the electrophysiological profile of Pro is unclear. The aim of this study is to elucidate the ionic mechanisms of Pro effects in the heart. In single isolated ventricular myocytes from guinea-pig, extracellular application of Pro markedly and reversibly abbreviates action potential duration, and decreases the rate of upstroke (dV/dt)max, amplitude and overshoot of action potential in a dose-dependent manner. Additionally, it produces a slight, but significant hyperpolarization of the resting membrane potential. Pro at 25, 50 and 100 μM reduces L-type Ca2+ current (ICa,L) amplitude to 89.1, 61.9 and 45.8% of control, respectively, and significantly slows the decay kinetics of ICa,L at higher concentration. The steady state inactivation of ICa,L is shifted negatively by 5.9–7.0 mV (at 50–100 μM Pro), whereas the voltage-dependent activation of ICa,L remains unchanged. In contrast, Pro at 100 μM has no evident effects on T-type Ca2+ current (ICa,T). In the presence of Pro, both the inward rectifier (IK1) and delayed rectifier (IK) potassium currents are variably inhibited, depending on Pro concentrations. Sodium current (INa), recorded in low [Na+]o (40 mM) solution, is more potently suppressed by Pro. At 25 μM, Pro significantly attenuated INa at most of the test voltages (−60∼+40 mV, with a 53% reduction at −30 mV. Thus, Pro is not a selective Ca2+ channel antagonist. Rather, it acts as a promiscuous inhibitor of cation channel currents including ICa,L, IK, IK1 as well as INa. These findings may provide some mechanistic explanations for the therapeutic actions of Pro in the heart. PMID:10696087

High Doses of Amphetamine Augment, Rather Than Disrupt, Exocytotic Dopamine Release in the Dorsal and Ventral Striatum of the Anesthetized Rat

PubMed Central

Ramsson, Eric S.; Howard, Christopher D.; Covey, Dan P.; Garris, Paul A.

2011-01-01

High doses of amphetamine (AMPH) are thought to disrupt normal patterns of action potential-dependent dopaminergic neurotransmission by depleting vesicular stores of dopamine (DA) and inducing robust non-exocytotic DA release or efflux via dopamine transporter (DAT) reversal. However, these cardinal AMPH actions have been difficult to establish definitively in vivo. Here, we use fast-scan cyclic voltammetry (FSCV) in the urethane-anesthetized rat to evaluate the effects of 10 and 20 mg/kg AMPH on vesicular DA release and DAT function in dorsal and ventral striata. An equivalent high dose of cocaine (40 mg/kg) was also examined for comparison to psychostimulants acting preferentially by DAT inhibition. Parameters describing exocytotic DA release and neuronal DA uptake were determined from dynamic DA signals evoked by mild electrical stimulation previously established to be reinforcing. High-sensitivity FSCV with nanomolar detection was used to monitor changes in the background voltammetric signal as an index of DA efflux. Both doses of AMPH and cocaine markedly elevated evoked DA levels over the entire 2-h time course in the dorsal and ventral striatum. These increases were mediated by augmented vesicular DA release and diminished DA uptake typically acting concurrently. AMPH, but not cocaine, induced a slow, DA-like rise in some baseline recordings. However, this effect was highly variable in amplitude and duration, modest, and generally not present at all. These data thus describe a mechanistically similar activation of action potential-dependent dopaminergic neurotransmission by AMPH and cocaine in vivo. Moreover, DA efflux appears to be a unique, but secondary, AMPH action. PMID:21806614

Actions of (-)-baclofen on rat dorsal horn neurons.

PubMed

Kangrga, I; Jiang, M C; Randić, M

1991-10-25

The actions of a gamma-aminobutyric acid B (GABAB) agonist, (-)-baclofen, on the electrophysiological properties of neurons and synaptic transmission in the spinal dorsal horn (laminae I-IV) were examined by using intracellular recordings in spinal cord slice from young rats. In addition, the effects of baclofen on the dorsal root stimulation-evoked outflow of glutamate and aspartate from the spinal dorsal horn were examined by using high performance liquid chromatography (HPLC) with flourimetric detection. Superfusion of baclofen (5 nM to 10 microM) hyperpolarized, in a stereoselective and bicuculline-insensitive manner, the majority (86%) of tested neurons. The hyperpolarization was associated with a decrease in membrane resistance and persisted in a nominally zero-Ca2+, 10 mM Mg(2+)- or a TTX-containing solution. Our findings indicate that the hyperpolarizing effect of baclofen is probably due to an increase in conductance to potassium ions. Baclofen decreased the direct excitability of dorsal horn neurons, enhanced accommodation of spike discharge, and reduced the duration of Ca(2+)-dependent action potentials. Baclofen depressed, or blocked, excitatory postsynaptic potentials evoked by electrical stimulation of the dorsal roots. Spontaneously occurring synaptic potentials were also reversibly depressed by baclofen. Whereas baclofen did not produce any consistent change in the rate of the basal outflow of glutamate and aspartate, the stimulation-evoked release of the amino acids was blocked. The present results suggest that baclofen, by activating GABAB receptors, may modulate spinal afferent processing in the superficial dorsal horn by at least two mechanisms: (1) baclofen depresses excitatory synaptic transmission primarily by a presynaptic mechanism involving a decrease in the release of excitatory amino acids, and (2) at higher concentrations, the hyperpolarization and increased membrane conductance may contribute to the depressant effect of baclofen on excitatory synaptic transmission in the rat spinal dorsal horn.

Long-Term Recordings of Arcuate Nucleus Kisspeptin Neurons Reveal Patterned Activity That Is Modulated by Gonadal Steroids in Male Mice.

PubMed

Vanacker, Charlotte; Moya, Manuel Ricu; DeFazio, R Anthony; Johnson, Michael L; Moenter, Suzanne M

2017-10-01

Pulsatile release of gonadotropin-releasing hormone (GnRH) is key to fertility. Pulse frequency is modulated by gonadal steroids and likely arises subsequent to coordination of GnRH neuron firing activity. The source of rhythm generation and the site of steroid feedback remain critical unanswered questions. Arcuate neurons that synthesize kisspeptin, neurokinin B, and dynorphin (KNDy) may be involved in both of these processes. We tested the hypotheses that action potential firing in KNDy neurons is episodic and that gonadal steroids regulate this pattern. Targeted extracellular recordings were made of green fluorescent protein-identified KNDy neurons in brain slices from adult male mice that were intact, castrated, or castrated and treated with estradiol or dihydrotestosterone (DHT). KNDy neurons exhibited marked peaks and nadirs in action potential firing activity during recordings lasting 1 to 3.5 hours. Peaks, identified by Cluster analysis, occurred more frequently in castrated than intact mice, and either estradiol or DHT in vivo or blocking neurokinin type 3 receptor in vitro restored peak frequency to intact levels. The frequency of peaks in firing rate and estradiol regulation of this frequency is similar to that observed for GnRH neurons, whereas DHT suppressed firing in KNDy but not GnRH neurons. We further examined the patterning of action potentials to identify bursts that may be associated with increased neuromodulator release. Burst frequency and duration are increased in castrated compared with intact and steroid-treated mice. The observation that KNDy neurons fire in an episodic manner that is regulated by steroid feedback is consistent with a role for these neurons in GnRH pulse generation and regulation. Copyright © 2017 Endocrine Society.

Modulation of KCNQ1 alternative splicing regulates cardiac IKs and action potential repolarization.

PubMed

Lee, Hsiang-Chun; Rudy, Yoram; Po-Yuan, Phd; Sheu, Sheng-Hsiung; Chang, Jan-Gowth; Cui, Jianmin

2013-08-01

Slow delayed-rectifier potassium current (IKs) channels, made of the pore-forming KCNQ1 and auxiliary KCNE1 subunits, play a key role in determining action potential duration (APD) in cardiac myocytes. The consequences of drug-induced KCNQ1 splice alteration remain unknown. To study the modulation of KCNQ1 alternative splicing by amiloride and the consequent changes in IKs and action potentials (APs) in ventricular myocytes. Canine endocardial, midmyocardial, and epicardial ventricular myocytes were isolated. Levels of KCNQ1a and KCNQ1b as well as a series of splicing factors were quantified by using the reverse transcriptase-polymerase chain reaction and Western blot. The effect of amiloride-induced changes in the KCNQ1b/total KCNQ1 ratio on AP was measured by using whole-cell patch clamp with and without isoproterenol. With 50 μmol/L of amiloride for 6 hours, KCNQ1a at transcriptional and translational levels increased in midmyocardial myocytes but decreased in endo- and epicardial myocytes. Likewise, changes in splicing factors in midmyocardial were opposite to that in endo- and epicardial myocytes. In midmyocardial myocytes amiloride shortened APD and decreased isoproterenol-induced early afterdepolarizations significantly. The same amiloride-induced effects were demonstrated by using human ventricular myocyte model for AP simulations under beta-adrenergic stimulation. Moreover, amiloride reduced the transmural dispersion of repolarization in pseudo-electrocardiogram. Amiloride regulates IKs and APs with transmural differences and reduces arrhythmogenicity through the modulation of KCNQ1 splicing. We suggested that the modulation of KCNQ1 splicing may help prevent arrhythmia. Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

AdE-1, a new inotropic Na(+) channel toxin from Aiptasia diaphana, is similar to, yet distinct from, known anemone Na(+) channel toxins.

PubMed

Nesher, Nir; Shapira, Eli; Sher, Daniel; Moran, Yehu; Tsveyer, Liora; Turchetti-Maia, Ana Luiza; Horowitz, Michal; Hochner, Binyamin; Zlotkin, Eliahu

2013-04-01

Heart failure is one of the most prevalent causes of death in the western world. Sea anemone contains a myriad of short peptide neurotoxins affecting many pharmacological targets, several of which possess cardiotonic activity. In the present study we describe the isolation and characterization of AdE-1 (ion channel modifier), a novel cardiotonic peptide from the sea anemone Aiptasia diaphana, which differs from other cnidarian toxins. Although AdE-1 has the same cysteine residue arrangement as sea anemone type 1 and 2 Na(+) channel toxins, its sequence contains many substitutions in conserved and essential sites and its overall homology to other toxins identified to date is low (<36%). Physiologically, AdE-1 increases the amplitude of cardiomyocyte contraction and slows the late phase of the twitch relaxation velocity with no induction of spontaneous twitching. It increases action potential duration of cardiomyocytes with no effect on its threshold and on the cell's resting potential. Similar to other sea anemone Na(+) channel toxins such as Av2 (Anemonia viridis toxin II), AdE-1 markedly inhibits Na(+) current inactivation with no significant effect on current activation, suggesting a similar mechanism of action. However, its effects on twitch relaxation velocity, action potential amplitude and on the time to peak suggest that this novel toxin affects cardiomyocyte function via a more complex mechanism. Additionally, Av2's characteristic delayed and early after-depolarizations were not observed. Despite its structural differences, AdE-1 physiologic effectiveness is comparable with Av2 with a similar ED(50) value to blowfly larvae. This finding raises questions regarding the extent of the universality of structure-function in sea anemone Na(+) channel toxins.

Changes in Ca(2+) cycling proteins underlie cardiac action potential prolongation in a pressure-overloaded guinea pig model with cardiac hypertrophy and failure.

PubMed

Ahmmed, G U; Dong, P H; Song, G; Ball, N A; Xu, Y; Walsh, R A; Chiamvimonvat, N

2000-03-17

Ventricular arrhythmias are common in both cardiac hypertrophy and failure; cardiac failure in particular is associated with a significant increase in the risk of sudden cardiac death. We studied the electrophysiologic changes in a guinea pig model with aortic banding resulting in cardiac hypertrophy at 4 weeks and progressing to cardiac failure at 8 weeks using whole-cell patch-clamp and biochemical techniques. Action potential durations (APDs) were significantly prolonged in banded animals at 4 and 8 weeks compared with age-matched sham-operated animals. APDs at 50% and 90% repolarization (APD(50) and APD(90) in ms) were the following: 4 week, banded, 208+/-51 and 248+/-49 (n = 15); 4 week, sham, 189+/-68 and 213+/-69 (n = 16); 8 week, banded, 197+/-40 and 226+/-40 (n = 21); and 8 week, sham, 156+/-42 and 189+/-45 (n = 22), respectively; P<0.05 comparing banded versus sham-operated animals. We observed no significant differences in the K(+) currents between the 2 groups of animals at 4 and 8 weeks. However, banded animals exhibited a significant increase in Na(+) and Na(+)-Ca(2+) exchange current densities compared with controls. Furthermore, we have found a significant attenuation in the Ca(2+)-dependent inactivation of the L-type Ca(2+) current in the banded compared with sham-operated animals, likely as a result of the significant downregulation of the sarcoplasmic reticulum Ca(2+) ATPase, which has been documented previously in the heart failure animals. Our data provide an alternate mechanism for APD prolongation in cardiac hypertrophy and failure and support the notion that there is close interaction between Ca(2+) handling and action potential profile.

Appropriate Mechanochemical Conditions for Corrosion-Fatigue Testing of Magnesium Alloys for Temporary Bioimplant Applications

NASA Astrophysics Data System (ADS)

Harandi, Shervin Eslami; Singh Raman, R. K.

2015-05-01

Magnesium (Mg) alloys possess great potential as bioimplants. A temporary implant employed as support for the repair of a fractured bone must possess sufficient strength to maintain their mechanical integrity for the required duration of healing. However, Mg alloys are susceptible to sudden cracking or fracture under the simultaneous action of cyclic loading and the corrosive physiological environment, i.e., corrosion fatigue (CF). Investigations of such fracture should be performed under appropriate mechanochemical conditions that appropriately simulate the actual human body conditions. This article reviews the existing knowledge on CF of Mg alloys in simulated body fluid and describes a relatively more accurate testing procedure developed in the authors' laboratory.

Prediction of Thorough QT study results using action potential simulations based on ion channel screens.

PubMed

Mirams, Gary R; Davies, Mark R; Brough, Stephen J; Bridgland-Taylor, Matthew H; Cui, Yi; Gavaghan, David J; Abi-Gerges, Najah

2014-01-01

Detection of drug-induced pro-arrhythmic risk is a primary concern for pharmaceutical companies and regulators. Increased risk is linked to prolongation of the QT interval on the body surface ECG. Recent studies have shown that multiple ion channel interactions can be required to predict changes in ventricular repolarisation and therefore QT intervals. In this study we attempt to predict the result of the human clinical Thorough QT (TQT) study, using multiple ion channel screening which is available early in drug development. Ion current reduction was measured, in the presence of marketed drugs which have had a TQT study, for channels encoded by hERG, CaV1.2, NaV1.5, KCNQ1/MinK, and Kv4.3/KChIP2.2. The screen was performed on two platforms - IonWorks Quattro (all 5 channels, 34 compounds), and IonWorks Barracuda (hERG & CaV1.2, 26 compounds). Concentration-effect curves were fitted to the resulting data, and used to calculate a percentage reduction in each current at a given concentration. Action potential simulations were then performed using the ten Tusscher and Panfilov (2006), Grandi et al. (2010) and O'Hara et al. (2011) human ventricular action potential models, pacing at 1Hz and running to steady state, for a range of concentrations. We compared simulated action potential duration predictions with the QT prolongation observed in the TQT studies. At the estimated concentrations, simulations tended to underestimate any observed QT prolongation. When considering a wider range of concentrations, and conventional patch clamp rather than screening data for hERG, prolongation of ≥5ms was predicted with up to 79% sensitivity and 100% specificity. This study provides a proof-of-principle for the prediction of human TQT study results using data available early in drug development. We highlight a number of areas that need refinement to improve the method's predictive power, but the results suggest that such approaches will provide a useful tool in cardiac safety assessment. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Latest aspects of aldosterone actions on the heart muscle.

PubMed

Kritis, A A; Gouta, C P; Liaretidou, E I; Kallaras, K I

2016-02-01

The genomic action of aldosterone has already been known to the scientific community and is well-documented to a satisfactory degree. However, the existence of rapid, non-genomic aldosterone actions has repeatedly been proven. These actions are apparent to a lot of tissues, among which the cardiac tissue, with the cardiac cells being responsible for the secretion of endogenous aldosterone. In the genomic pathway, the connection between the hormone and its receptor results increased reabsorption of sodium and water and excretion of potassium. Thus, the genomic procedure reacts indirectly on cardiovascular system by altering the blood pressure. New studies have shed light on unknown aspects of the non-genomic mechanism, which is sometimes performed by means of mineralocorticoid receptor (MR), while others through an MR-independent pathway. It is believed that aldosterone exerts its non-genomic action with the help of a different receptor, probably a G protein coupled receptor. A possible target is protein kinase C (PKC), and PKCε is postulated increase the permeability of the membrane of the cardiac cells to sodium, resulting in delayed repolarization and prolongation of action potential. These findings totally agree with and account for the serendipitous finding of our laboratory, that there is a positive correlation between plasma aldosterone levels and left ventricle (LV) contraction duration. Also, aldosterone has been proven to exacerbate the oxidative stress and induce vasoconstriction by acting on the vascular resistance and the cardiac output. Finally, this article deals with the role of aldosterone in cardiac fibrosis and the latest aspects of aldosterone actions on the heart muscle as well as providing a historical overview of the landmarks pertaining aldosterone's research.

Developing Critical Thinking through Socratic Questioning: An Action Research Study

ERIC Educational Resources Information Center

Sahamid, Husniah

2016-01-01

An action research study was conducted among 24 Form 4 level Malaysian students, aged 16. The duration of the study was five months and constituted 16 one-hour literature lessons (short stories from the secondary level Malaysian English Language Upper Secondary Level school syllabus). This paper describes my experience as a teacher-as-researcher…

Do You "See'" What I "See"? Differentiation of Visual Action Words

ERIC Educational Resources Information Center

Dickinson, Joël; Cirelli, Laura; Szeligo, Frank

2014-01-01

Dickinson and Szeligo ("Can J Exp Psychol" 62(4):211--222, 2008) found that processing time for simple visual stimuli was affected by the visual action participants had been instructed to perform on these stimuli (e.g., see, distinguish). It was concluded that these effects reflected the differences in the durations of these various…

Exclusionary Discipline Practices across Students' Racial/Ethnic Backgrounds and Disability Status: Findings from the Pacific Northwest

ERIC Educational Resources Information Center

Vincent, Claudia G.; Sprague, Jeffrey R.; Tobin, Tary J.

2012-01-01

We examined 2009-2010 data on exclusionary discipline practices from one state in the Pacific Northwest of the United States across students' racial/ethnic backgrounds and disability status. Our focus was on proportionate representation in exclusionary discipline actions and in the duration of those disciplinary actions. Descriptive outcomes…

Juxtaposition of the changes in intracellular calcium and force during staircase potentiation at 30 and 37°C

PubMed Central

Vandenboom, Rene

2014-01-01

Ca2+ entry during the action potential stimulates muscle contraction. During repetitive low frequency stimulation, skeletal muscle undergoes staircase potentiation (SP), a progressive increase in the peak twitch force induced by each successive stimulus. Multiple mechanisms, including myosin regulatory light chain phosphorylation, likely contribute to SP, a temperature-dependent process. Here, we used the Ca2+-sensitive fluorescence indicators acetoxymethyl (AM)-furaptra and AM-fura-2 to examine the intracellular Ca2+ transient (ICT) and the baseline Ca2+ level at the onset of each ICT during SP at 30 and 37°C in mouse lumbrical muscle. The stimulation protocol, 8 Hz for 8 s, resulted in a 27 ± 3% increase in twitch force at 37°C and a 7 ± 2% decrease in twitch force at 30°C (P < 0.05). Regardless of temperature, the peak rate of force production (+df/dt) was higher in all twitches relative to the first twitch (P < 0.05). Consistent with the differential effects of stimulation on twitch force at the two temperatures, raw ICT amplitude decreased during repetitive stimulation at 30°C (P < 0.05) but not at 37°C. Cytosolic Ca2+ accumulated during SP such that baseline Ca2+ at the onset of ICTs occurring late in the train was higher (P < 0.05) than that of those occurring early in the train. ICT duration increased progressively at both temperatures. This effect was not entirely proportional to the changes in twitch duration, as twitch duration characteristically decreased before increasing late in the protocol. This is the first study identifying a changing ICT as an important, and temperature-sensitive, modulator of muscle force during repetitive stimulation. Moreover, we extend previous observations by demonstrating that contraction-induced increases in baseline Ca2+ coincide with greater +df/dt but not necessarily with higher twitch force. PMID:25422504

Cystic Fibrosis Gene Encodes a cAMP-Dependent Chloride Channel in Heart

NASA Astrophysics Data System (ADS)

Hart, Padraig; Warth, John D.; Levesque, Paul C.; Collier, Mei Lin; Geary, Yvonne; Horowitz, Burton; Hume, Joseph R.

1996-06-01

cAMP-dependent chloride channels in heart contribute to autonomic regulation of action potential duration and membrane potential and have been inferred to be due to cardiac expression of the epithelial cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. In this report, a cDNA from rabbit ventricle was isolated and sequenced, which encodes an exon 5 splice variant (exon 5-) of CFTR, with >90% identity to human CFTR cDNA present in epithelial cells. Expression of this cDNA in Xenopus oocytes gave rise to robust cAMP-activated chloride currents that were absent in control water-injected oocytes. Antisense oligodeoxynucleotides directed against CFTR significnatly reduced the density of cAMP-dependent chloride currents in acutely cultured myocytes, thereby establishing a direct functional link between cardiac expression of CFTR protein and an endogenous chloride channel in native cardiac myocytes.

Novel anisotropic engineered cardiac tissues: studies of electrical propagation.

PubMed

Bursac, Nenad; Loo, Yihua; Leong, Kam; Tung, Leslie

2007-10-05

The goal of this study was to engineer cardiac tissue constructs with uniformly anisotropic architecture, and to evaluate their electrical function using multi-site optical mapping of cell membrane potentials. Anisotropic polymer scaffolds made by leaching of aligned sucrose templates were seeded with neonatal rat cardiac cells and cultured in rotating bioreactors for 6-14 days. Cells aligned and interconnected inside the scaffolds and when stimulated by a point electrode, supported macroscopically continuous, anisotropic impulse propagation. By culture day 14, the ratio of conduction velocities along vs. across cardiac fibers reached a value of 2, similar to that in native neonatal ventricles, while action potential duration and maximum capture rate, respectively, decreased to 120ms and increased to approximately 5Hz. The shorter culture time and larger scaffold thickness were associated with increased incidence of sustained reentrant arrhythmias. In summary, this study is the first successful attempt to engineer a cm(2)-size, functional anisotropic cardiac tissue patch.

Predicting durations of online collective actions based on Peaks' heights

NASA Astrophysics Data System (ADS)

Lu, Peng; Nie, Shizhao; Wang, Zheng; Jing, Ziwei; Yang, Jianwu; Qi, Zhongxiang; Pujia, Wangmo

2018-02-01

Capturing the whole process of collective actions, the peak model contains four stages, including Prepare, Outbreak, Peak, and Vanish. Based on the peak model, one of the key variables, factors and parameters are further investigated in this paper, which is the rate between peaks and spans. Although the durations or spans and peaks' heights are highly diversified, it seems that the ratio between them is quite stable. If the rate's regularity is discovered, we can predict how long the collective action lasts and when it ends based on the peak's height. In this work, we combined mathematical simulations and empirical big data of 148 cases to explore the regularity of ratio's distribution. It is indicated by results of simulations that the rate has some regularities of distribution, which is not normal distribution. The big data has been collected from the 148 online collective actions and the whole processes of participation are recorded. The outcomes of empirical big data indicate that the rate seems to be closer to being log-normally distributed. This rule holds true for both the total cases and subgroups of 148 online collective actions. The Q-Q plot is applied to check the normal distribution of the rate's logarithm, and the rate's logarithm does follow the normal distribution.

Myocardium distribution of sertindole and its metabolite dehydrosertindole in guinea-pigs.

PubMed

Canal-Raffin, Mireille; Titier, Karine; Déridet, Evelyne; Martinez, Béatrice; Abouelfath, Abdelilah; Miras, Alain; Gromb, Sophie; Molimard, Mathieu; Moore, Nicholas

2006-05-01

Sertindole, like other atypical antipsychotics, has been shown to increase the action potential duration and QT interval in a concentration dependent manner, in in vitro electrophysiological studies. However, this does not always translate into increased duration of the QT interval, increased risk of torsade de pointes or sudden death in clinical practice. The reasons for these apparent discrepancies are unclear and many studies have underscored the importance of the interpretation of in vitro electrophysiological data in the context of other pharmacodynamic (e.g. cardiac ion channels target, receptor affinity) and pharmacokinetic parameters (total plasma drug concentration and drug distribution). To address the possible relevance of the concentrations used in experimental studies, the myocardium distribution of sertindole and its metabolite was determined after single and repeated intraperitoneal administration to guinea-pigs. The data suggest that the plasma concentration appears to predict the concentration in the myocardium and that the myocardium concentrations of sertindole are 3.1 times higher than plasma concentrations. Using these data, the relevance of in vitro electrophysiological studies to clinical plasma concentrations has been appraised. Copyright 2006 John Wiley & Sons, Ltd.

Heat and moisture exchangers and breathing system filters: their use in anaesthesia and intensive care. Part 1 - history, principles and efficiency.

PubMed

Wilkes, A R

2011-01-01

Heat and moisture exchangers and breathing system filters are intended to replace the normal warming, humidifying and filtering functions of the upper airways when these structures are bypassed during anaesthesia and intensive care. Guidance on their use continues to evolve. The aim of this part of the review is to describe the principles of their action and efficiency and to summarise the findings from clinical and laboratory studies. Based on previous studies, an appropriate minimum target for moisture output is 30 and 20 g.m⁻³ for long-duration use in intensive care and short-duration use in anaesthesia, respectively. The practice of reusing a breathing system in anaesthesia, provided it is protected by a filter, assumes that the filter is effective. However, there is wide variation in the gas-borne filtration performance, and contaminated condensate can potentially pass through some filters under typical pressures encountered during mechanical ventilation. © 2010 The Author. Anaesthesia © 2010 The Association of Anaesthetists of Great Britain and Ireland.

The Expanding Diversity of Mycobacterium tuberculosis Drug Targets.

PubMed

Wellington, Samantha; Hung, Deborah T

2018-05-11

After decades of relative inactivity, a large increase in efforts to discover antitubercular therapeutics has brought insights into the biology of Mycobacterium tuberculosis (Mtb) and promising new drugs such as bedaquiline, which inhibits ATP synthase, and the nitroimidazoles delamanid and pretomanid, which inhibit both mycolic acid synthesis and energy production. Despite these advances, the drug discovery pipeline remains underpopulated. The field desperately needs compounds with novel mechanisms of action capable of inhibiting multi- and extensively drug -resistant Mtb (M/XDR-TB) and, potentially, nonreplicating Mtb with the hope of shortening the duration of required therapy. New knowledge about Mtb, along with new methods and technologies, has driven exploration into novel target areas, such as energy production and central metabolism, that diverge from the classical targets in macromolecular synthesis. Here, we review new small molecule drug candidates that act on these novel targets to highlight the methods and perspectives advancing the field. These new targets bring with them the aspiration of shortening treatment duration as well as a pipeline of effective regimens against XDR-TB, positioning Mtb drug discovery to become a model for anti-infective discovery.

AZD-3043: A Novel, Metabolically-Labile Sedative/Hypnotic Agent with Rapid and Predictable Emergence from Hypnosis

PubMed Central

Egan, Talmage D.; Obara, Shinju; Jenkins, Thomas E.; Jaw-Tsai, Sarah S.; Amagasu, Shanti; Cook, Daniel R.; Steffensen, Scott C.; Beattie, David T.

2013-01-01

Background Propofol can be associated with delayed awakening after prolonged infusion. The aim of this study was to characterize the preclinical pharmacology of AZD-3043, a positive allosteric modulator of the γ-aminobutyric acidA (GABAA) receptor containing a metabolically-labile ester moiety. We postulated that its metabolic pathway would result in a short acting clinical profile. Methods The effects of AZD-3043, propofol and propanidid were studied on GABAA receptor-mediated chloride currents in embryonic rat cortical neurons. Radioligand binding studies were also performed. The in vitro stability of AZD-3043 in whole blood and liver microsomes was evaluated. The duration of the loss of righting reflex and effects on the electroencephalograph evoked by bolus or infusion intravenous (IV) administration were assessed in rats. A mixed-effects kinetic-dynamic model using minipigs permitted exploration of the clinical pharmacology of AZD-3043. Results AZD-3043 potentiated GABAA receptor-mediated chloride currents and inhibited [35S]tert-butylbicyclophosphorothionate binding to GABAA receptors. AZD-3043 was rapidly hydrolyzed in liver microsomes from humans and animals. AZD-3043 produced hypnosis and electroencephalograph depression in rats. Compared to propofol, AZD-3043 was shorter acting in rats and pigs. Computer simulation using the porcine kinetic-dynamic model demonstrated that AZD-3043 has very short 50 and 80% decrement times independent of infusion duration. Conclusions AZD-3043 is a positive allosteric modulator of the GABAA receptor in vitro and a sedative/hypnotic agent in vivo. The esterase dependent metabolic pathway results in rapid clearance and short duration of action even for long infusions. AZD-3043 may have clinical potential as a sedative/hypnotic agent with rapid and predictable recovery. PMID:22531340

Botulinum Toxin and Muscle Atrophy: A Wanted or Unwanted Effect.

PubMed

Durand, Paul D; Couto, Rafael A; Isakov, Raymond; Yoo, Donald B; Azizzadeh, Babak; Guyuron, Bahman; Zins, James E

2016-04-01

While the facial rejuvenating effect of botulinum toxin type A is well known and widespread, its use in body and facial contouring is less common. We first describe its use for deliberate muscle volume reduction, and then document instances of unanticipated and undesirable muscle atrophy. Finally, we investigate the potential long-term adverse effects of botulinum toxin-induced muscle atrophy. Although the use of botulinum toxin type A in the cosmetic patient has been extensively studied, there are several questions yet to be addressed. Does prolonged botulinum toxin treatment increase its duration of action? What is the mechanism of muscle atrophy and what is the cause of its reversibility once treatment has stopped? We proceed to examine how prolonged chemodenervation with botulinum toxin can increase its duration of effect and potentially contribute to muscle atrophy. Instances of inadvertent botulinum toxin-induced atrophy are also described. These include the "hourglass deformity" secondary to botulinum toxin type A treatment for migraine headaches, and a patient with atrophy of multiple facial muscles from injections for hemifacial spasm. Numerous reports demonstrate that muscle atrophy after botulinum toxin type A treatment occurs and is both reversible and temporary, with current literature supporting the notion that repeated chemodenervation with botulinum toxin likely responsible for both therapeutic and incidental temporary muscle atrophy. Furthermore, duration of response may be increased with subsequent treatments, thus minimizing frequency of reinjection. Practitioners should be aware of the temporary and reversible effect of botulinum toxin-induced muscle atrophy and be prepared to reassure patients on this matter. © 2016 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.

Pro‐arrhythmic atrial phenotypes in incrementally paced murine Pgc1β −/− hearts: effects of age

PubMed Central

Valli, Haseeb; Ahmad, Shiraz; Fraser, James A.; Jeevaratnam, Kamalan

2017-01-01

New Findings What is the central question of this study? Can we experimentally replicate atrial pro‐arrhythmic phenotypes associated with important chronic clinical conditions, including physical inactivity, obesity, diabetes mellitus and metabolic syndrome, compromising mitochondrial function, and clarify their electrophysiological basis? What is the main finding and its importance? Electrocardiographic and intracellular cardiomyocyte recording at progressively incremented pacing rates demonstrated age‐dependent atrial arrhythmic phenotypes in Langendorff‐perfused murine Pgc1β −/− hearts for the first time. We attributed these to compromised action potential conduction and excitation wavefronts, whilst excluding alterations in recovery properties or temporal electrophysiological instabilities, clarifying these pro‐arrhythmic changes in chronic metabolic disease. Atrial arrhythmias, most commonly manifesting as atrial fibrillation, represent a major clinical problem. The incidence of atrial fibrillation increases with both age and conditions associated with energetic dysfunction. Atrial arrhythmic phenotypes were compared in young (12–16 week) and aged (>52 week) wild‐type (WT) and peroxisome proliferative activated receptor, gamma, coactivator 1 beta (Ppargc1b)‐deficient (Pgc1β −/−) Langendorff‐perfused hearts, previously used to model mitochondrial energetic disorder. Electrophysiological explorations were performed using simultaneous whole‐heart ECG and intracellular atrial action potential (AP) recordings. Two stimulation protocols were used: an S1S2 protocol, which imposed extrasystolic stimuli at successively decremented intervals following regular pulse trains; and a regular pacing protocol at successively incremented frequencies. Aged Pgc1β −/− hearts showed greater atrial arrhythmogenicity, presenting as atrial tachycardia and ectopic activity. Maximal rates of AP depolarization (dV/dt max) were reduced in Pgc1β −/− hearts. Action potential latencies were increased by the Pgc1β −/− genotype, with an added interactive effect of age. In contrast, AP durations to 90% recovery (APD90) were shorter in Pgc1β −/− hearts despite similar atrial effective recovery periods amongst the different groups. These findings accompanied paradoxical decreases in the incidence and duration of alternans in the aged and Pgc1β −/− hearts. Limiting slopes of restitution curves of APD90 against diastolic interval were correspondingly reduced interactively by Pgc1β −/− genotype and age. In contrast, reduced AP wavelengths were associated with Pgc1β −/− genotype, both independently and interacting with age, through the basic cycle lengths explored, with the aged Pgc1β −/− hearts showing the shortest wavelengths. These findings thus implicate AP wavelength in possible mechanisms for the atrial arrhythmic changes reported here. PMID:28960529

Memory for time distinguishes between perception and action.

PubMed

Bueti, Domenica; Walsh, Vincent

2010-01-01

Our experience of time is unlike that of other features of the sensory world such as colour, movement, touch, or sound because there is no unique receptor system through which it is received. However, since time can be perceived, remembered, estimated, and compared in a way analogous to other sensory experiences, it should perhaps be subject to some of the same architectures or principles that have advanced understanding in these other domains. By adapting a task designed to test visual memory within a perception/action framework we investigated whether memory for time is affected by the use to which temporal information is put. When remembering a visual or auditory duration for subsequent motor production, storage is biased by a delay of up to 8 s. When the same duration is remembered for subsequent perception, however, there is no such effect of delay on memory. The results suggest a distinction in temporal memory that parallels the perception/action dichotomy in vision.

Conflicting and complementary ethics of animal welfare considerations in reintroductions.

PubMed

Harrington, Lauren A; Moehrenschlager, Axel; Gelling, Merryl; Atkinson, Rob P D; Hughes, Joelene; Macdonald, David W

2013-06-01

Despite differences in focus, goals, and strategies between conservation biology and animal welfare, both are inextricably linked in many ways, and greater consideration of animal welfare, although important in its own right, also has considerable potential to contribute to conservation success. Nevertheless, animal welfare and animal ethics are not always considered explicitly within conservation practice. We systematically reviewed the recent scientific peer-reviewed and online gray literature on reintroductions of captive-bred and wild-caught animals (mammals, birds, amphibians, and reptiles) to quantify the occurrence of animal welfare issues. We considered monitoring that could be indicative of the animal's welfare status and supportive management actions that could improve animal welfare (regardless of whether the aim was explicitly animal-welfare orientated). Potential welfare issues (of variable nature and extent) were recorded in 67% of 199 projects reviewed; the most common were mortality >50%, dispersal or loss of animals, disease, and human conflict. Most (>70%) projects monitored survival, 18% assessed body condition, and 2% monitored stress levels. Animal welfare, explicitly, was referred to in 6% of projects. Supportive actions, most commonly use of on-site prerelease pens and provision of supplemental food or water, were implemented in 79% of projects, although the extent and duration of support varied. Practitioners can address animal-welfare issues in reintroductions by considering the potential implications for individual animals at all stages of the release process using the decision tree presented. We urge practitioners to report potential animal-welfare issues, describe mitigation actions, and evaluate their efficacy to facilitate transparent evaluation of common moral dilemmas and to advance communal strategies for dealing with them. Currently, comparative mortality rates, health risks, postrelease stress, effectiveness of supportive measures, and behavior of individuals warrant further research to improve animal welfare in reintroductions and to increase success of such projects. © 2013 Society for Conservation Biology.

Relationship between auditory thresholds, central spontaneous activity and hair cell loss after acoustic trauma

PubMed Central

Mulders, W.H.A.M.; Ding, D.; Salvi, R.; Robertson, D.

2011-01-01

Acoustic trauma caused by exposure to a very loud sound increases spontaneous activity in central auditory structures such as the inferior colliculus. This hyperactivity has been suggested as a neural substrate for tinnitus, a phantom hearing sensation. In previous studies we have described a tentative link between the frequency region of hearing impairment and the corresponding tonotopic regions in the inferior colliculus showing hyperactivity. In this study we further investigated the relationship between cochlear compound action potential threshold loss, cochlear outer and inner hair cell loss and central hyperactivity in inferior colliculus of guinea pigs. Two weeks after a 10 kHz pure tone acoustic trauma, a tight relationship was demonstrated between the frequency region of compound action potential threshold loss and frequency regions in the inferior colliculus showing hyperactivity. Extending the duration of the acoustic trauma from 1 to 2 h did not result in significant increases in final cochlear threshold loss, but did result in a further increase of spontaneous firing rates in the inferior colliculus. Interestingly, hair cell loss was not present in the frequency regions where elevated cochlear thresholds and central hyperactivity were measured, suggesting that subtle changes in hair cell or primary afferent neural function are sufficient for central hyperactivity to be triggered and maintained. PMID:21491427

Spiral-wave dynamics in a mathematical model of human ventricular tissue with myocytes and Purkinje fibers.

PubMed

Nayak, Alok Ranjan; Panfilov, A V; Pandit, Rahul

2017-02-01

We present systematic numerical studies of the possible effects of the coupling of human endocardial and Purkinje cells at cellular and two-dimensional tissue levels. We find that the autorhythmic-activity frequency of the Purkinje cell in a composite decreases with an increase in the coupling strength; this can even eliminate the autorhythmicity. We observe a delay between the beginning of the action potentials of endocardial and Purkinje cells in a composite; such a delay increases as we decrease the diffusive coupling, and eventually a failure of transmission occurs. An increase in the diffusive coupling decreases the slope of the action-potential-duration-restitution curve of an endocardial cell in a composite. By using a minimal model for the Purkinje network, in which we have a two-dimensional, bilayer tissue, with a layer of Purkinje cells on top of a layer of endocardial cells, we can stabilize spiral-wave turbulence; however, for a sparse distribution of Purkinje-ventricular junctions, at which these two layers are coupled, we can also obtain additional focal activity and many complex transient regimes. We also present additional effects resulting from the coupling of Purkinje and endocardial layers and discuss the relation of our results to the studies performed in anatomically accurate models of the Purkinje network.

An infrared optical pacing system for high-throughput screening of cardiac electrophysiology in human cardiomyocytes (Conference Presentation)

NASA Astrophysics Data System (ADS)

McPheeters, Matt T.; Wang, Yves T.; Laurita, Kenneth R.; Jenkins, Michael W.

2017-02-01

Cardiomyocytes derived from human induced pluripotent stem cells (hiPS-HCM) have the potential to provide individualized therapies for patients and to test drug candidates for cardiac toxicity. In order for hiPS-CM to be useful for such applications, there is a need for high-throughput technology to rapidly assess cardiac electrophysiology parameters. Here, we designed and tested a fully contactless optical mapping (OM) and optical pacing (OP) system capable of imaging and point stimulation of hiPS-CM in small wells. OM allowed us to characterize cardiac electrophysiological parameters (conduction velocity, action potential duration, etc.) using voltage-sensitive dyes with high temporal and spatial resolution over the entire well. To improve OM signal-to-noise ratio, we tested a new voltage-sensitive dye (Fluovolt) for accuracy and phototoxicity. Stimulation is essential because most electrophysiological parameters are rate dependent; however, traditional methods utilizing electrical stimulation is difficult in small wells. To overcome this limitation, we utilized OP (λ = 1464 nm) to precisely control heart rate with spatial precision without the addition of exogenous agents. We optimized OP parameters (e.g., well size, pulse width, spot size) to achieve robust pacing and minimize the threshold radiant exposure. Finally, we tested system sensitivity using Flecainide, a drug with well described action on multiple electrophysiological properties.

The Role of Potassium Channels in Arabidopsis thaliana Long Distance Electrical Signalling: AKT2 Modulates Tissue Excitability While GORK Shapes Action Potentials.

PubMed

Cuin, Tracey Ann; Dreyer, Ingo; Michard, Erwan

2018-03-21

Fast responses to an external threat depend on the rapid transmission of signals through a plant. Action potentials (APs) are proposed as such signals. Plant APs share similarities with their animal counterparts; they are proposed to depend on the activity of voltage-gated ion channels. Nonetheless, despite their demonstrated role in (a)biotic stress responses, the identities of the associated voltage-gated channels and transporters remain undefined in higher plants. By demonstrating the role of two potassium-selective channels in Arabidopsis thaliana in AP generation and shaping, we show that the plant AP does depend on similar Kv -like transport systems to those of the animal signal. We demonstrate that the outward-rectifying potassium-selective channel GORK limits the AP amplitude and duration, while the weakly-rectifying channel AKT2 affects membrane excitability. By computational modelling of plant APs, we reveal that the GORK activity not only determines the length of an AP but also the steepness of its rise and the maximal amplitude. Thus, outward-rectifying potassium channels contribute to both the repolarisation phase and the initial depolarisation phase of the signal. Additionally, from modelling considerations we provide indications that plant APs might be accompanied by potassium waves, which prime the excitability of the green cable.

A cardiac electrical activity model based on a cellular automata system in comparison with neural network model.

PubMed

Khan, Muhammad Sadiq Ali; Yousuf, Sidrah

2016-03-01

Cardiac Electrical Activity is commonly distributed into three dimensions of Cardiac Tissue (Myocardium) and evolves with duration of time. The indicator of heart diseases can occur randomly at any time of a day. Heart rate, conduction and each electrical activity during cardiac cycle should be monitor non-invasively for the assessment of "Action Potential" (regular) and "Arrhythmia" (irregular) rhythms. Many heart diseases can easily be examined through Automata model like Cellular Automata concepts. This paper deals with the different states of cardiac rhythms using cellular automata with the comparison of neural network also provides fast and highly effective stimulation for the contraction of cardiac muscles on the Atria in the result of genesis of electrical spark or wave. The specific formulated model named as "States of automaton Proposed Model for CEA (Cardiac Electrical Activity)" by using Cellular Automata Methodology is commonly shows the three states of cardiac tissues conduction phenomena (i) Resting (Relax and Excitable state), (ii) ARP (Excited but Absolutely refractory Phase i.e. Excited but not able to excite neighboring cells) (iii) RRP (Excited but Relatively Refractory Phase i.e. Excited and able to excite neighboring cells). The result indicates most efficient modeling with few burden of computation and it is Action Potential during the pumping of blood in cardiac cycle.

Cutaneous electrical stimulation treatment in unresolved facial nerve paralysis: an exploratory study.

PubMed

Hyvärinen, Antti; Tarkka, Ina M; Mervaala, Esa; Pääkkönen, Ari; Valtonen, Hannu; Nuutinen, Juhani

2008-12-01

The purpose of this study was to assess clinical and neurophysiological changes after 6 mos of transcutaneous electrical stimulation in patients with unresolved facial nerve paralysis. A pilot case series of 10 consecutive patients with chronic facial nerve paralysis either of idiopathic origin or because of herpes zoster oticus participated in this open study. All patients received below sensory threshold transcutaneous electrical stimulation for 6 mos for their facial nerve paralysis. The intervention consisted of gradually increasing the duration of electrical stimulation of three sites on the affected area for up to 6 hrs/day. Assessments of the facial nerve function were performed using the House-Brackmann clinical scale and neurophysiological measurements of compound motor action potential distal latencies on the affected and nonaffected sides. Patients were tested before and after the intervention. A significant improvement was observed in the facial nerve upper branch compound motor action potential distal latency on the affected side in all patients. An improvement of one grade in House-Brackmann scale was observed and some patients also reported subjective improvement. Transcutaneous electrical stimulation treatment may have a positive effect on unresolved facial nerve paralysis. This study illustrates a possibly effective treatment option for patients with the chronic facial paresis with no other expectations of recovery.

Spiral-wave dynamics in a mathematical model of human ventricular tissue with myocytes and Purkinje fibers

NASA Astrophysics Data System (ADS)

Nayak, Alok Ranjan; Panfilov, A. V.; Pandit, Rahul

2017-02-01

We present systematic numerical studies of the possible effects of the coupling of human endocardial and Purkinje cells at cellular and two-dimensional tissue levels. We find that the autorhythmic-activity frequency of the Purkinje cell in a composite decreases with an increase in the coupling strength; this can even eliminate the autorhythmicity. We observe a delay between the beginning of the action potentials of endocardial and Purkinje cells in a composite; such a delay increases as we decrease the diffusive coupling, and eventually a failure of transmission occurs. An increase in the diffusive coupling decreases the slope of the action-potential-duration-restitution curve of an endocardial cell in a composite. By using a minimal model for the Purkinje network, in which we have a two-dimensional, bilayer tissue, with a layer of Purkinje cells on top of a layer of endocardial cells, we can stabilize spiral-wave turbulence; however, for a sparse distribution of Purkinje-ventricular junctions, at which these two layers are coupled, we can also obtain additional focal activity and many complex transient regimes. We also present additional effects resulting from the coupling of Purkinje and endocardial layers and discuss the relation of our results to the studies performed in anatomically accurate models of the Purkinje network.

Using delay differential equations to induce alternans in a model of cardiac electrophysiology.

PubMed

Eastman, Justin; Sass, Julian; Gomes, Johnny M; Dos Santos, Rodrigo Weber; Cherry, Elizabeth M

2016-09-07

Cardiac electrical alternans is a period-2 dynamical behavior with alternating long and short action potential durations (APD) that often precedes dangerous arrhythmias associated with cardiac arrest. Despite the importance of alternans, many current ordinary differential equations models of cardiac electrophysiology do not produce alternans, thereby limiting the use of these models for studying the mechanisms that underlie this condition. Because delay differential equations (DDEs) commonly induce complex dynamics in other biological systems, we investigate whether incorporating DDEs can lead to alternans development in cardiac models by studying the Fox et al. canine ventricular action potential model. After suppressing the alternans in the original model, we show that alternans can be obtained by introducing DDEs in the model gating variables, and we quantitatively compare the DDE-induced alternans with the alternans present in the original model. We analyze the behavior of the voltage, currents, and gating variables of the model to study the effects of the delays and to determine how alternans develops in that setting, and we discuss the mathematical and physiological implications of our findings. In future work, we aim to apply our approach to induce alternans in models that do not naturally exhibit such dynamics. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pharmacology Risk Report

NASA Technical Reports Server (NTRS)

2010-01-01

It seems very likely that the actions of administered drugs on crewmembers during spaceflight are different than they are on Earth, but even after more than 40 years of spaceflight experience, the answers to most questions about medication use during missions remain unanswered. Use of medications with insufficient knowledge about their actual activities may result in inadequate treatment and may even reduce performance and well-being in particular circumstances. There is evidence that this has already occurred during and immediately after spaceflights. The spaceflight pharmaceutical activity knowledge base must be improved to enable flight surgeons and crewmembers to make better decisions about using pharmaceuticals inflight. The spaceflight environment induces changes in human physiology, and these changes have been the subject of much study over the past few decades. These studies are confounded by the small number of potential subjects, as well by the inability to separate the different stressors of spaceflight (radiation exposure from microgravity, for example). In every physiological system, the details of spaceflight-induced physiological changes are not well understood. Despite this fact, crewmembers are treated with pharmaceuticals to reduce or prevent medical problems, with insufficient information as to drug function on their altered physiological systems. There are two major concerns about pharmaceutical use in the unusual environment of spaceflight. The actions of pharmaceuticals on physiology altered by a spaceflight environment are currently assumed to be the same as the actions in terrestrial use. This has yet to be established. The wide range of physiological systems altered by spaceflight and the degree of change experienced in some of them make it very likely that alterations in pharmaceutical action will be seen. As the duration of missions lengthens to include more distant exploration, it becomes more likely that problems will be encountered. Secondly, the integrity of stored pharmaceuticals must be established to ensure that adequate amounts of active compounds are available in each dose and that degradation to toxic compounds is minimized. This risk is also dependent on mission duration, since longer missions will require that drugs be stored much longer than their usual terrestrial shelf-lives.

Transmural ultrasound imaging of thermal lesion and action potential changes in perfused canine cardiac wedge preparations by high intensity focused ultrasound ablation.

PubMed

Wu, Ziqi; Gudur, Madhu S R; Deng, Cheri X

2013-01-01

Intra-procedural imaging is important for guiding cardiac arrhythmia ablation. It is difficult to obtain intra-procedural correlation of thermal lesion formation with action potential (AP) changes in the transmural plane during ablation. This study tested parametric ultrasound imaging for transmural imaging of lesion and AP changes in high intensity focused ultrasound (HIFU) ablation using coronary perfused canine ventricular wedge preparations (n = 13). The preparations were paced from epi/endocardial surfaces and subjected to HIFU application (3.5 MHz, 11 Hz pulse-repetition-frequency, 70% duty cycle, duration 4 s, 3500 W/cm(2)), during which simultaneous optical mapping (1 kframes/s) using di-4-ANEPPS and ultrasound imaging (30 MHz) of the same transmural surface of the wedge were performed. Spatiotemporally correlated AP measurements and ultrasound imaging allowed quantification of the reduction of AP amplitude (APA), shortening of AP duration at 50% repolarization, AP triangulation, decrease of optical AP rise, and change of conduction velocity along tissue depth direction within and surrounding HIFU lesions. The threshold of irreversible change in APA correlating to lesions was determined to be 43 ± 1% with a receiver operating characteristic (ROC) area under curve (AUC) of 0.96 ± 0.01 (n = 13). Ultrasound imaging parameters such as integrated backscatter, Rayleigh (α) and log-normal (σ) parameters, cumulative extrema of σ were tested, with the cumulative extrema of σ performing the best in detecting lesion (ROC AUC 0.89 ± 0.01, n = 13) and change of APA (ROC AUC 0.79 ± 0.03, n = 13). In conclusion, characteristic tissue and AP changes in HIFU ablation were identified and spatiotemporally correlated using optical mapping and ultrasound imaging. Parametric ultrasound imaging using cumulative extrema of σ can detect HIFU lesion and APA reduction.

Transmural Ultrasound Imaging of Thermal Lesion and Action Potential Changes in Perfused Canine Cardiac Wedge Preparations by High Intensity Focused Ultrasound Ablation

PubMed Central

Wu, Ziqi; Gudur, Madhu S. R.; Deng, Cheri X.

2013-01-01

Intra-procedural imaging is important for guiding cardiac arrhythmia ablation. It is difficult to obtain intra-procedural correlation of thermal lesion formation with action potential (AP) changes in the transmural plane during ablation. This study tested parametric ultrasound imaging for transmural imaging of lesion and AP changes in high intensity focused ultrasound (HIFU) ablation using coronary perfused canine ventricular wedge preparations (n = 13). The preparations were paced from epi/endocardial surfaces and subjected to HIFU application (3.5 MHz, 11 Hz pulse-repetition-frequency, 70% duty cycle, duration 4 s, 3500 W/cm2), during which simultaneous optical mapping (1 kframes/s) using di-4-ANEPPS and ultrasound imaging (30 MHz) of the same transmural surface of the wedge were performed. Spatiotemporally correlated AP measurements and ultrasound imaging allowed quantification of the reduction of AP amplitude (APA), shortening of AP duration at 50% repolarization, AP triangulation, decrease of optical AP rise, and change of conduction velocity along tissue depth direction within and surrounding HIFU lesions. The threshold of irreversible change in APA correlating to lesions was determined to be 43±1% with a receiver operating characteristic (ROC) area under curve (AUC) of 0.96±0.01 (n = 13). Ultrasound imaging parameters such as integrated backscatter, Rayleigh (α) and log-normal (σ) parameters, cumulative extrema of σ were tested, with the cumulative extrema of σ performing the best in detecting lesion (ROC AUC 0.89±0.01, n = 13) and change of APA (ROC AUC 0.79±0.03, n = 13). In conclusion, characteristic tissue and AP changes in HIFU ablation were identified and spatiotemporally correlated using optical mapping and ultrasound imaging. Parametric ultrasound imaging using cumulative extrema of σ can detect HIFU lesion and APA reduction. PMID:24349337

Design and validation of a tissue bath 3-D printed with PLA for optically mapping suspended whole heart preparations.

PubMed

Entz, Michael; King, D Ryan; Poelzing, Steven

2017-12-01

With the sudden increase in affordable manufacturing technologies, the relationship between experimentalists and the designing process for laboratory equipment is rapidly changing. While experimentalists are still dependent on engineers and manufacturers for precision electrical, mechanical, and optical equipment, it has become a realistic option for in house manufacturing of other laboratory equipment with less precise design requirements. This is possible due to decreasing costs and increasing functionality of desktop three-dimensional (3-D) printers and 3-D design software. With traditional manufacturing methods, iterative design processes are expensive and time consuming, and making more than one copy of a custom piece of equipment is prohibitive. Here, we provide an overview to design a tissue bath and stabilizer for a customizable, suspended, whole heart optical mapping apparatus that can be produced significantly faster and less expensive than conventional manufacturing techniques. This was accomplished through a series of design steps to prevent fluid leakage in the areas where the optical imaging glass was attached to the 3-D printed bath. A combination of an acetone dip along with adhesive was found to create a water tight bath. Optical mapping was used to quantify cardiac conduction velocity and action potential duration to compare 3-D printed baths to a bath that was designed and manufactured in a machine shop. Importantly, the manufacturing method did not significantly affect conduction, action potential duration, or contraction, suggesting that 3-D printed baths are equally effective for optical mapping experiments. NEW & NOTEWORTHY This article details three-dimensional printable equipment for use in suspended whole heart optical mapping experiments. This equipment is less expensive than conventional manufactured equipment as well as easily customizable to the experimentalist. The baths can be waterproofed using only a three-dimensional printer, acetone, a glass microscope slide, c-clamps, and adhesive. Copyright © 2017 the American Physiological Society.

Differential Changes in QTc Duration during In-Hospital Haloperidol Use

PubMed Central

Blom, Marieke T.; Bardai, Abdennasser; van Munster, Barbara C.; Nieuwland, Mei-Ing; de Jong, Hendrik; van Hoeijen, Daniel A.; Spanjaart, Anne M.; de Boer, Anthonius; de Rooij, Sophia E.; Tan, Hanno L.

2011-01-01

Aims To evaluate changes in QT duration during low-dose haloperidol use, and determine associations between clinical variables and potentially dangerous QT prolongation. Methods In a retrospective cohort study in a tertiary university teaching hospital in The Netherlands, all 1788 patients receiving haloperidol between 2005 and 2007 were studied; ninety-seven were suitable for final analysis. Rate-corrected QT duration (QTc) was measured before, during and after haloperidol use. Clinical variables before haloperidol use and at the time of each ECG recording were retrieved from hospital charts. Mixed model analysis was used to estimate changes in QT duration. Risk factors for potentially dangerous QT prolongation were estimated by logistic regression analysis. Results Patients with normal before-haloperidol QTc duration (male ≤430 ms, female ≤450 ms) had a significant increase in QTc duration of 23 ms during haloperidol use; twenty-three percent of patients rose to abnormal levels (male ≥450 ms, female ≥470 ms). In contrast, a significant decrease occurred in patients with borderline (male 430–450 ms, female 450–470 ms) or abnormal before-haloperidol QTc duration (15 ms and 46 ms, respectively); twenty-three percent of patients in the borderline group, and only 9% of patients in the abnormal group obtained abnormal levels. Potentially dangerous QTc prolongation was independently associated with surgery before haloperidol use (ORadj 34.9, p = 0.009) and before-haloperidol QTc duration (ORadj 0.94, p = 0.004). Conclusion QTc duration during haloperidol use changes differentially, increasing in patients with normal before-haloperidol QTc duration, but decreasing in patients with prolonged before-haloperidol QTc duration. Shorter before-haloperidol QTc duration and surgery before haloperidol use predict potentially dangerous QTc prolongation. PMID:21961030

Persistent increased PKMζ in long-term and remote spatial memory.

PubMed

Hsieh, Changchi; Tsokas, Panayiotis; Serrano, Peter; Hernández, A Iván; Tian, Dezhi; Cottrell, James E; Shouval, Harel Z; Fenton, André Antonio; Sacktor, Todd Charlton

2017-02-01

PKMζ is an autonomously active PKC isoform that is thought to maintain both LTP and long-term memory. Whereas persistent increases in PKMζ protein sustain the kinase's action in LTP, the molecular mechanism for the persistent action of PKMζ during long-term memory has not been characterized. PKMζ inhibitors disrupt spatial memory when introduced into the dorsal hippocampus from 1day to 1month after training. Therefore, if the mechanisms of PKMζ's persistent action in LTP maintenance and long-term memory were similar, persistent increases in PKMζ would last for the duration of the memory, far longer than most other learning-induced gene products. Here we find that spatial conditioning by aversive active place avoidance or appetitive radial arm maze induces PKMζ increases in dorsal hippocampus that persist from 1day to 1month, coinciding with the strength and duration of memory retention. Suppressing the increase by intrahippocampal injections of PKMζ-antisense oligodeoxynucleotides prevents the formation of long-term memory. Thus, similar to LTP maintenance, the persistent increase in the amount of autonomously active PKMζ sustains the kinase's action during long-term and remote spatial memory maintenance. Copyright © 2016. Published by Elsevier Inc.

Experimental and Conformational Analyses of Interactions between Butenafine and Lipids

PubMed Central

Mingeot-Leclercq, Marie-Paule; Gallet, Xavier; Flore, Christel; Van Bambeke, Françoise; Peuvot, Jacques; Brasseur, Robert

2001-01-01

Butenafine (N-4-tert-butylbenzyl-N-methyl-1-naphtalenemethylamine hydrochloride) is an antifungal agent of the benzylamine class that has excellent therapeutic efficacy and a remarkably long duration of action when applied topically to treat various mycoses. Given the lipophilic nature of the molecule, efficacy may be related to an interaction with cell membrane phospholipids and permeabilization of the fungal cell wall. Similarly, high lipophilicity could account for the long duration of action, since fixation to lipids in cutaneous tissues might allow them to act as local depots for slow release of the drug. We have therefore used computer-assisted conformational analysis to investigate the interaction of butenafine with lipids and extended these observations with experimental studies in vitro using liposomes. Conformational analysis of mixed monolayers of phospholipids with the neutral and protonated forms of butenafine highlighted a possible interaction with both the hydrophilic and hydrophobic domains of membrane phospholipids. Studies using liposomes demonstrated that butenafine increases membrane fluidity [assessed by fluorescence polarization of 1-(4-trimethylammonium-phenyl)-6-phenyl-1,3,5-hexatriene and 1,6-diphenylhexatriene] and membrane permeability (studied by release of calcein from liposomes). The results show, therefore, that butenafine readily interacts with lipids and is incorporated into membrane phospholipids. These findings may help explain the excellent antifungal efficacy and long duration of action of this drug when it is used as a topical antifungal agent in humans. PMID:11709307

Effect of duration of the GnRH agonists in the luteal phase in the outcome of assisted reproduction cycles.

PubMed

Geber, Selmo; Sampaio, Marcos

2013-06-01

The effect of long-acting GnRHa, in the luteal phase, during ART cycles varies from one patient to another. The aim of this study was to evaluate whether the effect of long-acting GnRHa in the luteal phase, in ART cycles, affects pregnancy rates according to the duration of its action in such phase. This is a retrospective study of 367 patients submitted to ovulation induction for in vitro fertilization/intracytoplasmic sperm injection procedures that used long-acting depot GnRHa for pituitary suppression. Patients were stratified according to the period of action of the agonist in the luteal phase: group 1, ≤ 6 days; group 2, 7 to 12 days; and group 3, >12 days. The following variables were analyzed: ovarian response, age, infertility causes and pregnancy rates. Group 1 (n = 53) had a mean age of 33.8 ± 4.55 years (23-44 years) and a pregnancy rate of 45.2%. In group 2 (n = 118), mean age was 33.7 ± 4.5 years (24-44 years) and the pregnancy rate was 38.9%. In group 3 (n = 196), mean age was 33.7 ± 4.4 years (23-43 years) and the pregnancy rate was 47.4%. Regardless of the duration of depot GnRHa action in the luteal phase, no significant association with pregnancy rates was found.

Origin and Properties of Striatal Local Field Potential Responses to Cortical Stimulation: Temporal Regulation by Fast Inhibitory Connections

PubMed Central

Galiñanes, Gregorio L.; Braz, Barbara Y.; Murer, Mario Gustavo

2011-01-01

Evoked striatal field potentials are seldom used to study corticostriatal communication in vivo because little is known about their origin and significance. Here we show that striatal field responses evoked by stimulating the prelimbic cortex in mice are reduced by more than 90% after infusing the AMPA receptor antagonist CNQX close to the recording electrode. Moreover, the amplitude of local field responses and dPSPs recorded in striatal medium spiny neurons increase in parallel with increasing stimulating current intensity. Finally, the evoked striatal fields show several of the basic known properties of corticostriatal transmission, including paired pulse facilitation and topographical organization. As a case study, we characterized the effect of local GABAA receptor blockade on striatal field and multiunitary action potential responses to prelimbic cortex stimulation. Striatal activity was recorded through a 24 channel silicon probe at about 600 µm from a microdialysis probe. Intrastriatal administration of the GABAA receptor antagonist bicuculline increased by 65±7% the duration of the evoked field responses. Moreover, the associated action potential responses were markedly enhanced during bicuculline infusion. Bicuculline enhancement took place at all the striatal sites that showed a response to cortical stimulation before drug infusion, but sites showing no field response before bicuculline remained unresponsive during GABAA receptor blockade. Thus, the data demonstrate that fast inhibitory connections exert a marked temporal regulation of input-output transformations within spatially delimited striatal networks responding to a cortical input. Overall, we propose that evoked striatal fields may be a useful tool to study corticostriatal synaptic connectivity in relation to behavior. PMID:22163020

Amphetamine Paradoxically Augments Exocytotic Dopamine Release and Phasic Dopamine Signals

PubMed Central

Daberkow, DP; Brown, HD; Bunner, KD; Kraniotis, SA; Doellman, MA; Ragozzino, ME; Garris, PA; Roitman, MF

2013-01-01

Drugs of abuse hijack brain reward circuitry during the addiction process by augmenting action potential-dependent phasic dopamine release events associated with learning and goal-directed behavior. One prominent exception to this notion would appear to be amphetamine (AMPH) and related analogs, which are proposed instead to disrupt normal patterns of dopamine neurotransmission by depleting vesicular stores and promoting non-exocytotic dopamine efflux via reverse transport. This mechanism of AMPH action, though, is inconsistent with its therapeutic effects and addictive properties - which are thought to be reliant on phasic dopamine signaling. Here we used fast-scan cyclic voltammetry in freely moving rats to interrogate principal neurochemical responses to AMPH in the striatum and relate these changes to behavior. First, we showed that AMPH dose-dependently enhanced evoked dopamine responses to phasic-like current pulse trains for up to two hours. Modeling the data revealed that AMPH inhibited dopamine uptake but also unexpectedly potentiated vesicular dopamine release. Second, we found that AMPH increased the amplitude, duration and frequency of spontaneous dopamine transients, the naturally occurring, non-electrically evoked, phasic increases in extracellular dopamine. Finally, using an operant sucrose reward paradigm, we showed that low-dose AMPH augmented dopamine transients elicited by sucrose-predictive cues. However, operant behavior failed at high-dose AMPH, which was due to phasic dopamine hyperactivity and the decoupling of dopamine transients from the reward predictive cue. These findings identify up-regulation of exocytotic dopamine release as a key AMPH action in behaving animals and support a unified mechanism of abused drugs to activate phasic dopamine signaling. PMID:23303926

Human auditory event-related potentials predict duration judgments.

PubMed

Bendixen, Alexandra; Grimm, Sabine; Schröger, Erich

2005-08-05

Internal clock models postulate a pulse accumulation process underlying timing activities, with more accumulated pulses resulting in longer perceived durations. We investigated whether this accumulation is reflected in the amplitude of event-related brain potentials (ERPs) elicited by auditory stimuli with durations of 400-600 ms. In a duration discrimination paradigm, we found more negative amplitudes to physically identical stimuli when they were judged as longer than the memorized standard duration (500 ms) as compared to being classified as shorter. This sustained negativity was already developing during the first 100 ms after stimulus onset. It could not be explained as a bias to respond with a particular hand (lateralized readiness potential), but rather reflects a processing difference between the tones to be judged as shorter or longer. Our results are in line with models of time processing which assume that higher numbers of accumulated pulses of a temporal processor result in an increase in perceived duration.

Bioavailabilities of rectal and oral methadone in healthy subjects

PubMed Central

Dale, Ola; Sheffels, Pamela; Kharasch, Evan D

2004-01-01

Aims Rectal administration of methadone may be an alternative to intravenous and oral dosing in cancer pain, but the bioavailability of the rectal route is not known. The aim of this study was to compare the absolute rectal bioavailability of methadone with its oral bioavailability in healthy humans. Methods Seven healthy subjects (six males, one female, aged 20–39 years) received 10 mg d5-methadone-HCl rectally (5 ml in 20% glycofurol) together with either d0-methadone intravenously (5 mg) or orally (10 mg) on two separate occasions. Blood samples for the LC-MS analyses of methadone and it's metabolite EDDP were drawn for up to 96 h. Noninvasive infrared pupillometry was peformed at the same time as blood sampling. Results The mean absolute rectal bioavalability of methadone was 0.76 (0.7, 0.81), compared to 0.86 (0.75, 0.97) for oral administration (mean (95% CI)). Rectal absorption of methadone was more rapid than after oral dosing with Tmax values of 1.4 (0.9, 1.8) vs. 2.8 (1.6, 4.0) h. The extent of formation of the metabolite EDDP did not differ between routes of administration. Single doses of methadone had a duration of action of at least 10 h and were well tolerated. Conclusions Rectal administration of methadone results in rapid absorption, a high bioavailability and long duration of action. No evidence of presystemic elimination was seen. Rectal methadone has characteristics that make it a potential alternative to intravenous and oral administration, particularly in cancer pain and palliative care. PMID:15255797

Adjuvant effect of melatonin on anesthesia induced by thiopental sodium, ketamine, and ether in rats.

PubMed

Budhiraja, S; Singh, J

2005-12-01

This study evaluated the anesthetic effects of thiopental sodium, ketamine, and ether with concurrent administration of melatonin. The loss of righting reflex was taken to assess the onset of anesthesia. Melatonin (20 mg/kg, p.o.) potentiated the anesthetic effects of thiopental sodium (20 mg/kg, i.v.) and ketamine (50 mg/kg, i.p.). Melatonin pretreatment caused rapid onset of anesthesia after ketamine and thiopental sodium administration while the duration of action of these agents was prolonged. Melatonin failed to alter anesthetic effects of ether (2 mg/kg by open method) in rats. This study suggests that melatonin modulate mechanisms involved in induction of thiopental sodium and ketamine anesthesia. Copyright 2005 Prous Science. All rights reserved.

Sex-, tissue-, and exposure duration-dependent effects of imidacloprid modulated by piperonyl butoxide and menadione in rats. Part I: oxidative and neurotoxic potentials.

PubMed

Yardimci, Mustafa; Sevgiler, Yusuf; Rencuzogullari, Eyyup; Arslan, Mehmet; Buyukleyla, Mehmet; Yilmaz, Mehmet

2014-12-01

Earlier research has evidenced the oxidative and neurotoxic potential of imidacloprid, a neonicotinoid insecticide, in different animal species. The primary aim of this study was to determine how metabolic modulators piperonyl butoxide and menadione affect imidacloprid's adverse action in the liver and kidney of Sprague-Dawley rats of both sexes. The animals were exposed to imidacloprid alone (170 mg kg⁻¹) or in combination with piperonyl butoxide (100 mg kg⁻¹) or menadione (25 mg kg⁻¹) for 12 and 24 h. Their liver and kidney homogenates were analysed spectrophotometrically for glutathione peroxidase, glutathione S-transferase, catalase, total cholinesterase specific activities, total glutathione, total protein content, and lipid peroxidation levels. Imidacloprid displayed its prooxidative and neurotoxic effects predominantly in the kidney of male rats after 24 h of exposure. Our findings suggest that the observed differences in prooxidative and neurotoxic potential of imidacloprid could be related to differences in its metabolism between the sexes. Co-exposure (90-min pre-treatment) with piperonyl butoxide or menadione revealed tissue-specific effect of imidacloprid on total cholinesterase activity. Increased cholinesterase activity in the kidney could be an adaptive response to imidacloprid-induced oxidative stress. In the male rat liver, co-exposure with piperonyl butoxide or menadione exacerbated imidacloprid toxicity. In female rats, imidacloprid+menadione co-exposure caused prooxidative effects, while no such effects were observed with imidacloprid alone or menadione alone. In conclusion, sex-, tissue-, and duration-specific effects of imidacloprid are remarkable points in its toxicity.

Knowledge to Action - Understanding Natural Hazards-Induced Power Outage Scenarios for Actionable Disaster Responses

NASA Astrophysics Data System (ADS)

Kar, B.; Robinson, C.; Koch, D. B.; Omitaomu, O.

2017-12-01

The Sendai Framework for Disaster Risk Reduction 2015-2030 identified the following four priorities to prevent and reduce disaster risks: i) understanding disaster risk; ii) strengthening governance to manage disaster risk; iii) investing in disaster risk reduction for resilience and; iv) enhancing disaster preparedness for effective response, and to "Build Back Better" in recovery, rehabilitation and reconstruction. While forecasting and decision making tools are in place to predict and understand future impacts of natural hazards, the knowledge to action approach that currently exists fails to provide updated information needed by decision makers to undertake response and recovery efforts following a hazard event. For instance, during a tropical storm event advisories are released every two to three hours, but manual analysis of geospatial data to determine potential impacts of the event tends to be time-consuming and a post-event process. Researchers at Oak Ridge National Laboratory have developed a Spatial Decision Support System that enables real-time analysis of storm impact based on updated advisory. A prototype of the tool that focuses on determining projected power outage areas and projected duration of outages demonstrates the feasibility of integrating science with decision making for emergency management personnel to act in real time to protect communities and reduce risk.

The roles of mid-myocardial and epicardial cells in T-wave alternans development: a simulation study.

PubMed

Janusek, D; Svehlikova, J; Zelinka, J; Weigl, W; Zaczek, R; Opolski, G; Tysler, M; Maniewski, R

2018-05-08

The occurrence of T-wave alternans in electrocardiographic signals was recently linked to susceptibility to ventricular arrhythmias and sudden cardiac death. Thus, by detecting and comprehending the origins of T-wave alternans, it might be possible to prevent such events. Here, we simulated T-wave alternans in a computer-generated human heart model by modulating the action potential duration and amplitude during the first part of the repolarization phase. We hypothesized that changes in the intracardiac alternans patterns of action potential properties would differentially influence T-wave alternans measurements at the body surface. Specifically, changes were simulated globally in the whole left and right ventricles to simulate concordant T-wave alternans, and locally in selected regions to simulate discordant and regional discordant, hereinafter referred to as "regional", T-wave alternans. Body surface potential maps and 12-lead electrocardiographic signals were then computed. In depth discrimination, the influence of epicardial layers on T-wave alternans development was significantly higher than that of mid-myocardial cells. Meanwhile, spatial discrimination revealed that discordant and regional action potential property changes had a higher influence on T-wave alternans amplitude than concordant changes. Notably, varying T-wave alternans sources yielded distinct body surface potential map patterns for T-wave alternans amplitude, which can be used for location of regions within hearts exhibiting impaired repolarization. The highest ability for T-wave alternans detection was achieved in lead V1. Ultimately, we proposed new parameters Vector Magnitude Alternans and Vector Angle Alternans, with higher ability for T-wave alternans detection when using multi-lead electrocardiographic signals processing than for single leads. Finally, QT alternans was found to be associated with the process of T-wave alternans generation. The distributions of the body surface T-wave alternans amplitude have been shown to have unique patterns depending on the type of alternans (concordant, discordant or regional) and the location of the disturbance in the heart. The influence of epicardial cells on T-wave alternans development is significantly higher than that of mid-myocardial cells, among which the sub-endocardial layer exerted the highest influence. QT interval alternans is identified as a phenomenon that correlate with T-wave alternans.

Probiotics in the treatment of acute rotavirus diarrhoea. A randomized, double-blind, controlled trial using two different probiotic preparations in Bolivian children.

PubMed

Grandy, Giuseppe; Medina, Marcos; Soria, Richard; Terán, Carlos G; Araya, Magdalena

2010-08-25

Evidence suggests that probiotics reduce rotavirus diarrhoea duration. Although there are several probiotic strains potentially useful, daily practice is often limited by the type and number of products locally available. In general, information about combined products is scarce. In this study we compare the effect of two probiotic products in the treatment of diarrhoea in children less than 2 years of age. A Randomized double-blind controlled clinical trial in children hospitalized for acute rotavirus diarrhoea, in the Paediatric Centre Albina Patino, Cochabamba, Bolivia.Participants were children aged 1 - 23 months, who were randomly assigned to receive one of three treatments: Oral rehydration therapy plus placebo; Oral rehydration solution plus Saccharomyces boulardii; or Oral rehydration solution plus a compound containing Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium longum and Saccharomyces boulardii. Sample size was 20 per group and the outcomes were duration of diarrhoea, of fever, of vomiting and of hospitalization. 64 cases finished the protocol. On admission, patients' characteristics were similar. Median duration of diarrhoea (p = 0.04) in children who received the single species product (58 hours) was shorter than in controls (84.5 hrs). Comparing children that received the single probiotic product and controls showed shorter duration of fever (18 vs 67 hrs) (p = 0.0042) and the mixed probiotic of vomiting (0 vs 42.5 hrs) (p = 0.041). There was no effect on duration of hospitalization (p = 0.31). When experimental groups were merged, statistical significance of changes increased (total duration of diarrhoea, fever and vomiting P = 0.025, P = 0.025 and P = 0.014, respectively). Both products decreased the duration of diarrhoea compared to oral rehydration solution alone. This decrease was significant only for the single species product which also decreased the duration of fever. With the multiple species product there was no vomiting subsequent to the initiation of treatment. The quantity of probiotic bacteria needed for optimum treatment of gastroenteritis remains to be determined, particularly when multiple species are included in the product.Trial registration: ClinicalTrials.gov ID: NCT00981877Link: https://register.clinicaltrials.gov/prs/app/action/SelectProtocol/sid/S0002653/selectaction/View/ts/2/uid/U0000N04 Clinical trials NCT ID: NCT00981877.

The waterpipe: time for action.

PubMed

Maziak, Wasim

2008-11-01

The waterpipe, known in many cultures under different shapes and names (e.g. hookah, shisha, narghile), is a centuries-old tobacco use method that is witnessing a world-wide surge in popularity. This popularity is most noticeable among youths, and is surpassing cigarette smoking among this group in some societies. Many factors may have contributed to the recent waterpipe spread, including the introduction of sweetened/flavored waterpipe tobacco (known as Maassel), its reduced-harm perception, the thriving café culture, mass media and the internet. The passage of smoke through water on its way to the smoker underlies much of the common misperception that waterpipe use is less harmful than cigarettes. The health/addictive profile of waterpipe compared to cigarettes is largely unresearched and is likely to be influenced by the properties of smoke, duration and frequency of use, type of tobacco used, volume of smoke inhaled and the contribution of charcoal. However, the accumulation of evidence about the harmful and addictive potential of waterpipe use is outpacing the public health response to this health risk. A timely public health and policy action is needed in order to curb the emerging waterpipe smoking epidemic.

Action potentials reliably invade axonal arbors of rat neocortical neurons

PubMed Central

Cox, Charles L.; Denk, Winfried; Tank, David W.; Svoboda, Karel

2000-01-01

Neocortical pyramidal neurons have extensive axonal arborizations that make thousands of synapses. Action potentials can invade these arbors and cause calcium influx that is required for neurotransmitter release and excitation of postsynaptic targets. Thus, the regulation of action potential invasion in axonal branches might shape the spread of excitation in cortical neural networks. To measure the reliability and extent of action potential invasion into axonal arbors, we have used two-photon excitation laser scanning microscopy to directly image action-potential-mediated calcium influx in single varicosities of layer 2/3 pyramidal neurons in acute brain slices. Our data show that single action potentials or bursts of action potentials reliably invade axonal arbors over a range of developmental ages (postnatal 10–24 days) and temperatures (24°C-30°C). Hyperpolarizing current steps preceding action potential initiation, protocols that had previously been observed to produce failures of action potential propagation in cultured preparations, were ineffective in modulating the spread of action potentials in acute slices. Our data show that action potentials reliably invade the axonal arbors of neocortical pyramidal neurons. Failures in synaptic transmission must therefore originate downstream of action potential invasion. We also explored the function of modulators that inhibit presynaptic calcium influx. Consistent with previous studies, we find that adenosine reduces action-potential-mediated calcium influx in presynaptic terminals. This reduction was observed in all terminals tested, suggesting that some modulatory systems are expressed homogeneously in most terminals of the same neuron. PMID:10931955

42 CFR 456.524 - Notification of Administrator's action and duration of variance.

Code of Federal Regulations, 2010 CFR

2010-10-01

..., DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS UTILIZATION CONTROL Utilization Review Plans: FFP, Waivers, and Variances for Hospitals and Mental Hospitals Ur Plan: Remote...

46 CFR 153.912 - Certificate of inhibition or stabilization.

Code of Federal Regulations, 2010 CFR

2010-10-01

... inhibitor or stabilizer is effective. (5) Any temperature limitations qualifying the inhibitor's or stabilizer's effective lifetime. (6) The action to be taken should the duration of the voyage exceed the...

Pharmacological effects and potential therapeutic targets of DT-13.

PubMed

Khan, Ghulam Jilany; Rizwan, Mohsin; Abbas, Muhammad; Naveed, Muhammad; Boyang, Yu; Naeem, Muhammad Ahsan; Khan, Sara; Yuan, Shengtao; Baig, Mirza Muhammad Faran Ashraf; Sun, Li

2018-01-01

DT-13 is an isolated compound from Dwarf lillytruf tuber and currently among active research drugs by National Natural Science foundation of China for its several potential effects. The drug has been reported for its multiple pharmacological actions however no thorough review studies are available on it. Our present study is highlighting the pros and cons of DT-13 focusing on its potential pharmacological actions, therapeutic utilization and further exploration for novel targets. The drug possesses very low toxicity profile, quick onset and long duration of action with slow elimination that combinely makes it favorable for the clinical studies. In vivo and in vitro studies show that the drug regulates multiple cellular functions for its several pharmacological effects including, anti-adhesive effects via regulation of tissue factor and transforming growth factor; anti-migratory effects through indirect regulation of NM-IIA in the tumor microenvironment, Tissue factor, down-regulation of CCR5-CCL5 axis and MMP-2/9 inhibition; anti-metastatic effects via regulation of MMPs and tissue factor; pro-apoptotic effects by modulation of endocytosis of EGF receptor; anti-angiogenic effects via regulation of HIF-1α,ERK, Akt signalling and autophagy inducing characteristics by regulating PI3K/Akt/mTOR signalling pathway. In addition to anti-tumor activities, DT-13 has significant anti-inflammatory, cardioprotective, hepatoprotective and immunomodulating effects. Pharmaceutical dosage form and targeted drug delivery system for DT-13 has not been established yet. Moreover, DT-13, has not been studied for its action on brain, colorectal, hepatic, pancreatic, prostate and blood cancers. Similarly the effects of drug on carbohydrate and glucose metabolism is another niche yet to be explored. In some traditional therapies, crude drug from the plant is used against diabetic and neurological disorders that are not reported in scientific literature, however due to profound effects of DT-13 on blood and cerebral ischemic disorders, it is reasonable to hypothesize that there could be an association of DT-13 that require further exploration. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Sympathetic Nervous Regulation of Calcium and Action Potential Alternans in the Intact Heart.

PubMed

Winter, James; Bishop, Martin J; Wilder, Catherine D E; O'Shea, Christopher; Pavlovic, Davor; Shattock, Michael J

2018-01-01

Rationale: Arrhythmogenic cardiac alternans are thought to be an important determinant for the initiation of ventricular fibrillation. There is limited information on the effects of sympathetic nerve stimulation (SNS) on alternans in the intact heart and the conclusions of existing studies, focused on investigating electrical alternans, are conflicted. Meanwhile, several lines of evidence implicate instabilities in Ca handling, not electrical restitution, as the primary mechanism underpinning alternans. Despite this, there have been no studies on Ca alternans and SNS in the intact heart. The present study sought to address this, by application of voltage and Ca optical mapping for the simultaneous study of APD and Ca alternans in the intact guinea pig heart during direct SNS. Objective : To determine the effects of SNS on APD and Ca alternans in the intact guinea pig heart and to examine the mechanism(s) by which the effects of SNS are mediated. Methods and Results : Studies utilized simultaneous voltage and Ca optical mapping in isolated guinea pig hearts with intact innervation. Alternans were induced using a rapid dynamic pacing protocol. SNS was associated with rate-independent shortening of action potential duration (APD) and the suppression of APD and Ca alternans, as indicated by a shift in the alternans threshold to faster pacing rates. Qualitatively similar results were observed with exogenous noradrenaline perfusion. In contrast with previous reports, both SNS and noradrenaline acted to flatten the slope of the electrical restitution curve. Pharmacological block of the slow delayed rectifying potassium current (I Ks ), sufficient to abolish I Ks -mediated APD-adaptation, partially reversed the effects of SNS on pacing-induced alternans. Treatment with cyclopiazonic acid, an inhibitor of the sarco(endo)plasmic reticulum ATPase, had opposite effects to that of SNS, acting to increase susceptibility to alternans, and suggesting that accelerated Ca reuptake into the sarcoplasmic reticulum is a major mechanism by which SNS suppresses alternans in the guinea pig heart. Conclusions : SNS suppresses calcium and action potential alternans in the intact guinea pig heart by an action mediated through accelerated Ca handling and via increased I Ks .

Examination of muscle composition and motor unit behavior of the first dorsal interosseous of normal and overweight children.

PubMed

Miller, Jonathan D; Sterczala, Adam J; Trevino, Michael A; Herda, Trent J

2018-05-01

We examined differences between normal weight (NW) and overweight (OW) children aged 8-10 yr in strength, muscle composition, and motor unit (MU) behavior of the first dorsal interosseous. Ultrasonography was used to determine muscle cross-sectional area (CSA), subcutaneous fat (sFAT), and echo intensity (EI). MU behavior was assessed during isometric muscle actions at 20% and 50% of maximal voluntary contraction (MVC) by analyzing electromyography amplitude (EMG RMS ) and relationships between mean firing rates (MFR), recruitment thresholds (RT), and MU action potential amplitudes (MUAP size ) and durations (MUAP time ). The OW group had significantly greater EI than the NW group ( P = 0.002; NW, 47.99 ± 6.01 AU; OW, 58.90 ± 10.63 AU, where AU is arbitrary units) with no differences between groups for CSA ( P = 0.688) or MVC force ( P = 0.790). MUAP size was larger for NW than OW in relation to RT ( P = 0.002) and for MUs expressing similar MFRs ( P = 0.011). There were no significant differences ( P = 0.279-0.969) between groups for slopes or y-intercepts from the MFR vs. RT relationships. MUAP time was larger in OW ( P = 0.015) and EMG RMS was attenuated in OW compared with NW ( P = 0.034); however, there were no significant correlations ( P = 0.133-0.164, r = 0.270-0.291) between sFAT and EMG RMS . In a muscle that does not support body mass, the OW children had smaller MUAP size as well as greater EI, although anatomical CSA was similar. This contradicts previous studies examining larger limb muscles. Despite evidence of smaller MUs, the OW children had similar isometric strength compared with NW children. NEW & NOTEWORTHY Ultrasound data and motor unit action potential sizes suggest that overweight children have poorer muscle composition and smaller motor units in the first dorsal interosseous than normal weight children. Evidence is presented that suggests differences in action potential size cannot be explained by differences in subcutaneous fat alone.

Botulinum toxin A, brain and pain.

PubMed

Matak, Ivica; Lacković, Zdravko

2014-01-01

Botulinum neurotoxin type A (BoNT/A) is one of the most potent toxins known and a potential biological threat. At the same time, it is among the most widely used therapeutic proteins used yearly by millions of people, especially for cosmetic purposes. Currently, its clinical use in certain types of pain is increasing, and its long-term duration of effects represents a special clinical value. Efficacy of BoNT/A in different types of pain has been found in numerous clinical trials and case reports, as well as in animal pain models. However, sites and mechanisms of BoNT/A actions involved in nociception are a matter of controversy. In analogy with well known neuroparalytic effects in peripheral cholinergic synapses, presently dominant opinion is that BoNT/A exerts pain reduction by inhibiting peripheral neurotransmitter/inflammatory mediator release from sensory nerves. On the other hand, growing number of behavioral and immunohistochemical studies demonstrated the requirement of axonal transport for BoNT/A's antinociceptive action. In addition, toxin's enzymatic activity in central sensory regions was clearly identified after its peripheral application. Apart from general pharmacology, this review summarizes the clinical and experimental evidence for BoNT/A antinociceptive activity and compares the data in favor of peripheral vs. central site and mechanism of action. Based on literature review and published results from our laboratory we propose that the hypothesis of peripheral site of BoNT/A action is not sufficient to explain the experimental data collected up to now. Copyright © 2014 Elsevier Ltd. All rights reserved.

ARCH: Adaptive recurrent-convolutional hybrid networks for long-term action recognition

PubMed Central

Xin, Miao; Zhang, Hong; Wang, Helong; Sun, Mingui; Yuan, Ding

2017-01-01

Recognition of human actions from digital video is a challenging task due to complex interfering factors in uncontrolled realistic environments. In this paper, we propose a learning framework using static, dynamic and sequential mixed features to solve three fundamental problems: spatial domain variation, temporal domain polytrope, and intra- and inter-class diversities. Utilizing a cognitive-based data reduction method and a hybrid “network upon networks” architecture, we extract human action representations which are robust against spatial and temporal interferences and adaptive to variations in both action speed and duration. We evaluated our method on the UCF101 and other three challenging datasets. Our results demonstrated a superior performance of the proposed algorithm in human action recognition. PMID:29290647

Anesthetic Activity of Alfaxalone Compared with Ketamine in Mice

PubMed Central

Siriarchavatana, Parkpoom; Ayers, Jessica D; Kendall, Lon V

2016-01-01

Alfaxalone encased in hydroxypropyl-β-cyclodextrin is a neuroactive steroid compound that has recently been approved in the United States for use as an anesthetic in dogs and cats. We evaluated the use of alfaxalone compared with ketamine, both alone and in combination with xylazine, for anesthesia of C57BL/6 mice. We assessed time to onset of anesthesia, duration of action, reflex responses, respiratory rate, and clinical signs. Alfaxalone (80 mg/kg IP) induced a light surgical plane of anesthesia in all mice, with a time to onset of 2.2 ± 0.2 min and duration of 57.1 ± 3.8 min, whereas ketamine (80 mg/kg IP) provided only sedative effects (time to onset, 5.4 ± 0.4 min; duration, 6.9 ± 0.8 min). Clinically, alfaxalone caused a spectrum of activities, including popcorn-like jumping movements after injection, intense scratching of the face, hyperresponsiveness to noise or touch, and marked limb jerking during recovery. Adding xylazine to the single-agent protocols achieved deep surgical anesthesia (duration: alfaxalone + xylazine, 80.3 ± 17.8 min; ketamine + xylazine, 37.4 ± 8.2 min) and ameliorated the adverse clinical signs. Our preliminary analysis suggests that, because of its side effects, alfaxalone alone is not a viable anesthetic option for mice. Although alfaxalone combined with xylazine appeared to be a more viable option, some mice still experienced mild adverse reactions, and the long duration of action might be problematic regarding the maintenance of body temperature and monitoring of recovery. Further studies evaluating different routes of administration and drug combinations are warranted. PMID:27423149

[The action of low-intensity extremely high-freguency electromagnetic radiation on growth parameters for bacteria Enterococcus hirae].

PubMed

Oganian, V; Sarkisian, A; Tadevosian, A; Torchunian, A

2008-01-01

It has been found that the exposure of Enterococcus hirae ATCC9790, grown under anaerobic conditions for 30 min or 1 h, to low-intensity (flux capacity 0.06 mW/sm2) coherent electromagnetic radiation (EMI) of extremely high-frequency 45 - 53 GHz), or millimeter waves causes a marked prolongation of the lag-growth phase and a decrease in their specific growth rate, the inhibitory effect increasing in the frequency range from 49 to 53 GHz. The effect enhanced as duration of expocure was encreased from 30 min to 1 h; however, further increase in exposure duration to 2 h did not cause an enhancement of the effect. It has been shown that the action of extremely high-frequency EMI on these bacteria does not depend on medium pH (pH 8.0 or pH 6.0). It is proposed that these bacteria have defensive or reparation mechanisms which compensate for the action of radiation; the occurrence of different mechanisms for pH regulation is not ruled out.

Acyclovir reduces the duration of fever in patients with infectious mononucleosis-like illness.

PubMed

Usami, Osamu; Saitoh, Hiroki; Ashino, Yugo; Hattori, Toshio

2013-02-01

Acyclovir is known for its antiviral activity against some pathogenic viruses such as the Epstein-Barr virus (EBV) that causes infectious mononucleosis (IM) and IM-like illness. Therefore, we empirically administered acyclovir to patients with suspected EBV-IM and IM like-illness, upon their admission to our hospital. We admitted 25 patients, who were hospitalized for fever and lymphadenopathy, to the Tohoku University Hospital Infectious Disease Ward. As part of treatment, 8 of these patients were given acyclovir (750 mg/day) with their consent and were assigned to the acyclovir group; the remaining 17 patients were assigned to the control group. The mean age of acyclovir patients (all men) was 42±5.2 years, and that of control patients (13 men and 4 women) was 31±3.0 years. The cause of illness was confirmed as EBV-IM in 6 patients (1, acyclovir; 5, control), and remained unknown for the other 19 IM-like illness patients (7, acyclovir; 12, control). A shorter duration of hospitalization and fever was observed in the acyclovir compared to that in the control patients (hospitalization duration: 16±3.7 vs. 27±7.7 days, P=0.36; fever duration: 4.5±1.8 vs. 18±6.5 days, P=0.04). Additionally, serum amyloid A (SAA) levels were lower in acyclovir than that in control patients (98±37 vs. 505±204 µg/mL, P=0.02). Therefore, we propose that acyclovir is a potential therapeutic agent for both EBV-IM and IM like-illnesses. Future studies should further examine its mechanism of action.

Reflex regulation during sustained and intermittent submaximal contractions in humans

PubMed Central

Duchateau, Jacques; Balestra, Costantino; Carpentier, Alain; Hainaut, Karl

2002-01-01

To investigate whether the intensity and duration of a sustained contraction influences reflex regulation, we compared sustained fatiguing contractions at 25 % and 50 % of maximal voluntary contraction (MVC) force in the human abductor pollicis brevis (APB) muscle. Because the activation of motoneurones during fatigue may be reflexively controlled by the metabolic status of the muscle, we also compared reflex activities during sustained and intermittent (6 s contraction, 4 s rest) contractions at 25 % MVC for an identical duration. The short-latency Hoffmann(H) reflex and the long-latency reflex (LLR) were recorded during voluntary contractions, before, during and after the fatigue tests, with each response normalised to the compound muscle action potential (M-wave). The results showed that fatigue during sustained contractions was inversely related to the intensity, and hence the duration, of the effort. The MVC force and associated surface electromyogram (EMG) declined by 26.2 % and 35.2 %, respectively, after the sustained contraction at 50 % MVC, and by 34.2 % and 44.2 % after the sustained contraction at 25 % MVC. Although the average EMG increased progressively with time during the two sustained fatiguing contractions, the amplitudes of the H and LLR reflexes decreased significantly. Combined with previous data (Duchateau & Hainaut, 1993), the results show that the effect on the H reflex is independent of the intensity of the sustained contraction, whereas the decline in the LLR is closely related to the duration of the contraction. Because there were no changes in the intermittent test at 25 % MVC, the results indicate that the net excitatory spinal and supraspinal reflex-mediated input to the motoneurone pool is reduced. This decline in excitation to the motoneurones, however, can be temporarily compensated by an enhancement of the central drive. PMID:12068054

A Chimera Na+-Pump Rhodopsin as an Effective Optogenetic Silencer

PubMed Central

Hoque, Mohammad Razuanul; Ishizuka, Toru; Inoue, Keiichi; Abe-Yoshizumi, Rei; Igarashi, Hiroyuki; Mishima, Takaaki; Kandori, Hideki

2016-01-01

With the progress of optogenetics, the activities of genetically identified neurons can be optically silenced to determine whether the neurons in question are necessary for the network performance of the behavioral expression. This logical induction is expected to be improved by the application of the Na+ pump rhodopsins (NaRs), which hyperpolarize the membrane potential with negligible influence on the ionic/pH balance. Here, we made several chimeric NaRs between two NaRs, KR2 and IaNaR from Krokinobacter eikastus and Indibacter alkaliphilus, respectively. We found that one of these chimeras, named I1K6NaR, exhibited some improvements in the membrane targeting and photocurrent properties over native NaRs. The I1K6NaR-expressing cortical neurons were stably silenced by green light irradiation for a certain long duration. With its rapid kinetics and voltage dependency, the photoactivation of I1K6NaR would specifically counteract the generation of action potentials with less hyperpolarization of the neuronal membrane potential than KR2. PMID:27861619

ELECTROCARDIOGRAPHIC CHANGES IN RABBITS SUBJECTED TO THE CHRONIC ACTION OF RADIOACTIVE ZINC DURING INTRAVENOUS ADMINISTRATION OF ADRENALINE AND INHALATION OF AMMONIA (in Russian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ovakimov, V.G.; Bibikhin, L.N.; Saitanov, A.O.

1963-09-01

The employment of pharmacological loadings (administration of adrenaline and inhalation of ammonia) in rabbits subjected to the chronic action of radioactive zinc (1 and 10 mu C/kg) disclosed changes in the sensitivity of adrenoreactive systems of the myocardium (in adrenaline test) and an altered intensity and duration of reflex bradycardia (in ammonia test). (auth)

[Pharmacological action and clinical aspects of salmeterol].

PubMed

Oguri, Kojiro

2003-09-01

Previous systemic beta(2) agonists such as procatrol tablets and tulobuterol patch were developed in Japan to address nocturnal symptoms and maintenance of lung function in asthmatic patients. Salmeterol, a potent and highly selective in beta(2) adrenocepter agonist with a duration of action greater than 12 h, was developed to provide long duration of bronchodilation with binding to a non-active site in the beta(2)-adrenocepter. Salmeterol is administrated via dry power inhalation and clinical studies have showed it has a good efficacy and a good safety profile, similar to inhaled steroids. Indeed, many clinical studies showed that salmeterol demonstrated better efficacy than long-acting beta(2)-agonist oral bronchodilators, theophyllines, and leukotriene-receptor antagonists in asthmatic patients and anticholinergic agents and theophyllines in COPD patients. Salmeterol will provide clinical benefits for Japanese asthma and COPD patients.

Magnesium sulfate accelerates the onset of low-dose rocuronium in patients undergoing laryngeal microsurgery.

PubMed

Choi, Eun-Su; Jeong, Woo-Jin; Ahn, Soon-Hyun; Oh, Ah-Young; Jeon, Young-Tae; Do, Sang-Hwan

2017-02-01

We evaluated the effect of magnesium sulfate-an enhancer of neuromuscular blockade-on onset and duration of low dose of rocuronium, and on operating conditions during laryngeal microsurgery. Randomized, prospective, double-blinded study. Eighty-four patients scheduled for elective laryngeal microsurgery. Patients were randomly allocated to receive different doses of rocuronium: 0.6 mg/kg (group C, n=28), 0.45 mg/kg (group LR, n=28), or 0.45 mg/kg plus magnesium sulfate 30 mg/kg (group LM, n=28). We measured the onset time and duration of action of rocuronium, and evaluated the surgeon's satisfaction with the operating conditions. Group LR showed significantly delayed onset time (group C: 87±22 seconds, group LR: 127±47 seconds, and group LM: 89±32 seconds; P=.001) and maximal suppression than did other groups (group C: 102±30 seconds, group LR: 155±66 seconds, and group LM: 105±36 seconds; P=.002). Duration of action of rocuronium was significantly longer in group C than in other groups (group C: 39±7 minutes, group LR: 28±8 minutes, group LRM: 31±8 minutes; P<.001). Laryngoscope placement score (P=.002), surgeon's satisfaction (P=.005), and sore throat (P=.035) were significantly worse in group LR. Magnesium sulfate 30 mg/kg accelerated the onset and improved operating conditions of low-dose rocuronium without prolongation of action. Copyright © 2016 Elsevier Inc. All rights reserved.

Amphetamine Elicits Opposing Actions on Readily Releasable and Reserve Pools for Dopamine

PubMed Central

Covey, Dan P.; Juliano, Steven A.; Garris, Paul A.

2013-01-01

Amphetamine, a highly addictive drug with therapeutic efficacy, exerts paradoxical effects on the fundamental communication modes employed by dopamine neurons in modulating behavior. While amphetamine elevates tonic dopamine signaling by depleting vesicular stores and driving non-exocytotic release through reverse transport, this psychostimulant also activates phasic dopamine signaling by up-regulating vesicular dopamine release. We hypothesized that these seemingly incongruent effects arise from amphetamine depleting the reserve pool and enhancing the readily releasable pool. This novel hypothesis was tested using in vivo voltammetry and stimulus trains of varying duration to access different vesicular stores. We show that amphetamine actions are stimulus dependent in the dorsal striatum. Specifically, amphetamine up-regulated vesicular dopamine release elicited by a short-duration train, which interrogates the readily releasable pool, but depleted release elicited by a long-duration train, which interrogates the reserve pool. These opposing actions of vesicular dopamine release were associated with concurrent increases in tonic and phasic dopamine responses. A link between vesicular depletion and tonic signaling was supported by results obtained for amphetamine in the ventral striatum and cocaine in both striatal sub-regions, which demonstrated augmented vesicular release and phasic signals only. We submit that amphetamine differentially targeting dopamine stores reconciles the paradoxical activation of tonic and phasic dopamine signaling. Overall, these results further highlight the unique and region-distinct cellular mechanisms of amphetamine and may have important implications for its addictive and therapeutic properties. PMID:23671560

Rocuronium duration of action under sevoflurane, desflurane or propofol anaesthesia.

PubMed

Maidatsi, P G; Zaralidou, A Th; Gorgias, N K; Amaniti, E N; Karakoulas, K A; Giala, M M

2004-10-01

We conducted a prospective randomized study to evaluate whether the duration of action of a single bolus dose of rocuronium is influenced by maintenance of anaesthesia with sevoflurane, desflurane or propofol infusion. Fifty-seven ASA I-II patients undergoing elective abdominal surgery were enrolled in this study. Anaesthesia was induced with thiopental 3-5 mg kg(-1) or propofol 2.5 mg kg(-1) and fentanyl 5 microg kg(-1) and tracheal intubation was facilitated with rocuronium 0.9 mg kg(-1). Thereafter patients were randomly allocated to three different groups to receive sevoflurane, desflurane or propofol for maintenance of anaesthesia. Recovery of neuromuscular function was monitored by single twitch stimulation of the ulnar nerve and by recording the adductor pollicis response using accelerometry. Intergroup recovery times to 5% of control value of single twitch were analysed using analysis of variance with Bonferroni correction. The mean (95% confidence interval) recovery time to 5% of control value of single twitch during desflurane anaesthesia was 90.18 (86.11-94.25) min. Significantly shorter recovery times were observed during sevoflurane or propofol anaesthesia, 58.86 (54.73-62.99) min and 51.11 (45.47-56.74) min, respectively (P < 0.001). There were also significant differences in the recovery time between groups receiving desflurane vs. sevoflurane (P < 0.001) and desflurane vs. propofol (P < 0.001). Desflurane anaesthesia significantly prolongs the duration of action of rocuronium at 0.9 mg kg(-1) single bolus dose, compared to sevoflurane or propofol anaesthesia maintenance regimens.

The newer aspect of dexmedetomidine use in dentistry: As an additive to local anesthesia, initial experience, and review of literature.

PubMed

Kumar, Prashant; Thepra, Manju; Bhagol, Amrish; Priya, Kannu; Singh, Virendra

2016-01-01

Despite the availability of a wide variety of pharmacological agents in the field of anesthesia, there has always been a continuous search for newer local anesthetic agents with improved efficacy, potency, and better handling properties. Dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, is an emerging agent for provision of additive local anesthetic effect if used with conventional local anesthetics, which can be implicated in dentistry for performing many minor oral surgical procedures. The present paper reports a pilot study comparing clinical efficacy and potency of this newer emerging drug in combination with lignocaine. Ten patients undergoing orthodontic extraction for correction of malocclusion and other dentofacial deformities requiring orthodontic treatment were locally infiltrated with 2% lignocaine plus dexmedetomidine 1μ/ml and 2% lignocaine plus adrenaline in 1:200,000 dilution at two different appointments. The onset of action, duration of action, and pain threshold were assessed. Onset of action was found to be faster with longer duration of action with the newer drug dexmedetomidine and lignocaine combination when compared with combination of lignocaine and adrenaline. The study demonstrated that the combination of dexmedetomidine with lignocaine enhances the local anesthetic potency of lignocaine without significant systemic effects when locally injected into oral mucosa.

The Extent of Active Processing of a Long-Duration Stimulus Modulates the Scalp-Recorded Sustained Potential

ERIC Educational Resources Information Center

Campbell, Kenneth; Herzig, Alyssa; Jashmidi, Parastoo

2009-01-01

A long-duration stimulus will elicit a negative sustained potential (SP) that is maximum in amplitude over fronto-central areas of the scalp. This study examines how the duration of active attentional processing of the stimulus might also elicit a nonsensory contingent negative variation (CNV) that overlaps and summates to the SP. Subjects were…

A cell-based assay to assess the persistence of action of agonists acting at recombinant human beta(2) adrenoceptors.

PubMed

Summerhill, Susan; Stroud, Timothy; Nagendra, Roshini; Perros-Huguet, Christelle; Trevethick, Michael

2008-01-01

The aim was to establish a robust, 96-well, cell-based assay to assess the potency and persistence of action of agonists acting at human recombinant beta(2) adrenoceptors expressed in CHO (Chinese Hamster Ovary) cells and to compare this with published duration of action data in guinea pig isolated trachea and human bronchus. Cells were treated with either: (i) beta-adrenoceptor agonist for 30 min, washed and cyclicAMP (cAMP) measured 30 min later-termed 'washed' cells or, (ii) treated with solvent for 30 min, washed, and then treated with beta-adrenoceptor agonist for 30 min and cAMP measured-termed 'unwashed' cells. The 'washed' EC(50) was divided by the 'unwashed' EC(50) to determine a rightward shift concentration ratio, which was indicative of the persistence of action at the receptor. At the beta(2) adrenoceptor salmeterol, carmoterol and indacaterol were resistant to washing with a concentration ratio of <5, indicating a long persistence of action, whereas formoterol, isoprenaline and salbutamol were washed out with a ratio of 32, >294 and >800 respectively, suggesting a shorter persistence of action. At beta(1) and beta(3) adrenoceptors all compounds washed out. The persistent effects of salmeterol at beta(2) following washing could be reversed by the selective beta(2) antagonist ICI 118551, suggesting continued receptor activation. The data presented agree well with published data assessing duration of action of beta(2) agonists in human isolated bronchus and guinea pig isolated trachea. Key features are: (a) it is a 96-well format which can be used to assess many compounds in a single experiment, (b) both potency and persistence of agonist action are assessed in the same assay, (c) any effects of concentration on the persistence of action can be highlighted, and (d) it allows triage of compounds prior to tissue bath studies thus reducing the use of animal tissue.

The Effect of Task Duration on Event-Based Prospective Memory: A Multinomial Modeling Approach

PubMed Central

Zhang, Hongxia; Tang, Weihai; Liu, Xiping

2017-01-01

Remembering to perform an action when a specific event occurs is referred to as Event-Based Prospective Memory (EBPM). This study investigated how EBPM performance is affected by task duration by having university students (n = 223) perform an EBPM task that was embedded within an ongoing computer-based color-matching task. For this experiment, we separated the overall task’s duration into the filler task duration and the ongoing task duration. The filler task duration is the length of time between the intention and the beginning of the ongoing task, and the ongoing task duration is the length of time between the beginning of the ongoing task and the appearance of the first Prospective Memory (PM) cue. The filler task duration and ongoing task duration were further divided into three levels: 3, 6, and 9 min. Two factors were then orthogonally manipulated between-subjects using a multinomial processing tree model to separate the effects of different task durations on the two EBPM components. A mediation model was then created to verify whether task duration influences EBPM via self-reminding or discrimination. The results reveal three points. (1) Lengthening the duration of ongoing tasks had a negative effect on EBPM performance while lengthening the duration of the filler task had no significant effect on it. (2) As the filler task was lengthened, both the prospective and retrospective components show a decreasing and then increasing trend. Also, when the ongoing task duration was lengthened, the prospective component decreased while the retrospective component significantly increased. (3) The mediating effect of discrimination between the task duration and EBPM performance was significant. We concluded that different task durations influence EBPM performance through different components with discrimination being the mediator between task duration and EBPM performance. PMID:29163277

Dynamic nigrostriatal dopamine biases action selection

PubMed Central

Howard, Christopher D.; Li, Hao; Geddes, Claire E.; Jin, Xin

2017-01-01

Summary Dopamine is thought to play a critical role in reinforcement learning and goal-directed behavior, but its function in action selection remains largely unknown. Here, we demonstrate that nigrostriatal dopamine biases ongoing action selection. When mice were trained to dynamically switch the action selected at different time points, changes in firing rate of nigrostriatal dopamine neurons, as well as dopamine signaling in the dorsal striatum, were found to be associated with action selection. This dopamine profile is specific to behavioral choice, scalable with interval duration, and doesn’t reflect reward prediction error, timing, or value as single factors alone. Genetic deletion of NMDA receptors on dopamine or striatal neurons, or optogenetic manipulation of dopamine concentration, alters dopamine signaling and biases action selection. These results unveil a crucial role of nigrostriatal dopamine in integrating diverse information for regulating upcoming actions and have important implications for neurological disorders including Parkinson’s disease and substance dependence. PMID:28285820

Dynamic Nigrostriatal Dopamine Biases Action Selection.

PubMed

Howard, Christopher D; Li, Hao; Geddes, Claire E; Jin, Xin

2017-03-22

Dopamine is thought to play a critical role in reinforcement learning and goal-directed behavior, but its function in action selection remains largely unknown. Here we demonstrate that nigrostriatal dopamine biases ongoing action selection. When mice were trained to dynamically switch the action selected at different time points, changes in firing rate of nigrostriatal dopamine neurons, as well as dopamine signaling in the dorsal striatum, were found to be associated with action selection. This dopamine profile is specific to behavioral choice, scalable with interval duration, and doesn't reflect reward prediction error, timing, or value as single factors alone. Genetic deletion of NMDA receptors on dopamine or striatal neurons or optogenetic manipulation of dopamine concentration alters dopamine signaling and biases action selection. These results unveil a crucial role of nigrostriatal dopamine in integrating diverse information for regulating upcoming actions, and they have important implications for neurological disorders, including Parkinson's disease and substance dependence. Copyright © 2017 Elsevier Inc. All rights reserved.

Evaluation of the myoelectrical activity of the equine ileum infected with Strongylus vulgaris larvae.

PubMed

Berry, C R; Merritt, A M; Burrows, C F; Campbell, M; Drudge, J H

1986-01-01

Five weanling ponies were subjected to an intensive 6-week deworming program after which 4 Ag-AgCl bipolar electrodes were implanted surgically on the distal ileum. For 3 hours each day for 5 consecutive days, ileal myoelectrical activity was recorded from fed ponies under 3 sequential conditions: preinoculation, after oral administration of 1,000 killed Strongylus vulgaris infective larvae (3 ponies), and after oral administration of 1,000 live S vulgaris infective larvae. Recordings were analyzed for slow wave frequency, percentage duration of phases I, II, and III of the migrating myoelectrical complex (MMC), and the frequency of distinct, rapidly migrating action-potential complexes within phase 2 of the MMC. After administration of live and killed infected 3rd-stage larvae, there was a marked increase in the number of disrupted phase III complexes, and a significant (P less than 0.001) increase in the number of migrating action-potential complexes. In addition, after inoculation of live 3rd-stage larvae, there was a significant increase (P less than 0.001) in the percentage of time that the MMC was occupied by prolonged periods devoid of spike activity (phase I). The results indicate that S vulgaris larval mucosal penetration and submucosal migration can cause changes in ileal myoelectrical activity that could cause colic, and that larval antigen alone within the lumen may disrupt ileal motility.

A Mathematical Model of Neonatal Rat Atrial Monolayers with Constitutively Active Acetylcholine-Mediated K+ Current

PubMed Central

Majumder, Rupamanjari; Jangsangthong, Wanchana; Feola, Iolanda; Ypey, Dirk L.; Pijnappels, Daniël A.; Panfilov, Alexander V.

2016-01-01

Atrial fibrillation (AF) is the most frequent form of arrhythmia occurring in the industrialized world. Because of its complex nature, each identified form of AF requires specialized treatment. Thus, an in-depth understanding of the bases of these arrhythmias is essential for therapeutic development. A variety of experimental studies aimed at understanding the mechanisms of AF are performed using primary cultures of neonatal rat atrial cardiomyocytes (NRAMs). Previously, we have shown that the distinct advantage of NRAM cultures is that they allow standardized, systematic, robust re-entry induction in the presence of a constitutively-active acetylcholine-mediated K+ current (IKACh-c). Experimental studies dedicated to mechanistic explorations of AF, using these cultures, often use computer models for detailed electrophysiological investigations. However, currently, no mathematical model for NRAMs is available. Therefore, in the present study we propose the first model for the action potential (AP) of a NRAM with constitutively-active acetylcholine-mediated K+ current (IKACh-c). The descriptions of the ionic currents were based on patch-clamp data obtained from neonatal rats. Our monolayer model closely mimics the action potential duration (APD) restitution and conduction velocity (CV) restitution curves presented in our previous in vitro studies. In addition, the model reproduces the experimentally observed dynamics of spiral wave rotation, in the absence and in the presence of drug interventions, and in the presence of localized myofibroblast heterogeneities. PMID:27332890

Phase correlated adequate afferent action potentials as a drive of human spinal oscillators.

PubMed

Schalow, G

1993-12-01

1. By recording, with 2 pairs of wire electrodes, single-fibre action potentials (APs) from lower sacral nerve roots of a brain-dead human and a patient with spinal cord lesion, impulse patterns of afferent APs and impulse trains of oscillatory firing motoneurons could be identified and correlated. 2. Two highly activated secondary muscle spindle afferents increased and decreased their activity at about 0.3 Hz. The duration of the doublet interspike interval of a secondary spindle afferent fibre showed no correlation to the oscillation period of the motoneuron. 3. A continuously oscillatory firing motoneuron innervating the external and sphincter showed more transient breaks with the reduction of the number of phase correlated APs from 2 spindle afferents, indicating a looser oscillation. A transient brake of a 157 msec period alpha 2-oscillation could be correlated to the shift of a interspike interval distribution peak from 150 to 180 msec of the adequate afferent input, which suggests a transient loss of the necessary phase relation. 4. Oscillatory firing alpha 2-motoneurons innervating the external bladder and anal sphincters fired independently according to their phase correlated APs from the urinary bladder stretch receptor and muscle spindle afferents respectively; the bladder motoneuron slightly inhibited the anal motoneuron. 5. Receptors of the afferents and innervation sites of oscillatory firing motoneurons could be located within the urinary tract and the anal canal.

Caffeine depression of spontaneous activity in rabbit sino-atrial node cells.

PubMed

Satoh, H

1993-05-01

1. Effects of caffeine on the action potentials and the membrane currents in spontaneously beating rabbit sino-atrial (SA) node cells were examined using a two-microelectrode technique. 2. Cumulative administrations of caffeine (1-10 mM) caused a negative chronotropic effect in a concentration-dependent manner, which was not modified by atropine (0.1 microM). At 10 mM, caffeine increased the amplitude and prolonged the duration of action potentials significantly; the other parameters were unaffected. 3. In 3 of 16 preparations, caffeine (5 mM) elicited arrhythmia. At high Ca2+ (8.1 mM), caffeine (5 mM) increased the incidence of arrhythmia. 4. Caffeine (0.5-10 mM) enhanced the slow inward current, but at 10 mM decreased the enhanced peak current by 5 mM. The hyperpolarization-activated inward current was also enhanced by caffeine, but 10 mM caffeine decreased the current peak as compared with that at 5 mM. In addition, caffeine inhibited the delayed rectifying outward current in a concentration-dependent manner, accompanied by a depressed activation curve without any shift in the half-maximum activation voltage. 5. Caffeine elevated the cytoplasmic Ca2+ level in the SA node cells loaded with Ca(2+)-sensitive fluorescent dye (fura-2). 6. These results suggest that caffeine enhances and/or inhibits the ionic currents and elicits arrhythmia due to the induction of cellular calcium overload.

Advanced Environmental Monitoring and Control Program: Strategic Plan

NASA Technical Reports Server (NTRS)

Schmidt, Gregory

1996-01-01

Human missions in space, from short-duration shuttle missions lasting no more than several days to the medium-to-long-duration missions planned for the International Space Station, face a number of hazards that must be understood and mitigated for the mission to be carried out safely. Among these hazards are those posed by the internal environment of the spacecraft itself; through outgassing of toxic vapors from plastics and other items, failures or off-nominal operations of spacecraft environmental control systems, accidental exposure to hazardous compounds used in experiments: all present potential hazards that while small, may accumulate and pose a danger to crew health. The first step toward mitigating the dangers of these hazards is understanding the internal environment of the spacecraft and the compounds contained within it. Future spacecraft will have integrated networks of redundant sensors which will not only inform the crew of hazards, but will pinpoint the problem location and, through analysis by intelligent systems, recommend and even implement a course of action to stop the problem. This strategic plan details strategies to determine NASA's requirements for environmental monitoring and control systems for future spacecraft, and goals and objectives for a program to answer these needs.

The alkaloid matrine of the root of Sophora flavescens prevents arrhythmogenic effect of ouabain.

PubMed

Zhou, Yuhong; Wu, Yun; Deng, Lin; Chen, Lanlan; Zhao, Dandan; Lv, Lifang; Chen, Xu; Man, Jinyu; Wang, Yansong; Shan, Hongli; Lu, Yanjie

2014-06-15

Matrine, a alkaloid of the root of Sophora flavescens, has multiple protective effects on the cardiovascular system including cardiac arrhythmias. However, the molecular and ionic mechanisms of matrine have not been well investigated. Our study aimed at to shed a light on the issue to investigate the antiarrhythmic effects of matrine by using ouabain to construct an arrhythmic model of cardiomyocytes. In this experiment, matrine significantly and dose-dependently increased the doses of ouabain required to induce cardiac arrhythmias and decreased the duration of arrhythmias in guinea pigs. In cardiomyocytes of guinea pigs, ouabain 10 μM prolonged action potential duration by 80% (p<0.05) and increased L-type Ca(2+) currents and Ca(2+) transients induced by KCl (p<0.05). Matrine 100 μM shortened the prolongation of APD and prevented the increase of L-type Ca(2+) currents and Ca(2+) transients induced by ouabain. Taken together, these findings provide the first evidence that matrine possessed arrhythmogenic effect of ouabain by inhibiting of L-type Ca(2+) currents and Ca(2+) overload in guinea pigs. Copyright © 2014 Elsevier GmbH. All rights reserved.

A review and framework for understanding the potential impact of poor solid waste management on health in developing countries.

PubMed

Ziraba, Abdhalah K; Haregu, Tilahun Nigatu; Mberu, Blessing

2016-01-01

The increase in solid waste generated per capita in Africa has not been accompanied by a commensurate growth in the capacity and funding to manage it. It is reported that less than 30% of urban waste in developing countries is collected and disposed appropriately. The implications of poorly managed waste on health are numerous and depend on the nature of the waste, individuals exposed, duration of exposure and availability of interventions for those exposed. To present a framework for understanding the linkages between poor solid waste management, exposure and associated adverse health outcomes. The framework will aid understanding of the relationships, interlinkages and identification of the potential points for intervention. Development of the framework was informed by a review of literature on solid waste management policies, practices and its impact on health in developing countries. A configurative synthesis of literature was applied to develop the framework. Several iterations of the framework were reviewed by experts in the field. Each linkage and outcomes are described in detail as outputs of this study. The resulting framework identifies groups of people at a heightened risk of exposure and the potential health consequences. Using the iceberg metaphor, the framework illustrates the pathways and potential burden of ill-health related to solid waste that is hidden but rapidly unfolding with our inaction. The existing evidence on the linkage between poor solid waste management and adverse health outcomes calls to action by all stakeholders in understanding, prioritizing, and addressing the issue of solid waste in our midst to ensure that our environment and health are preserved. A resulting framework developed in this study presents a clearer picture of the linkages between poor solid waste management and could guide research, policy and action.

Antiarrhythmic effect of IKr activation in a cellular model of LQT3.

PubMed

Diness, Jonas Goldin; Hansen, Rie Schultz; Nissen, Jakob Dahl; Jespersen, Thomas; Grunnet, Morten

2009-01-01

Long QT syndrome type 3 (LQT3) is an inherited cardiac disorder caused by gain-of-function mutations in the cardiac voltage-gated sodium channel, Na(v)1.5. LQT3 is associated with the polymorphic ventricular tachycardia torsades de pointes (TdP), which can lead to syncope and sudden cardiac death. The sea anemone toxin ATX-II has been shown to inhibit the inactivation of Na(v)1.5, thereby closely mimicking the underlying cause of LQT3 in patients. The hypothesis for this study was that activation of the I(Kr) current could counteract the proarrhythmic effects of ATX-II. Two different activators of I(Kr), NS3623 and mallotoxin (MTX), were used in patch clamp studies of ventricular cardiac myocytes acutely isolated from guinea pig to test the effects of selective I(Kr) activation alone and in the presence of ATX-II. Action potentials were elicited at 1 Hz by current injection and the cells were kept at 32 degrees C to 35 degrees C. NS3623 significantly shortened action potential duration at 90% repolarization (APD(90)) compared with controls in a dose-dependent manner. Furthermore, it reduced triangulation, which is potentially antiarrhythmic. Application of ATX-II (10 nM) was proarrhythmic, causing a profound increase of APD(90) as well as early afterdepolarizations and increased beat-to-beat variability. Two independent I(Kr) activators attenuated the proarrhythmic effects of ATX-II. NS3623 did not affect the late sodium current (I(NaL)) in the presence of ATX-II. Thus, the antiarrhythmic effect of NS3623 is likely to be caused by selective I(Kr) activation. The present data show the antiarrhythmic potential of selective I(Kr) activation in a cellular model of the LQT3 syndrome.

Twitch and tetanic force responses and longitudinal propagation of action potentials in skinned skeletal muscle fibres of the rat

PubMed Central

Posterino, G S; Lamb, G D; Stephenson, D G

2000-01-01

Transverse electrical field stimulation (50 V cm−1, 2 ms duration) of mechanically skinned skeletal muscle fibres of the rat elicited twitch and tetanic force responses (36 ± 4 and 83 ± 4 % of maximum Ca2+-activated force, respectively; n = 23) closely resembling those in intact fibres. The responses were steeply dependent on the field strength and were eliminated by inclusion of 10 μm tetrodotoxin (TTX) in the (sealed) transverse tubular (T-) system of the skinned fibres and by chronic depolarisation of the T-system. Spontaneous twitch-like activity occurred sporadically in many fibres, producing near maximal force in some instances (mean time to peak: 190 ± 40 ms; n = 4). Such responses propagated as a wave of contraction longitudinally along the fibre at a velocity of 13 ± 3 mm s−1 (n = 7). These spontaneous contractions were also inhibited by inclusion of TTX in the T-system and by chronic depolarisation. We examined whether the T-tubular network was interconnected longitudinally using fibre segments that were skinned for only ∼2/3 of their length, leaving the remainder of each segment intact with its T-system open to the bathing solution. After such fibres were exposed to TTX (60 μm), the adjacent skinned region (with its T-system not open to the solution) became unresponsive to subsequent electrical stimulation in ∼50 % of cases (7/15), indicating that TTX was able to diffuse longitudinally inside the fibre via the tubular network over hundreds of sarcomeres. These experiments show that excitation–contraction coupling in mammalian muscle fibres involves action potential propagation both transversally and longitudinally within the tubular system. Longitudinal propagation of action potentials inside skeletal muscle fibres is likely to be an important safety mechanism for reducing conduction failure during fatigue and explains why, in developing skeletal muscle, the T-system first develops as an internal longitudinal network. PMID:10944176

Mathematical modeling physiological effects of the overexpression of β2-adrenoceptors in mouse ventricular myocytes.

PubMed

Rozier, Kelvin; Bondarenko, Vladimir E

2018-03-01

Transgenic (TG) mice overexpressing β 2 -adrenergic receptors (β 2 -ARs) demonstrate enhanced myocardial function, which manifests in increased basal adenylyl cyclase activity, enhanced atrial contractility, and increased left ventricular function in vivo. To gain insights into the mechanisms of these effects, we developed a comprehensive mathematical model of the mouse ventricular myocyte overexpressing β 2 -ARs. We found that most of the β 2 -ARs are active in control conditions in TG mice. The simulations describe the dynamics of major signaling molecules in different subcellular compartments, increased basal adenylyl cyclase activity, modifications of action potential shape and duration, and the effects on L-type Ca 2+ current and intracellular Ca 2+ concentration ([Ca 2+ ] i ) transients upon stimulation of β 2 -ARs in control, after the application of pertussis toxin, upon stimulation with a specific β 2 -AR agonist zinterol, and upon stimulation with zinterol in the presence of pertussis toxin. The model also describes the effects of the β 2 -AR inverse agonist ICI-118,551 on adenylyl cyclase activity, action potential, and [Ca 2+ ] i transients. The simulation results were compared with experimental data obtained in ventricular myocytes from TG mice overexpressing β 2 -ARs and with simulation data on wild-type mice. In conclusion, a new comprehensive mathematical model was developed that describes multiple experimental data on TG mice overexpressing β 2 -ARs and can be used to test numerous hypotheses. As an example, using the developed model, we proved the hypothesis of the major contribution of L-type Ca 2+ current to the changes in the action potential and [Ca 2+ ] i transient upon stimulation of β 2 -ARs with zinterol. NEW & NOTEWORTHY We developed a new mathematical model for transgenic mouse ventricular myocytes overexpressing β 2 -adrenoceptors that describes the experimental findings in transgenic mice. The model reveals mechanisms of the differential effects of stimulation of β 2 -adrenoceptors in wild-type and transgenic mice overexpressing β 2 -adrenoceptors.

Mechanisms of zolpidem-induced long QT syndrome: acute inhibition of recombinant hERG K+ channels and action potential prolongation in human cardiomyocytes derived from induced pluripotent stem cells

PubMed Central

Jehle, J; Ficker, E; Wan, X; Deschenes, I; Kisselbach, J; Wiedmann, F; Staudacher, I; Schmidt, C; Schweizer, PA; Becker, R; Katus, HA; Thomas, D

2013-01-01

Background and Purpose Zolpidem, a short-acting hypnotic drug prescribed to treat insomnia, has been clinically associated with acquired long QT syndrome (LQTS) and torsade de pointes (TdP) tachyarrhythmia. LQTS is primarily attributed to reduction of cardiac human ether-a-go-go-related gene (hERG)/IKr currents. We hypothesized that zolpidem prolongs the cardiac action potential through inhibition of hERG K+ channels. Experimental Approach Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record hERG currents from Xenopus oocytes and from HEK 293 cells. In addition, hERG protein trafficking was evaluated in HEK 293 cells by Western blot analysis, and action potential duration (APD) was assessed in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. Key Results Zolpidem caused acute hERG channel blockade in oocytes (IC50 = 61.5 μM) and in HEK 293 cells (IC50 = 65.5 μM). Mutation of residues Y652 and F656 attenuated hERG inhibition, suggesting drug binding to a receptor site inside the channel pore. Channels were blocked in open and inactivated states in a voltage- and frequency-independent manner. Zolpidem accelerated hERG channel inactivation but did not affect I–V relationships of steady-state activation and inactivation. In contrast to the majority of hERG inhibitors, hERG cell surface trafficking was not impaired by zolpidem. Finally, acute zolpidem exposure resulted in APD prolongation in hiPSC-derived cardiomyocytes. Conclusions and Implications Zolpidem inhibits cardiac hERG K+ channels. Despite a relatively low affinity of zolpidem to hERG channels, APD prolongation may lead to acquired LQTS and TdP in cases of reduced repolarization reserve or zolpidem overdose. PMID:23061993

Inotropic responses of the frog ventricle to adenosine triphosphate and related changes in endogenous cyclic nucleotides.

PubMed

Flitney, F W; Singh, J

1980-07-01

1. A study has been made of a well documented but poorly understood response of the isolated frog ventricle to treatment with exogenous adenosine 5' triphosphate (ATP). Measurements of membrane potential, isometric twitch tension and levels of endogenous 3',5'-cyclic nucleotides have been made at various times during the ATP-induced response. 2. ATP elicits a characteristic triphasic response, which comprises an initial, abrupt increase in contractility, rising to a maximum within a few beats (first phase); followed by a period when the twitch amplitude falls, sometimes to below the control level (second phase); and superceded by a more slowly developing and longer-lasting increase in contractile force (third phase). The response is unaffected by atropine, propranolol or phentolamine. However, the prostaglandin synthetase inhibitor indomethacin depresses the first phase and entirely suppresses the third phase. 3. The inotropic effects of ATP are accompanied by changes in the shape of the action potential. These effects are dose-related. The duration of the action potential (D-30mV) and its positive overshoot (O) are increased during all phases of the response, for [ATP]o's up to 10(-5) M. However, at higher [ATP]o's, D-30mV and O ar both reduced during the second phase (but not the first or third phase), when isometric twitch tension is also depressed. The relationship between action potential duration and twitch tension (P) for different [ATP]o's is linear for all three phases of the response, but the slopes of the curves (delta P/delta D) are markedly different, indicating that the sensitivity of the contractile system to membrane depolarization is not constant, but varies continuously throughout the response. 4. ATP has a potent stimulatory effect on the metabolism of endogenous 3',5'-cyclic nucleotides. The time courses of the changes in adenosine 3','5-cyclic monophosphate (3',5'-cyclic AMP) and guanosine 3',5'-cyclic monophosphate (3',5'-cyclic GMP) are complex, but the accompanying change in isometric twitch tension is paralleled closely by corresponding changes in the ratio 3',5'cyclic AMP:3',5'-cyclic GMP. 5. It is concluded that ATP exerts a dual effect on the ventricle and that the contractile response is regulated by changes in the metabolism of 3',5'-cyclic nucleotides. The effects of indomethacin indicate a possible involvement of prostaglandins in mediating the ATP response. It is suggested that the initial effect of ATP on the ventricle is to increase the permeability of the fibres to Ca2+. 6. The relationship between 3',5' cyclic nucleotide levels and ventricular contractility is discussed. It is postulated that the antagonistic effects of 3',5'-cyclic AMP and 3',5'-cyclic GMP are expressed at the level of certain phosphoproteins which regulate both the availability of Ca2+ and the sensitivity of the contractile proteins to Ca2+.

Inhibition of potassium currents is involved in antiarrhythmic effect of moderate ethanol on atrial fibrillation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Baode; Li, Chenxing

Excessive consumption of alcohol is a well-established risk factor of atrial fibrillation (AF). However, the effects of moderate alcohol drinking remain to be elucidated. This study was designed to determine the effects of moderate ethanol ingestion on atrial fibrillation and the electrophysiological mechanisms. In acetylcholine-induced canine and mouse AF models, the moderate ethanol prevented the generation and persistence of AF through prolonging the latent period of AF and shortening the duration of AF. The action potential duration (APD) was remarkably prolonged under the concentration range of 12.5–50.0 mM ethanol in guinea pig atrial myocytes. Ultra-rapid delayed rectified potassium currents (I{submore » Kv1.5}) were markedly inhibited by 12.5–50.0 mM ethanol in a concentration-dependent manner. Ethanol with 50.0 mM could inhibit rapid delayed rectifier potassium currents (I{sub hERG}). Ethanol under 6.25–50.0 mM did not affect on inward rectifier potassium currents (I{sub Kir2.1}). Collectively, the present study provided an evidence that moderate ethanol intake can prolong the APD of atrial myocytes by inhibition of I{sub Kv1.5} and I{sub hERG}, which contributed to preventing the development and duration of AF. - Highlights: • Moderate ethanol prevented the development of AF in animal models. • Moderate ethanol prolonged APD in guinea pig atrial myocytes. • Moderate ethanol inhibited Kv1.5 currents.« less

Acute amiodarone promotes drift and early termination of spiral wave re-entry.

PubMed

Nakagawa, Harumichi; Honjo, Haruo; Ishiguro, Yuko S; Yamazaki, Masatoshi; Okuno, Yusuke; Harada, Masahide; Takanari, Hiroki; Sakuma, Ichiro; Kamiya, Kaichiro; Kodama, Itsuo

2010-07-01

Intravenous application of amiodarone is commonly used in the treatment of life-threatening arrhythmias, but the underlying mechanism is not fully understood. The purpose of the present study is to investigate the acute effects of amiodarone on spiral wave (SW) re-entry, the primary organization machinery of ventricular tachycardia/fibrillation (VT/VF), in comparison with lidocaine. A two-dimensional ventricular myocardial layer was obtained from 24 Langendorff-perfused rabbit hearts, and epicardial excitations were analyzed by high-resolution optical mapping. During basic stimulation, amiodarone (5 microM) caused prolongation of action potential duration (APD) by 5.6%-9.1%, whereas lidocaine (15 microM) caused APD shortening by 5.0%-6.4%. Amiodarone and lidocaine reduced conduction velocity similarly. Ventricular tachycardias induced by DC stimulation in the presence of amiodarone were of shorter duration (sustained-VTs >30 s/total VTs: 2/58, amiodarone vs 13/52, control), whereas those with lidocaine were of longer duration (22/73, lidocaine vs 14/58, control). Amiodarone caused prolongation of VT cycle length and destabilization of SW re-entry, which is characterized by marked prolongation of functional block lines, frequent wavefront-tail interactions near the rotation center, and considerable drift, leading to its early annihilation via collision with anatomical boundaries. Spiral wave re-entry in the presence of lidocaine was more stabilized than in control. In the anisotropic ventricular myocardium, amiodarone destabilizes SW re-entry facilitating its early termination. Lidocaine, in contrast, stabilizes SW re-entry resulting in its persistence.

40 CFR 63.8490 - What records must I keep?

Code of Federal Regulations, 2010 CFR

2010-07-01

... 5 to this subpart to show continuous compliance with each emission limitation that applies to you... action taken. (2) For each deviation of an operating limit parameter value, the date, time, and duration...

Role of action potential configuration and the contribution of Ca2+ and K+ currents to isoprenaline-induced changes in canine ventricular cells

PubMed Central

Szentandrássy, N; Farkas, V; Bárándi, L; Hegyi, B; Ruzsnavszky, F; Horváth, B; Bányász, T; Magyar, J; Márton, I; Nánási, PP

2012-01-01

BACKGROUND AND PURPOSE Although isoprenaline (ISO) is known to activate several ion currents in mammalian myocardium, little is known about the role of action potential morphology in the ISO-induced changes in ion currents. Therefore, the effects of ISO on action potential configuration, L-type Ca2+ current (ICa), slow delayed rectifier K+ current (IKs) and fast delayed rectifier K+ current (IKr) were studied and compared in a frequency-dependent manner using canine isolated ventricular myocytes from various transmural locations. EXPERIMENTAL APPROACH Action potentials were recorded with conventional sharp microelectrodes; ion currents were measured using conventional and action potential voltage clamp techniques. KEY RESULTS In myocytes displaying a spike-and-dome action potential configuration (epicardial and midmyocardial cells), ISO caused reversible shortening of action potentials accompanied by elevation of the plateau. ISO-induced action potential shortening was absent in endocardial cells and in myocytes pretreated with 4-aminopyridine. Application of the IKr blocker E-4031 failed to modify the ISO effect, while action potentials were lengthened by ISO in the presence of the IKs blocker HMR-1556. Both action potential shortening and elevation of the plateau were prevented by pretreatment with the ICa blocker nisoldipine. Action potential voltage clamp experiments revealed a prominent slowly inactivating ICa followed by a rise in IKs, both currents increased with increasing the cycle length. CONCLUSIONS AND IMPLICATIONS The effect of ISO in canine ventricular cells depends critically on action potential configuration, and the ISO-induced activation of IKs– but not IKr– may be responsible for the observed shortening of action potentials. PMID:22563726

Role of action potential configuration and the contribution of C²⁺a and K⁺ currents to isoprenaline-induced changes in canine ventricular cells.

PubMed

Szentandrássy, N; Farkas, V; Bárándi, L; Hegyi, B; Ruzsnavszky, F; Horváth, B; Bányász, T; Magyar, J; Márton, I; Nánási, P P

2012-10-01

Although isoprenaline (ISO) is known to activate several ion currents in mammalian myocardium, little is known about the role of action potential morphology in the ISO-induced changes in ion currents. Therefore, the effects of ISO on action potential configuration, L-type Ca²⁺ current (I(Ca)), slow delayed rectifier K⁺ current (I(Ks)) and fast delayed rectifier K⁺ current (I(Kr)) were studied and compared in a frequency-dependent manner using canine isolated ventricular myocytes from various transmural locations. Action potentials were recorded with conventional sharp microelectrodes; ion currents were measured using conventional and action potential voltage clamp techniques. In myocytes displaying a spike-and-dome action potential configuration (epicardial and midmyocardial cells), ISO caused reversible shortening of action potentials accompanied by elevation of the plateau. ISO-induced action potential shortening was absent in endocardial cells and in myocytes pretreated with 4-aminopyridine. Application of the I(Kr) blocker E-4031 failed to modify the ISO effect, while action potentials were lengthened by ISO in the presence of the I(Ks) blocker HMR-1556. Both action potential shortening and elevation of the plateau were prevented by pretreatment with the I(Ca) blocker nisoldipine. Action potential voltage clamp experiments revealed a prominent slowly inactivating I(Ca) followed by a rise in I(Ks) , both currents increased with increasing the cycle length. The effect of ISO in canine ventricular cells depends critically on action potential configuration, and the ISO-induced activation of I(Ks) - but not I(Kr) - may be responsible for the observed shortening of action potentials. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Hippocampal 5-HT Input Regulates Memory Formation and Schaffer Collateral Excitation.

PubMed

Teixeira, Catia M; Rosen, Zev B; Suri, Deepika; Sun, Qian; Hersh, Marc; Sargin, Derya; Dincheva, Iva; Morgan, Ashlea A; Spivack, Stephen; Krok, Anne C; Hirschfeld-Stoler, Tessa; Lambe, Evelyn K; Siegelbaum, Steven A; Ansorge, Mark S

2018-06-06

The efficacy and duration of memory storage is regulated by neuromodulatory transmitter actions. While the modulatory transmitter serotonin (5-HT) plays an important role in implicit forms of memory in the invertebrate Aplysia, its function in explicit memory mediated by the mammalian hippocampus is less clear. Specifically, the consequences elicited by the spatio-temporal gradient of endogenous 5-HT release are not known. Here we applied optogenetic techniques in mice to gain insight into this fundamental biological process. We find that activation of serotonergic terminals in the hippocampal CA1 region both potentiates excitatory transmission at CA3-to-CA1 synapses and enhances spatial memory. Conversely, optogenetic silencing of CA1 5-HT terminals inhibits spatial memory. We furthermore find that synaptic potentiation is mediated by 5-HT4 receptors and that systemic modulation of 5-HT4 receptor function can bidirectionally impact memory formation. Collectively, these data reveal powerful modulatory influence of serotonergic synaptic input on hippocampal function and memory formation. Copyright © 2018 Elsevier Inc. All rights reserved.

Insulin glargine 300 units/mL: a guide for healthcare professionals involved in the management of diabetes.

PubMed

Strong, Jodi; Kruger, Davida; Novak, Lucia

2017-04-01

Insulin glargine 300 units/mL: Insulin glargine 300 units/mL (Gla-300) is a formulation of insulin glargine that delivers the same number of insulin units in one-third of the injectable volume of insulin glargine 100 units/mL (Gla-100). Glucose control: Recently approved in the United States and in Europe for use in type 1 and type 2 diabetes, Gla-300 has a more constant and evenly distributed glucose-lowering effect compared with Gla-100, with a duration of action beyond 24 hours and lower within-day and between-day intra-individual variability in blood glucose levels. These benefits translate into predictable and sustained glucose control from a once-daily injection, with potential for fewer hypoglycemia episodes and less weight gain. Case studies are presented to highlight the potential clinical benefits and considerations associated with initiating treatment with Gla-300 in people with type 1 and type 2 diabetes.

Human milk and breastfeeding: An intervention to mitigate toxic stress.

PubMed

Hallowell, Sunny G; Froh, Elizabeth B; Spatz, Diane L

The American Academy of Nursing has identified toxic stress in childhood as a health policy concern of high priority. Adult diseases (e.g., obesity, diabetes, hypertension and cardiovascular disease) should be viewed as developmental disorders that begin early in life that could be reduced with the alleviation of toxic stress in childhood. The provision of human milk/breastfeeding is an evidence-based intervention that may hold the greatest potential to mitigate the effects of toxic stress from the moment of birth. Assisting families to make an informed choice to initiate and continue breastfeeding from birth has the potential to address both the disparity in the quality of nutrition provided infants and the economic stress experienced by families who purchase formula. The Expert Panel on Breastfeeding endorses initiatives to improve the initiation, duration, and exclusivity of breastfeeding to mitigate the effects of toxic stress in this call to action for research to build the evidence to support these critical relationships. Copyright © 2016 Elsevier Inc. All rights reserved.

Inhalation by design: novel ultra-long-acting β(2)-adrenoreceptor agonists for inhaled once-daily treatment of asthma and chronic obstructive pulmonary disease that utilize a sulfonamide agonist headgroup.

PubMed

Glossop, Paul A; Lane, Charlotte A L; Price, David A; Bunnage, Mark E; Lewthwaite, Russell A; James, Kim; Brown, Alan D; Yeadon, Michael; Perros-Huguet, Christelle; Trevethick, Michael A; Clarke, Nicholas P; Webster, Robert; Jones, Rhys M; Burrows, Jane L; Feeder, Neil; Taylor, Stefan C J; Spence, Fiona J

2010-09-23

A novel series of potent and selective sulfonamide derived β(2)-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies.

Induced Pacemaker Activity on Toad Skin

PubMed Central

Bueno, Enrique J.; Corchs, Lelio

1968-01-01

The electrical transients produced on the isolated abdominal skin obtained from Bufo arenarum Hensel, under the influence of inward current pulses of constant intensity have been studied. When both faces of the skin are bathed with Ringer's solution, short pulses of inward current give rise to transient variations of the potential difference between both faces of the skin with "all-or-nothing" characteristics (action potentials, AP). When the outer face is bathed with a modified Ringer solution with low sodium content (2.4 mM), the transients are longer and they are only evident when the pulse is several hundred milliseconds long. With even longer pulses (several seconds) a repetitive activity can be elicited, with the electrical characteristics of a "pacemaker" activity. In all these "excitability" phenomena Na+ may be replaced by Li+ in the outer solution. The logarithm of the duration of AP's is inversely related to the logarithm of the increase in concentration of Na+ or Li+ in the solution bathing the external face of the skin. The duration of AP's is increased when the Ca++ concentration in the outer solution is raised. This effect is more evident with low sodium concentration on the outside. The evolution of the slope conductance during repetitive activity has been determined. The site and mechanisms of the "excitable" behavior of the skin and the induced repetitive activity are discussed. Under the experimental conditions employed the behavior of the skin is compared with that of normally excitable plasma membranes. PMID:5692095

Evidence for factors modulating radiation-induced G2-delay: potential application as radioprotectors

NASA Technical Reports Server (NTRS)

Cheong, N.; Zeng, Z. C.; Wang, Y.; Iliakis, G.

2001-01-01

Manipulation of checkpoint response to DNA damage can be developed as a means for protecting astronauts from the adverse effects of unexpected, or background exposures to ionizing radiation. To achieve this goal reagents need to be developed that protect cells from radiation injury by prolonging checkpoint response, thus promoting repair. We present evidence for a low molecular weight substance excreted by cells that dramatically increases the duration of the G2-delay. This compound is termed G2-Arrest Modulating Activity (GAMA). A rat cell line (A1-5) generated by transforming rat embryo fibroblasts with a temperature sensitive form of p53 plus H-ras demonstrates a dramatic increase in radiation resistance after exposure to low LET radiation that is not associated with an increase in the efficiency of rejoining of DNA double strand breaks. Radioresistance in this cell line correlates with a dramatic increase in the duration of the G2 arrest that is modulated by a GAMA produced by actively growing cells. The properties of GAMA suggest that it is a low molecular weight heat-stable peptide. Further characterization of this substance and elucidation of its mechanism of action may allow the development of a biological response modifier with potential applications as a radioprotector. GAMA may be useful for protecting astronauts from radiation injury as preliminary evidence suggests that it is able to modulate the response of cells exposed to heavy ion radiation, similar to that encountered in outer space.

Adverse drug reactions and drug–drug interactions with over-the-counter NSAIDs

PubMed Central

Moore, Nicholas; Pollack, Charles; Butkerait, Paul

2015-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have a long history of safe and effective use as both prescription and over-the-counter (OTC) analgesics/antipyretics. The mechanism of action of all NSAIDs is through reversible inhibition of cyclooxygenase enzymes. Adverse drug reactions (ADRs) including gastrointestinal bleeding as well as cardiovascular and renal effects have been reported with NSAID use. In many cases, ADRs may occur because of drug–drug interactions (DDIs) between the NSAID and a concomitant medication. For example, DDIs have been reported when NSAIDs are coadministered with aspirin, alcohol, some antihypertensives, antidepressants, and other commonly used medications. Because of the pharmacologic nature of these interactions, there is a continuum of risk in that the potential for an ADR is dependent on total drug exposure. Therefore, consideration of dose and duration of NSAID use, as well as the type or class of comedication administered, is important when assessing potential risk for ADRs. Safety findings from clinical studies evaluating prescription-strength NSAIDs may not be directly applicable to OTC dosing. Health care providers can be instrumental in educating patients that using OTC NSAIDs at the lowest effective dose for the shortest required duration is vital to balancing efficacy and safety. This review discusses some of the most clinically relevant DDIs reported with NSAIDs based on major sites of ADRs and classes of medication, with a focus on OTC ibuprofen, for which the most data are available. PMID:26203254

A STUDY ON THE COPING BEHAVIOURS OF WIVES OF ALCOHOLICS

PubMed Central

Rao, T.S. Sathyanarayana; Kuruvilla, K.

1992-01-01

A study was conducted on 30 wives of alcoholics using Orford-Guthrie's ‘coping with drinking’ questionnaire. Tlie commonest coping behaviour reported was discord, avoidance, indulgence and fearful withdrawal while marital breakdown, taking special action, assertion and sexual withdrawal were least frequent. There was no significant correlation between the coping behaviours and the variables like duration of marriage, duration of husband’s alcoholism, socio-economic and educational status. Implications of these findings are discussed and a cross cultural comparison is made. PMID:21776145

Drug interactions with neuromuscular blockers.

PubMed

Feldman, S; Karalliedde, L

1996-10-01

Drugs administered to patients undergoing anaesthesia may complicate the use of the neuromuscular blockers that are given to provide good surgical conditions. The various sites of interaction include actions on motor nerve conduction and spinal reflexes, acetylcholine (ACh) synthesis, mobilisation and release, sensitivity of the motor end plate to ACh and the ease of propagation of the motor action potential. In addition, many drugs affect the pharmacokinetics of neuromuscular blockers, especially as most drugs depend to a greater or lesser extent upon renal excretion. The clinically significant interaction between nondepolarisers and depolarisers may be due to blockade of the pre-synaptic nicotinic receptors by the depolarisers, leading to decreased ACh mobilisation and release. Synergism between nondepolarisers probably results from post-synaptic receptor mechanisms. Volatile anaesthetic agents affect the sensitivity of the motor end-plate (post-synaptic receptor blockade) in addition to having effects on pre-synaptic nicotinic function. The effects of nondepolarisers are likely to be potentiated and their action prolonged by large doses of local anaesthetics due to depression of nerve conduction, depression of ACh formation, mobilisation and release, decreases in post-synaptic receptor channel opening times and reductions in muscular contraction. Most antibacterials have effects on pre-synaptic mechanisms. Procainamide and quinidine principally block nicotinic receptor channels. Magnesium has a marked inhibitory effect on ACh release. Calcium antagonists could theoretically interfere with neurotransmitter release and muscle contractility. Phenytoin and lithium decrease ACh release, whilst corticosteroids and furosemide (frusemide) tend to increase the release of the transmitter. Ecothiopate, tacrine, organophosphates, propanidid, metoclopramide and bambuterol depress cholinesterase activity and prolong the duration of the neuromuscular block. The probability of clinically significant interactions increases in patients receiving several drugs with possible effects on neuromuscular transmission and muscle contraction.

Human ex-vivo action potential model for pro-arrhythmia risk assessment.

PubMed

Page, Guy; Ratchada, Phachareeya; Miron, Yannick; Steiner, Guido; Ghetti, Andre; Miller, Paul E; Reynolds, Jack A; Wang, Ken; Greiter-Wilke, Andrea; Polonchuk, Liudmila; Traebert, Martin; Gintant, Gary A; Abi-Gerges, Najah

2016-01-01

While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced pro-arrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach. Copyright © 2016 Elsevier Inc. All rights reserved.

Human ex-vivo action potential model for pro-arrhythmia risk assessment

PubMed Central

Page, Guy; Ratchada, Phachareeya; Miron, Yannick; Steiner, Guido; Ghetti, Andre; Miller, Paul E; Reynolds, Jack A; Wang, Ken; Greiter-Wilke, Andrea; Polonchuk, Liudmila; Traebert, Martin; Gintant, Gary A; Abi-Gerges, Najah

2016-01-01

While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2 Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced pro-arrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach. PMID:27235787

Electrophysiological and mechanical effects of caffeic acid phenethyl ester, a novel cardioprotective agent with antiarrhythmic activity, in guinea-pig heart.

PubMed

Chang, Gwo-Jyh; Chang, Chi-Jen; Chen, Wei-Jan; Yeh, Yung-Hsin; Lee, Hsiao-Yu

2013-02-28

Caffeic acid phenethyl ester (CAPE) is an active component of propolis that exhibits cardioprotective and antiarrhythmic effects. The detailed mechanisms underlying these effects, however, are not entirely understood. The aim of this study was to elucidate the electromechanical effects of CAPE in guinea-pig cardiac preparations. Intracardiac electrograms, left ventricular (LV) pressure, and the anti-arrhythmic efficacy were determined using isolated hearts. Action potentials of papillary muscles were assessed with microelectrodes, Ca(2+) transients were measured by fluorescence, and ion fluxes were measured by patch-clamp techniques. In a perfused heart model, CAPE prolonged the atrio-ventricular conduction interval, the Wenckebach cycle length, and the refractory periods of the AV node and His-Purkinje system, while shortening the QT interval. CAPE reduced the occurrence of reperfusion-induced ventricular fibrillation and decreased LV pressure in isolated hearts. In papillary muscles, CAPE shortened the action potential duration and reduced both the maximum upstroke velocity and contractile force. In fura-2-loaded single ventricular myocytes, CAPE decreased cell shortening and the Ca(2+) transient amplitude. Patch-clamp experiments revealed that CAPE produced a use-dependent decrease in L-type Ca(2+) current (ICa,L) (IC50=1.1 μM) and Na(+) current (INa) (IC50=0.43 μM), caused a negative-shift of the voltage-dependent inactivation and a delay of recovery from inactivation. CAPE decreased the delayed outward K(+) current (IK) slightly, without affecting the inward rectifier K(+) current (IK1). These results suggest that the preferential inhibition of Ca(2+) inward and Na(+) inward currents by CAPE may induce major electromechanical alterations in guinea-pig cardiac preparations, which may underlie its antiarrhythmic action. Copyright © 2013 Elsevier B.V. All rights reserved.

Effects of ZD7288 on firing pattern of thermosensitive neurons isolated from hypothalamus.

PubMed

Cai, Chunqing; Meng, Xiaojing; He, Junchu; Wu, Hangyu; Zou, Fei

2012-01-11

The role of the hyperpolarization-activated current (Ih) mediated by HCN channels in temperature sensing by the hypothalamus was addressed. In warm-sensitive neurons (WSNs), exposure to ZD7288, an inhibitor of Ih mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, decreased their action potential amplitudes and frequencies significantly. By contrast, ZD7288 had little or no effect on temperature-insensitive neurons (TINs). Exposure of WSNs to ZD7288 led to a significant increase in the duration of the inter-spike interval and a reduction of Ih irreversibly. These results suggest that ZD7288 have the contrasting effects on the firing patterns of WSNs versus TINs, which implies HCN channels play a central role in temperature sensing by hypothalamic neurons. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

A time dependent anatomically detailed model of cardiac conduction

NASA Technical Reports Server (NTRS)

Saxberg, B. E.; Grumbach, M. P.; Cohen, R. J.

1985-01-01

In order to understand the determinants of transitions in cardiac electrical activity from normal patterns to dysrhythmias such as ventricular fibrillation, we are constructing an anatomically and physiologically detailed finite element simulation of myocardial electrical propagation. A healthy human heart embedded in paraffin was sectioned to provide a detailed anatomical substrate for model calculations. The simulation of propagation includes anisotropy in conduction velocity due to fiber orientation as well as gradients in conduction velocities, absolute and relative refractory periods, action potential duration and electrotonic influence of nearest neighbors. The model also includes changes in the behaviour of myocardial tissue as a function of the past local activity. With this model, we can examine the significance of fiber orientation and time dependence of local propagation parameters on dysrhythmogenesis.

Duration of Action of Bupivacaine Hydrochloride Used for Palatal Sensory Nerve Block in Infant Pigs

PubMed Central

Holman, Shaina Devi; Gierbolini-Norat, Estela M.; Lukasik, Stacey L.; Campbell-Malone, Regina; Ding, Peng; German, Rebecca Z.

2015-01-01

Summary Bupivacaine hydrochloride is frequently used in veterinary dental procedures to reduce the amount of general anesthesia needed and to reduce post-procedural pain. The aim of this study was to develop a novel method to test local anesthetic duration in mammals. Six infant pigs were placed under deep/surgical anesthesia with 3 % isoflurane and oxygen while 0.5 ml of 0.5 % bupivacaine hydrochloride was injected to block the two greater palatine and the nasopalatine nerves. They were then maintained under light anesthesia with 0.5–1.0 % isoflurane. Beginning 15-minutes after the injection, 7 sites in the oral cavity were stimulated using a pointed dental waxing instrument, including 3 sites on the hard palate. The response, or lack of response, to the stimulus was recorded on video and in written record. The bupivacaine hydrochloride injections lasted 1 to 3-hours before the animals responded to the sensory stimulation with a reflexive movement. This study provides evidence that bupivacaine used to anesthetize the hard palate has a relatively short and variable duration of action far below what is expected based on its pharmacokinetic properties. PMID:25185333

Are there two forms of isometric muscle action? Results of the experimental study support a distinction between a holding and a pushing isometric muscle function.

PubMed

Schaefer, Laura V; Bittmann, Frank N

2017-01-01

In isometric muscle function, there are subjectively two different modes of performance: one can either hold isometrically - thus resist an impacting force - or push isometrically - therefore work against a stable resistance. The purpose of this study is to investigate whether or not two different isometric muscle actions - the holding vs. pushing one (HIMA vs PIMA) - can be distinguished by objective parameters. Ten subjects performed two different measuring modes at 80% of MVC realized by a special pneumatic system. During HIMA the subject had to resist the defined impacting force of the pneumatic system in an isometric position, whereby the force of the cylinder works in direction of elbow flexion against the subject. During PIMA the subject worked isometrically in direction of elbow extension against a stable position of the system. The signals of pressure, force, acceleration and mechanomyography/-tendography (MMG/MTG) of the elbow extensor (MMGtri/MTGtri) and the abdominal muscle (MMGobl) were recorded and evaluated concerning the duration of maintaining the force level (force endurance) and the characteristics of MMG-/MTG-signals. Statistical group differences comparing HIMA vs. PIMA were estimated using SPSS. Significant differences between HIMA and PIMA were especially apparent regarding the force endurance: During HIMA the subjects showed a decisively shorter time of stable isometric position (19 ± 8 s) in comparison with PIMA (41 ± 24 s; p  = .005). In addition, during PIMA the longest isometric plateau amounted to 59.4% of the overall duration time of isometric measuring, during HIMA it lasted 31.6% ( p  = .000). The frequency of MMG/MTG did not show significant differences. The power in the frequency ranges of 8-15 Hz and 10-29 Hz was significantly higher in the MTGtri performing HIMA compared to PIMA (but not for the MMGs). The amplitude of MMG/MTG did not show any significant difference considering the whole measurement. However, looking only at the last 10% of duration time (exhaustion), the MMGtri showed significantly higher amplitudes during PIMA. The results suggest that under holding isometric conditions muscles exhaust earlier. That means that there are probably two forms of isometric muscle action. We hypothesize two potential reasons for faster yielding during HIMA: (1) earlier metabolic fatigue of the muscle fibers and (2) the complexity of neural control strategies.

Neurotransmitter Release Can Be Stabilized by a Mechanism That Prevents Voltage Changes Near the End of Action Potentials from Affecting Calcium Currents

PubMed Central

Clarke, Stephen G.; Scarnati, Matthew S.

2016-01-01

At chemical synapses, presynaptic action potentials (APs) activate voltage-gated calcium channels, allowing calcium to enter and trigger neurotransmitter release. The duration, peak amplitude, and shape of the AP falling phase alter calcium entry, which can affect neurotransmitter release significantly. In many neurons, APs do not immediately return to the resting potential, but instead exhibit a period of depolarization or hyperpolarization referred to as an afterpotential. We hypothesized that presynaptic afterpotentials should alter neurotransmitter release by affecting the electrical driving force for calcium entry and calcium channel gating. In support of this, presynaptic calcium entry is affected by afterpotentials after standard instant voltage jumps. Here, we used the mouse calyx of Held synapse, which allows simultaneous presynaptic and postsynaptic patch-clamp recording, to show that the postsynaptic response is affected significantly by presynaptic afterpotentials after voltage jumps. We therefore tested the effects of presynaptic afterpotentials using simultaneous presynaptic and postsynaptic recordings and AP waveforms or real APs. Surprisingly, presynaptic afterpotentials after AP stimuli did not alter calcium channel responses or neurotransmitter release appreciably. We show that the AP repolarization time course causes afterpotential-induced changes in calcium driving force and changes in calcium channel gating to effectively cancel each other out. This mechanism, in which electrical driving force is balanced by channel gating, prevents changes in calcium influx from occurring at the end of the AP and therefore acts to stabilize synaptic transmission. In addition, this mechanism can act to stabilize neurotransmitter release when the presynaptic resting potential changes. SIGNIFICANCE STATEMENT The shape of presynaptic action potentials (APs), particularly the falling phase, affects calcium entry and small changes in calcium influx can produce large changes in postsynaptic responses. We hypothesized that afterpotentials, which often follow APs, affect calcium entry and neurotransmitter release. We tested this in calyx of Held nerve terminals, which allow simultaneous recording of presynaptic calcium currents and postsynaptic responses. Surprisingly, presynaptic afterpotentials did not alter calcium current or neurotransmitter release. We show that the AP falling phase causes afterpotential-induced changes in electrical driving force and calcium channel gating to cancel each other out. This mechanism regulates calcium entry at the end of APs and therefore stabilizes synaptic transmission. This also stabilizes responses when the presynaptic resting potential changes. PMID:27911759

Neurotransmitter Release Can Be Stabilized by a Mechanism That Prevents Voltage Changes Near the End of Action Potentials from Affecting Calcium Currents.

PubMed

Clarke, Stephen G; Scarnati, Matthew S; Paradiso, Kenneth G

2016-11-09

At chemical synapses, presynaptic action potentials (APs) activate voltage-gated calcium channels, allowing calcium to enter and trigger neurotransmitter release. The duration, peak amplitude, and shape of the AP falling phase alter calcium entry, which can affect neurotransmitter release significantly. In many neurons, APs do not immediately return to the resting potential, but instead exhibit a period of depolarization or hyperpolarization referred to as an afterpotential. We hypothesized that presynaptic afterpotentials should alter neurotransmitter release by affecting the electrical driving force for calcium entry and calcium channel gating. In support of this, presynaptic calcium entry is affected by afterpotentials after standard instant voltage jumps. Here, we used the mouse calyx of Held synapse, which allows simultaneous presynaptic and postsynaptic patch-clamp recording, to show that the postsynaptic response is affected significantly by presynaptic afterpotentials after voltage jumps. We therefore tested the effects of presynaptic afterpotentials using simultaneous presynaptic and postsynaptic recordings and AP waveforms or real APs. Surprisingly, presynaptic afterpotentials after AP stimuli did not alter calcium channel responses or neurotransmitter release appreciably. We show that the AP repolarization time course causes afterpotential-induced changes in calcium driving force and changes in calcium channel gating to effectively cancel each other out. This mechanism, in which electrical driving force is balanced by channel gating, prevents changes in calcium influx from occurring at the end of the AP and therefore acts to stabilize synaptic transmission. In addition, this mechanism can act to stabilize neurotransmitter release when the presynaptic resting potential changes. The shape of presynaptic action potentials (APs), particularly the falling phase, affects calcium entry and small changes in calcium influx can produce large changes in postsynaptic responses. We hypothesized that afterpotentials, which often follow APs, affect calcium entry and neurotransmitter release. We tested this in calyx of Held nerve terminals, which allow simultaneous recording of presynaptic calcium currents and postsynaptic responses. Surprisingly, presynaptic afterpotentials did not alter calcium current or neurotransmitter release. We show that the AP falling phase causes afterpotential-induced changes in electrical driving force and calcium channel gating to cancel each other out. This mechanism regulates calcium entry at the end of APs and therefore stabilizes synaptic transmission. This also stabilizes responses when the presynaptic resting potential changes. Copyright © 2016 the authors 0270-6474/16/3611559-14$15.00/0.

The human Nav1.5 F1486 deletion associated with long QT syndrome leads to impaired sodium channel inactivation and reduced lidocaine sensitivity

PubMed Central

Song, Weihua; Xiao, Yucheng; Chen, Hanying; Ashpole, Nicole M; Piekarz, Andrew D; Ma, Peilin; Hudmon, Andy; Cummins, Theodore R; Shou, Weinian

2012-01-01

The deletion of phenylalanine 1486 (F1486del) in the human cardiac voltage-gated sodium channel (hNav1.5) is associated with fatal long QT (LQT) syndrome. In this study we determined how F1486del impairs the functional properties of hNav1.5 and alters action potential firing in heterologous expression systems (human embryonic kidney (HEK) 293 cells) and their native cardiomyocyte background. Cells expressing hNav1.5-F1486del exhibited a loss-of-function alteration, reflected by an 80% reduction of peak current density, and several gain-of-function alterations, including reduced channel inactivation, enlarged window current, substantial augmentation of persistent late sodium current and an increase in ramp current. We also observed substantial action potential duration (APD) prolongation and prominent early afterdepolarizations (EADs) in neonatal cardiomyocytes expressing the F1486del channels, as well as in computer simulations of myocyte activity. In addition, lidocaine sensitivity was dramatically reduced, which probably contributed to the poor therapeutic outcome observed in the patient carrying the hNav1.5-F1486del mutation. Therefore, despite the significant reduction in peak current density, the F1486del mutation also leads to substantial gain-of-function alterations that are sufficient to cause APD prolongation and EADs, the predominant characteristic of LQTs. These data demonstrate that hNav1.5 mutations can have complex functional consequences and highlight the importance of identifying the specific molecular defect when evaluating potential treatments for individuals with prolonged QT intervals. PMID:22826127

Ivabradine prolongs phase 3 of cardiac repolarization and blocks the hERG1 (KCNH2) current over a concentration-range overlapping with that required to block HCN4.

PubMed

Lees-Miller, James P; Guo, Jiqing; Wang, Yibo; Perissinotti, Laura L; Noskov, Sergei Y; Duff, Henry J

2015-08-01

In Europe, ivabradine has recently been approved to treat patients with angina who have intolerance to beta blockers and/or heart failure. Ivabradine is considered to act specifically on the sinoatrial node by inhibiting the If current (the funny current) to slow automaticity. However, in vitro studies show that ivabradine prolongs phase 3 repolarization in ventricular tissue. No episodes of Torsades de Pointes have been reported in randomized clinical studies. The objective of this study is to assess whether ivabradine blocked the hERG1 current. In the present study we discovered that ivabradine prolongs action potential and blocks the hERG current over a range of concentrations overlapping with those required to block HCN4. Ivabradine produced tonic, rather than use-dependent block. The mutation Y652A significantly suppressed pharmacologic block of hERG by ivabradine. Disruption of C-type inactivation also suppressed block of hERG1 by ivabradine. Molecular docking and molecular dynamics simulations indicate that ivabradine may access the inner cavity of the hERG1 via a lipophilic route and has a well-defined binding site in the closed state of the channel. Structural organization of the binding pockets for ivabradine is discussed. Ivabradine blocks hERG and prolongs action potential duration. Our study is potentially important because it indicates the need for active post marketing surveillance of ivabradine. Importantly, proarrhythmia of a number of other drugs has only been discovered during post marketing surveillance. Copyright © 2015 Elsevier Ltd. All rights reserved.

Voltage-Sensitive Fluorescence of Indocyanine Green in the Heart

PubMed Central

Martišienė, Irma; Mačianskienė, Regina; Treinys, Rimantas; Navalinskas, Antanas; Almanaitytė, Mantė; Karčiauskas, Dainius; Kučinskas, Audrius; Grigalevičiūtė, Ramunė; Zigmantaitė, Vilma; Benetis, Rimantas; Jurevičius, Jonas

2016-01-01

So far, the optical mapping of cardiac electrical signals using voltage-sensitive fluorescent dyes has only been performed in experimental studies because these dyes are not yet approved for clinical use. It was recently reported that the well-known and widely used fluorescent dye indocyanine green (ICG), which has FDA approval, exhibits voltage sensitivity in various tissues, thus raising hopes that electrical activity could be optically mapped in the clinic. The aim of this study was to explore the possibility of using ICG to monitor cardiac electrical activity. Optical mapping experiments were performed on Langendorff rabbit hearts stained with ICG and perfused with electromechanical uncouplers. The residual contraction force and electrical action potentials were recorded simultaneously. Our research confirms that ICG is a voltage-sensitive dye with a dual-component (fast and slow) response to membrane potential changes. The fast component of the optical signal (OS) can have opposite polarities in different parts of the fluorescence spectrum. In contrast, the polarity of the slow component remains the same throughout the entire spectrum. Separating the OS into these components revealed two different voltage-sensitivity mechanisms for ICG. The fast component of the OS appears to be electrochromic in nature, whereas the slow component may arise from the redistribution of the dye molecules within or around the membrane. Both components quite accurately track the time of electrical signal propagation, but only the fast component is suitable for estimating the shape and duration of action potentials. Because ICG has voltage-sensitive properties in the entire heart, we suggest that it can be used to monitor cardiac electrical behavior in the clinic. PMID:26840736

Impaired Na⁺-dependent regulation of acetylcholine-activated inward-rectifier K⁺ current modulates action potential rate dependence in patients with chronic atrial fibrillation.

PubMed

Voigt, Niels; Heijman, Jordi; Trausch, Anne; Mintert-Jancke, Elisa; Pott, Lutz; Ravens, Ursula; Dobrev, Dobromir

2013-08-01

Shortened action-potential duration (APD) and blunted APD rate adaptation are hallmarks of chronic atrial fibrillation (cAF). Basal and muscarinic (M)-receptor-activated inward-rectifier K(+) currents (IK1 and IK,ACh, respectively) contribute to regulation of human atrial APD and are subject to cAF-dependent remodeling. Intracellular Na(+) ([Na(+)]i) enhances IK,ACh in experimental models but the effect of [Na(+)]i-dependent regulation of inward-rectifier K(+) currents on APD in human atrial myocytes is currently unknown. Here, we report a [Na(+)]i-dependent inhibition of outward IK1 in atrial myocytes from sinus rhythm (SR) or cAF patients. In contrast, IK,ACh activated by carbachol, a non-selective M-receptor agonist, increased with elevation of [Na(+)]i in SR. This [Na(+)]i-dependent IK,ACh regulation was absent in cAF. Including [Na(+)]i dependence of IK1 and IK,ACh in a recent computational model of the human atrial myocyte revealed that [Na(+)]i accumulation at fast rates inhibits IK1 and blunts physiological APD rate dependence in both groups. [Na(+)]i-dependent IK,ACh augmentation at fast rates increased APD rate dependence in SR, but not in cAF. These results identify impaired Na(+)-sensitivity of IK,ACh as one potential mechanism contributing to the blunted APD rate dependence in patients with cAF. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes". Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Feedforward Compensation Mediated by the Central and Peripheral Actions of a Single Neuropeptide Discovered Using Representational Difference Analysis

PubMed Central

Jing, Jian; Sweedler, Jonathan V; Cropper, Elizabeth C; Alexeeva, Vera; Park, Ji-Ho; Romanova, Elena V.; Xie, Fang; Dembrow, Nikolai C.; Ludwar, Bjoern C.; Weiss, Klaudiusz R; Vilim, Ferdinand S

2010-01-01

Compensatory mechanisms are often used to achieve stability by reducing variance, which can be accomplished via negative feedback during homeostatic regulation. In principle, compensation can also be implemented through feedforward mechanisms where a regulator acts to offset the anticipated output variation; however, few such neural mechanisms have been demonstrated. We provide evidence that an Aplysia neuropeptide, identified using an enhanced representational difference analysis procedure, implements feedforward compensation within the feeding network. We named the novel peptide allatotropin-related peptide (ATRP) because of its similarity to insect allatotropin. Mass spectrometry confirmed the peptide's identity, and in situ hybridization and immunostaining mapped its distribution in the Aplysia CNS. ATRP is present in the higher-order cerebral-buccal interneuron (CBI), CBI-4, but not in CBI-2. Previous work showed that CBI-4-elicited motor programs have a shorter protraction duration than those elicited by CBI-2. Here we show that ATRP shortens protraction duration of CBI-2-elicited ingestive programs, suggesting a contribution of ATRP to the parametric differences between CBI-4- and CBI-2-evoked programs. Importantly, because Aplysia muscle contractions are a graded function of motoneuronal activity, one consequence of the shortening of protraction is that it can weaken protraction movements. However, this potential weakening is offset by feedforward compensatory actions exerted by ATRP. Centrally, ATRP increases the activity of protraction motoneurons. Moreover, ATRP is present in peripheral varicosities of protraction motoneurons and enhances peripheral motoneuron-elicited protraction muscle contractions. Therefore, feedforward compensatory mechanisms mediated by ATRP make it possible to generate a faster movement with an amplitude that is not greatly reduced, thereby producing stability. PMID:21147994

Isoflurane modulates excitability in the mouse thalamus via GABA-dependent and GABA-independent mechanisms

PubMed Central

Ying, Shui-Wang; Werner, David F.; Homanics, Gregg E.; Harrison, Neil L.; Goldstein, Peter A.

2009-01-01

Summary GABAergic neurons in the reticular thalamic nucleus (RTN) synapse onto thalamocortical neurons in the ventrobasal (VB) thalamus, and this reticulo-thalamocortical pathway is considered an anatomic target for general anesthetic-induced unconsciousness. A mutant mouse was engineered to harbor two amino acid substitutions (S270H, L277A) in the GABAA receptor (GABAA-R) α1 subunit; this mutation abolished sensitivity to the volatile anesthetic isoflurane in recombinant GABAA-Rs, and reduced in vivo sensitivity to isoflurane in the loss-of-righting-reflex assay. We examined the effects of the double mutation on GABAA-R-mediated synaptic currents and isoflurane sensitivity by recording from thalamic neurons in brain slices. The double mutation accelerated the decay, and decreased the ½ width of, evoked inhibitory postsynaptic currents (eIPSCs) in VB neurons and attenuated isoflurane-induced prolongation of the eIPSC. The hypnotic zolpidem, a selective modulator of GABAA-Rs containing the α1 subunit, prolonged eIPSC duration regardless of genotype, indicating that mutant mice incorporate α1-subunit containing GABAA-Rs into synapses. In RTN neurons, which lack the α1 subunit, eIPSC duration was longer than in VB, regardless of genotype. Isoflurane reduced the efficacy of GABAergic transmission from RTN to VB, independent of genotype, suggesting a presynaptic action in RTN neurons. Consistent with this observation, isoflurane inhibited both tonic action potential and rebound burst firing in the presence of GABAA-R blockade. The suppressed excitability in RTN neurons is likely mediated by isoflurane-enhanced Ba2+-sensitive, but 4-aminopyridine-insenstive, potassium conductances. We conclude that isoflurane enhances inhibition of thalamic neurons in VB via GABAA-R-dependent, but in RTN via GABAA-R-independent, mechanisms. PMID:18948126

NS5806 partially restores action potential duration but fails to ameliorate calcium transient dysfunction in a computational model of canine heart failure.

PubMed

Maleckar, Mary M; Lines, Glenn T; Koivumäki, Jussi T; Cordeiro, Jonathan M; Calloe, Kirstine

2014-11-01

The study investigates how increased Ito, as mediated by the activator NS5806, affects excitation-contraction coupling in chronic heart failure (HF). We hypothesized that restoring spike-and-dome morphology of the action potential (AP) to a healthy phenotype would be insufficient to restore the intracellular Ca(2) (+) transient (CaT), due to HF-induced remodelling of Ca(2+) handling. An existing mathematical model of the canine ventricular myocyte was modified to incorporate recent experimental data from healthy and failing myocytes, resulting in models of both healthy and HF epicardial, midmyocardial, and endocardial cell variants. Affects of NS5806 were also included in HF models through its direct interaction with Kv4.3 and Kv1.4. Single-cell simulations performed in all models (control, HF, and HF + drug) and variants (epi, mid, and endo) assessed AP morphology and underlying ionic processes with a focus on calcium transients (CaT), how these were altered in HF across the ventricular wall, and the subsequent effects of varying compound concentration in HF. Heart failure model variants recapitulated a characteristic increase in AP duration (APD) in the disease. The qualitative effects of application of half-maximal effective concentration (EC50) of NS5806 on APs and CaT are heterogeneous and non-linear. Deepening in the AP notch with drug is a direct effect of the activation of Ito; both Ito and consequent alteration of IK1 kinetics cause decrease in AP plateau potential. Decreased APD50 and APD90 are both due to altered IK1. Analysis revealed that drug effects depend on transmurality. Ca(2+) transient morphology changes-increased amplitude and shorter time to peak-are due to direct increase in ICa,L and indirect larger SR Ca(2+) release subsequent to Ito activation. Downstream effects of a compound acting exclusively on sarcolemmal ion channels are difficult to predict. Remediation of APD to pre-failing state does not ameliorate dysfunction in CaT; however, restoration of notch depth appears to impart modest benefit and a likelihood of therapeutic value in modulating early repolarization. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

Caffeine and anaerobic performance: ergogenic value and mechanisms of action.

PubMed

Davis, J K; Green, J Matt

2009-01-01

The effect caffeine elicits on endurance performance is well founded. However, comparatively less research has been conducted on the ergogenic potential of anaerobic performance. Some studies showing no effect of caffeine on performance used untrained subjects and designs often not conducive to observing an ergogenic effect. Recent studies incorporating trained subjects and paradigms specific to intermittent sports activity support the notion that caffeine is ergogenic to an extent with anaerobic exercise. Caffeine seems highly ergogenic for speed endurance exercise ranging in duration from 60 to 180 seconds. However, other traditional models examining power output (i.e. 30-second Wingate test) have shown minimal effect of caffeine on performance. Conversely, studies employing sport-specific methodologies (i.e. hockey, rugby, soccer) with shorter duration (i.e. 4-6 seconds) show caffeine to be ergogenic during high-intensity intermittent exercise. Recent studies show caffeine affects isometric maximal force and offers introductory evidence for enhanced muscle endurance for lower body musculature. However, isokinetic peak torque, one-repetition maximum and muscular endurance for upper body musculature are less clear. Since relatively few studies exist with resistance training, a definite conclusion cannot be reached on the extent caffeine affects performance. It was previously thought that caffeine mechanisms were associated with adrenaline (epinephrine)-induced enhanced free-fatty acid oxidation and consequent glycogen sparing, which is the leading hypothesis for the ergogenic effect. It would seem unlikely that the proposed theory would result in improved anaerobic performance, since exercise is dominated by oxygen-independent metabolic pathways. Other mechanisms for caffeine have been suggested, such as enhanced calcium mobilization and phosphodiesterase inhibition. However, a normal physiological dose of caffeine in vivo does not indicate this mechanism plays a large role. Additionally, enhanced Na+/K+ pump activity has been proposed to potentially enhance excitation contraction coupling with caffeine. A more favourable hypothesis seems to be that caffeine stimulates the CNS. Caffeine acts antagonistically on adenosine receptors, thereby inhibiting the negative effects adenosine induces on neurotransmission, arousal and pain perception. The hypoalgesic effects of caffeine have resulted in dampened pain perception and blunted perceived exertion during exercise. This could potentially have favourable effects on negating decreased firing rates of motor units and possibly produce a more sustainable and forceful muscle contraction. The exact mechanisms behind caffeine's action remain to be elucidated.

Low Intensity and Frequency Pulsed Electromagnetic Fields Selectively Impair Breast Cancer Cell Viability

PubMed Central

Crocetti, Sara; Beyer, Christian; Schade, Grit; Egli, Marcel; Fröhlich, Jürg; Franco-Obregón, Alfredo

2013-01-01

Introduction A common drawback of many anticancer therapies is non-specificity in action of killing. We investigated the potential of ultra-low intensity and frequency pulsed electromagnetic fields (PEMFs) to kill breast cancer cells. Our criteria to accept this technology as a potentially valid therapeutic approach were: 1) cytotoxicity to breast cancer cells and; 2) that the designed fields proved innocuous to healthy cell classes that would be exposed to the PEMFs during clinical treatment. Methods MCF7 breast cancer cells and their normal counterparts, MCF10 cells, were exposed to PEMFs and cytotoxic indices measured in order to design PEMF paradigms that best kill breast cancer cells. The PEMF parameters tested were: 1) frequencies ranging from 20 to 50 Hz; 2) intensities ranging from 2 mT to 5 mT and; 3) exposure durations ranging from 30 to 90 minutes per day for up to three days to determine the optimum parameters for selective cancer cell killing. Results We observed a discrete window of vulnerability of MCF7 cells to PEMFs of 20 Hz frequency, 3 mT magnitude and exposure duration of 60 minutes per day. The cell damage accrued in response to PEMFs increased with time and gained significance after three days of consecutive daily exposure. By contrast, the PEMFs parameters determined to be most cytotoxic to breast cancer MCF-7 cells were not damaging to normal MCF-10 cells. Conclusion Based on our data it appears that PEMF-based anticancer strategies may represent a new therapeutic approach to treat breast cancer without affecting normal tissues in a manner that is non-invasive and can be potentially combined with existing anti-cancer treatments. PMID:24039828

State and location dependence of action potential metabolic cost in cortical pyramidal neurons.

PubMed

Hallermann, Stefan; de Kock, Christiaan P J; Stuart, Greg J; Kole, Maarten H P

2012-06-03

Action potential generation and conduction requires large quantities of energy to restore Na(+) and K(+) ion gradients. We investigated the subcellular location and voltage dependence of this metabolic cost in rat neocortical pyramidal neurons. Using Na(+)/K(+) charge overlap as a measure of action potential energy efficiency, we found that action potential initiation in the axon initial segment (AIS) and forward propagation into the axon were energetically inefficient, depending on the resting membrane potential. In contrast, action potential backpropagation into dendrites was efficient. Computer simulations predicted that, although the AIS and nodes of Ranvier had the highest metabolic cost per membrane area, action potential backpropagation into the dendrites and forward propagation into axon collaterals dominated energy consumption in cortical pyramidal neurons. Finally, we found that the high metabolic cost of action potential initiation and propagation down the axon is a trade-off between energy minimization and maximization of the conduction reliability of high-frequency action potentials.

One-dimensional "atom" with zero-range potential perturbed by finite sequence of zero-duration laser pulses

NASA Astrophysics Data System (ADS)

Gusev, A. A.; Chuluunbaatar, O.; Popov, Yu. V.; Vinitsky, S. I.; Derbov, V. L.; Lovetskiy, K. P.

2018-04-01

The exactly soluble model of a train of zero-duration electromagnetic pulses interacting with a 1D atom with short-range interaction potential modelled by a δ-function is considered. The model is related to the up-to-date laser techniques providing the duration of pulses as short as a few attoseconds and the intensities higher than 1014 W/cm2.

[Prolonged neuromuscular block in a patient with butyrylcholinesterase deficiency].

PubMed

Mabboux, I; Hary, B; Courcelle, S; Ceppa, F; Delacour, H

2016-05-01

Succinylcholine is a neuromuscular block whose duration of action depends on rapid hydrolysis by butyrylcholinesterase (BChE). In patients with common BChE activities, succinylcholine duration of action is short (10min). BChE deficiency induces a slower hydrolysis of the drug and consequently prolonged neuromuscular block, leading to apnea. We report a case of prolonged neuromuscular block after administration of succinylcholine in a 14-year-old boy. Biological investigations revealed a marked BChE deficiency (1099U/L) related to the presence of three point mutations in the BCHE gene in a compound heterozygous state: p.Asp70Gly (rs1799807), p.Ala539Tyr (rs1803274), and p.Phe118Valfs*12 (rs398124632). The diagnosis of genetic BChE deficiency (OMIM 177400) was retained. This case is intended to present the pathophysiology of genetic BChE deficiency, its management, and the diagnostic strategy to be implemented. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

The Use of Ratiometric Fluorescence Measurements of the Voltage Sensitive Dye Di-4-ANEPPS to Examine Action Potential Characteristics and Drug Effects on Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

PubMed

Hortigon-Vinagre, M P; Zamora, V; Burton, F L; Green, J; Gintant, G A; Smith, G L

2016-12-01

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and higher throughput platforms have emerged as potential tools to advance cardiac drug safety screening. This study evaluated the use of high bandwidth photometry applied to voltage-sensitive fluorescent dyes (VSDs) to assess drug-induced changes in action potential characteristics of spontaneously active hiPSC-CM. Human iPSC-CM from 2 commercial sources (Cor.4U and iCell Cardiomyocytes) were stained with the VSD di-4-ANEPPS and placed in a specialized photometry system that simultaneously monitors 2 wavebands of emitted fluorescence, allowing ratiometric measurement of membrane voltage. Signals were acquired at 10 kHz and analyzed using custom software. Action potential duration (APD) values were normally distributed in cardiomyocytes (CMC) from both sources though the mean and variance differed significantly (APD 90 : 229 ± 15 ms vs 427 ± 49 ms [mean ± SD, P < 0.01]; average spontaneous cycle length: 0.99 ± 0.02 s vs 1.47 ± 0.35 s [mean ± SD, P < 0.01], Cor.4U vs iCell CMC, respectively). The 10-90% rise time of the AP (T rise ) was ∼6 ms and was normally distributed when expressed as 1/[Formula: see text] in both cell preparations. Both cell types showed a rate dependence analogous to that of adult human cardiac cells. Furthermore, nifedipine, ranolazine, and E4031 had similar effects on cardiomyocyte electrophysiology in both cell types. However, ranolazine and E4031 induced early after depolarization-like events and high intrinsic firing rates at lower concentrations in iCell CMC. These data show that VSDs provide a minimally invasive, quantitative, and accurate method to assess hiPSC-CM electrophysiology and detect subtle drug-induced effects for drug safety screening while highlighting a need to standardize experimental protocols across preparations. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology.

Computational Models for Understanding of Structure, Function and Pharmacology of the Cardiac Potassium Channel Kv11.1 (hERG).

PubMed

Wacker, Soren; Noskov, Sergei Yu; Perissinotti, Laura L

2017-01-01

The rapid delayed rectifier current IKr is one of the major K+ currents involved in repolarization of the human cardiac action potential. Various inherited or drug-induced forms of the long QT syndrome (LQTS) in humans are linked to functional and structural modifications in the IKr conducting channels. IKr is carried by the potassium channel Kv11.1 encoded by the gene KCNH2 (commonly referred to as human ether-a-go-go-related gene or hERG) [1, 2]. The first necessary step for predicting emergent drug effects on the heart is determining and modeling the binding thermodynamics and kinetics of primary and major off-target drug interactions with subcellular targets. The bulk of drugs that target hERG channels are known to have complex interactions at the atomic scale. Accordingly, one of the goals for this review is to provide comprehensive guide in the universe of computational models aiming to refine our understanding of structure-function relations in Kv11.1 and its isoforms. The special emphasis is placed on the mapping of drug binding sites and tentative mechanisms of channel inhibition and activation by drugs. An overview over recent structural models and mapping of binding sites for blockers and activators of IKr current along with the discussion on agreements and discrepancies among different models is presented. There is an apparent reciprocity or feedback loop between drug binding and action potential of the cardiac myocytes. Thus one has to connect drug binding to a particular receptor so that its functional consequences impact on the action potential duration. The natural pathway is to develop multi-scale models that connect between receptor and cellular scales. The potential for such multi-scale model development is discussed through the lens of common gating models. Accordingly, the second part of this review covers an ongoing development of the kinetic models of gating transitions and cardiac ion currents carried by hERG channels with and without drug bound. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Effects of atracurium pretreatment with magnesium on speed of onset, duration, and recovery of neuromuscular blockade].

PubMed

Wu, Hong-Liang; Ye, Tie-Hu; Sun, Li

2009-02-01

To determine the effects of atracurium pretreatment with magnesium on speed of onset, duration, and recovery of neuromuscular block. Thirty patients who were undergoing elective gynecologic laparoscopic examination and treatments under general anesthesia were randomized into magnesium group (n = 15) and control group (n = 15). Before induction of general anesthesia, patients in magnesium group intravenously received MgSO4 30 mg/kg in saline within 5 minutes, and patients in control group received the same volume of saline without MgSO4. In both groups, the train-of-four (TOF) responses to stimuli of the ulnar nerve were measured at intervals of 12 seconds. Anesthesia was induced with Fentanyl and Propofol through target controlled infusion (TCI), and tracheal intubation was performed with 0.5 mg/kg atracurium after stabilization of the electromyography recording. The onset time of muscle relaxation, clinical duration of action, recovery index, and recovery time were recorded. To determine serum magnesium and calcium levels, blood samples were collected before MgSO4/saline infusion and at the end of operation. Haemodynamic changes and other responses during induction were also recorded. The onset time from the end of injection to maximum neuromuscular blockade was significantly shorter in magnesium group than in control group (P < 0.01). Duration of relaxant action, recovery index, and recovery time in magnesium group were significantly prolonged than in control group (P < 0.01). Serum magnesium level significantly decreased after management (P < 0.01), and there was also a decrease trend in magnesium group. No change of serum calcium levels in both groups was observed. No adverse event was reported. Prior administration of magnesium sulphate can increase the onset speed of atracurium and prolong the duration of atracurium-induced neuromuscular blockade.

Mental imagery of gravitational motion.

PubMed

Gravano, Silvio; Zago, Myrka; Lacquaniti, Francesco

2017-10-01

There is considerable evidence that gravitational acceleration is taken into account in the interaction with falling targets through an internal model of Earth gravity. Here we asked whether this internal model is accessed also when target motion is imagined rather than real. In the main experiments, naïve participants grasped an imaginary ball, threw it against the ceiling, and caught it on rebound. In different blocks of trials, they had to imagine that the ball moved under terrestrial gravity (1g condition) or under microgravity (0g) as during a space flight. We measured the speed and timing of the throwing and catching actions, and plotted ball flight duration versus throwing speed. Best-fitting duration-speed curves estimate the laws of ball motion implicit in the participant's performance. Surprisingly, we found duration-speed curves compatible with 0g for both the imaginary 0g condition and the imaginary 1g condition, despite the familiarity with Earth gravity effects and the added realism of performing the throwing and catching actions. In a control experiment, naïve participants were asked to throw the imaginary ball vertically upwards at different heights, without hitting the ceiling, and to catch it on its way down. All participants overestimated ball flight durations relative to the durations predicted by the effects of Earth gravity. Overall, the results indicate that mental imagery of motion does not have access to the internal model of Earth gravity, but resorts to a simulation of visual motion. Because visual processing of accelerating/decelerating motion is poor, visual imagery of motion at constant speed or slowly varying speed appears to be the preferred mode to perform the tasks. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sodium Pumps Mediate Activity-Dependent Changes in Mammalian Motor Networks

PubMed Central

Picton, Laurence D.; Nascimento, Filipe; Broadhead, Matthew J.; Sillar, Keith T.

2017-01-01

Ubiquitously expressed sodium pumps are best known for maintaining the ionic gradients and resting membrane potential required for generating action potentials. However, activity- and state-dependent changes in pump activity can also influence neuronal firing and regulate rhythmic network output. Here we demonstrate that changes in sodium pump activity regulate locomotor networks in the spinal cord of neonatal mice. The sodium pump inhibitor, ouabain, increased the frequency and decreased the amplitude of drug-induced locomotor bursting, effects that were dependent on the presence of the neuromodulator dopamine. Conversely, activating the pump with the sodium ionophore monensin decreased burst frequency. When more “natural” locomotor output was evoked using dorsal-root stimulation, ouabain increased burst frequency and extended locomotor episode duration, whereas monensin slowed and shortened episodes. Decreasing the time between dorsal-root stimulation, and therefore interepisode interval, also shortened and slowed activity, suggesting that pump activity encodes information about past network output and contributes to feedforward control of subsequent locomotor bouts. Using whole-cell patch-clamp recordings from spinal motoneurons and interneurons, we describe a long-duration (∼60 s), activity-dependent, TTX- and ouabain-sensitive, hyperpolarization (∼5 mV), which is mediated by spike-dependent increases in pump activity. The duration of this dynamic pump potential is enhanced by dopamine. Our results therefore reveal sodium pumps as dynamic regulators of mammalian spinal motor networks that can also be affected by neuromodulatory systems. Given the involvement of sodium pumps in movement disorders, such as amyotrophic lateral sclerosis and rapid-onset dystonia parkinsonism, knowledge of their contribution to motor network regulation also has considerable clinical importance. SIGNIFICANCE STATEMENT The sodium pump is ubiquitously expressed and responsible for at least half of total brain energy consumption. The pumps maintain ionic gradients and the resting membrane potential of neurons, but increasing evidence suggests that activity- and state-dependent changes in pump activity also influence neuronal firing. Here we demonstrate that changes in sodium pump activity regulate locomotor output in the spinal cord of neonatal mice. We describe a sodium pump-mediated afterhyperpolarization in spinal neurons, mediated by spike-dependent increases in pump activity, which is affected by dopamine. Understanding how sodium pumps contribute to network regulation and are targeted by neuromodulators, including dopamine, has clinical relevance due to the role of the sodium pump in diseases, including amyotrophic lateral sclerosis, parkinsonism, epilepsy, and hemiplegic migraine. PMID:28123025

Voltage-gated sodium channel expression and action potential generation in differentiated NG108-15 cells.

PubMed

Liu, Jinxu; Tu, Huiyin; Zhang, Dongze; Zheng, Hong; Li, Yu-Long

2012-10-25

The generation of action potential is required for stimulus-evoked neurotransmitter release in most neurons. Although various voltage-gated ion channels are involved in action potential production, the initiation of the action potential is mainly mediated by voltage-gated Na+ channels. In the present study, differentiation-induced changes of mRNA and protein expression of Na+ channels, Na+ currents, and cell membrane excitability were investigated in NG108-15 cells. Whole-cell patch-clamp results showed that differentiation (9 days) didn't change cell membrane excitability, compared to undifferentiated state. But differentiation (21 days) induced the action potential generation in 45.5% of NG108-15 cells (25/55 cells). In 9-day-differentiated cells, Na+ currents were mildly increased, which was also found in 21-day differentiated cells without action potential. In 21-day differentiated cells with action potential, Na+ currents were significantly enhanced. Western blot data showed that the expression of Na+ channels was increased with differentiated-time dependent manner. Single-cell real-time PCR data demonstrated that the expression of Na+ channel mRNA was increased by 21 days of differentiation in NG108-15 cells. More importantly, the mRNA level of Na+ channels in cells with action potential was higher than that in cells without action potential. Differentiation induces expression of voltage-gated Na+ channels and action potential generation in NG108-15 cells. A high level of the Na+ channel density is required for differentiation-triggered action potential generation.

Maximizing value in opioid utilization: Is oxycodone immediate release a good option for pain management?

PubMed

Pergolizzi, Joseph V; Köknel Talu, Gül; Zmponga, Gianpetrio; Erdine, Serdar; Taylor, Robert; Ayan, Burak; Raffa, Robert B

2015-01-01

The modern approach to the management of pain involves optimizing all aspects of the process. This includes utilization of pharmacologic and non-pharmacologic modalities, consideration of patient characteristics, proper matching of the physiology of the pain with the analgesic's mechanism of action (pharmacodynamics, PD), and the onset and duration of action (pharmacokinetics, PK). No single agent or formulation satisfies all of the requirements for all patients. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are effective options for inflammatory pain and, as is acetaminophen, for mild pain. Specialized agents are helpful for particular pains, such as for migraine headache. Opioids remain the standard option for severe pain. Although they are generally a safe and effective option, opioids can produce dose-limiting adverse effects and have abuse potential. The goal of pain therapy is thus to achieve the maximum pain relief with the least amount of opioid exposure. Against this background of measured approach to the use of analgesics, an immediate release (IR) oral formulation of the established opioid oxycodone has been developed to provide rapid onset of action and rate of titration, both of which could maximize temporal matching of dose with pain level and reduce total exposure to drug. This article considers the option of an immediate release (IR) oral formulation for the management of pain.

Comparison between the effects of inhaled isoprenaline and fenoterol on plasma cyclic AMP and heart rate in normal subjects.

PubMed Central

Fairfax, A J; Rehahn, M; Jones, D; O'Malley, B

1984-01-01

The time course of changes in plasma cyclic AMP, heart rate and bronchial tone after inhalation of fenoterol or isoprenaline from a dose-metered aerosol are reported in a group of normal subjects. After isoprenaline, plasma cyclic AMP increased rapidly reaching a peak by 10 min and returned to basal levels within 60 min. A rapid, transient rise in heart rate occurred that was maximal by 5 min and returned to a basal level by 45 min. After fenoterol, the changes in cyclic AMP and heart rate were of much longer duration. The rise in plasma cyclic AMP was slower in onset and of greater magnitude than for isoprenaline, reaching a peak by 20 min and remaining above basal level for more than 6 h. The maximum increase in heart rate after fenoterol was less than that observed with isoprenaline but an elevated rate persisted for 4 h after inhalation of fenoterol. Fenoterol is known to have a longer duration of action as a bronchodilator in comparison with isoprenaline. The prolonged rise in plasma cyclic AMP in normal subjects given inhaled fenoterol may reflect this long duration of action. The concomitant rise in heart rate, however, suggests that the duration of plasma cyclic AMP response may in part be due to the systemic effect of the fraction of inhaled fenoterol known to be absorbed via the buccal and intestinal routes. PMID:6322828

Speech-like orofacial oscillations in stump-tailed macaque (Macaca arctoides) facial and vocal signals.

PubMed

Toyoda, Aru; Maruhashi, Tamaki; Malaivijitnond, Suchinda; Koda, Hiroki

2017-10-01

Speech is unique to humans and characterized by facial actions of ∼5 Hz oscillations of lip, mouth or jaw movements. Lip-smacking, a facial display of primates characterized by oscillatory actions involving the vertical opening and closing of the jaw and lips, exhibits stable 5-Hz oscillation patterns, matching that of speech, suggesting that lip-smacking is a precursor of speech. We tested if facial or vocal actions exhibiting the same rate of oscillation are found in wide forms of facial or vocal displays in various social contexts, exhibiting diversity among species. We observed facial and vocal actions of wild stump-tailed macaques (Macaca arctoides), and selected video clips including facial displays (teeth chattering; TC), panting calls, and feeding. Ten open-to-open mouth durations during TC and feeding and five amplitude peak-to-peak durations in panting were analyzed. Facial display (TC) and vocalization (panting) oscillated within 5.74 ± 1.19 and 6.71 ± 2.91 Hz, respectively, similar to the reported lip-smacking of long-tailed macaques and the speech of humans. These results indicated a common mechanism for the central pattern generator underlying orofacial movements, which would evolve to speech. Similar oscillations in panting, which evolved from different muscular control than the orofacial action, suggested the sensory foundations for perceptual saliency particular to 5-Hz rhythms in macaques. This supports the pre-adaptation hypothesis of speech evolution, which states a central pattern generator for 5-Hz facial oscillation and perceptual background tuned to 5-Hz actions existed in common ancestors of macaques and humans, before the emergence of speech. © 2017 Wiley Periodicals, Inc.

Effects of premature stimulation on HERG K+ channels

PubMed Central

Lu, Yu; Mahaut-Smith, Martyn P; Varghese, Anthony; Huang, Christopher L-H; Kemp, Paul R; Vandenberg, Jamie I

2001-01-01

The unusual kinetics of human ether-à-go-go-related gene (HERG) K+ channels are consistent with a role in the suppression of arrhythmias initiated by premature beats. Action potential clamp protocols were used to investigate the effect of premature stimulation on HERG K+ channels, transfected in Chinese hamster ovary cells, at 37 °C. HERG K+ channel currents peaked during the terminal repolarization phase of normally paced action potential waveforms. However, the magnitude of the current and the time point at which conductance was maximal depended on the type of action potential waveform used (epicardial, endocardial, Purkinje fibre or atrial). HERG K+ channel currents recorded during premature action potentials consisted of an early transient outward current followed by a sustained outward current. The magnitude of the transient current component showed a biphasic dependence on the coupling interval between the normally paced and premature action potentials and was maximal at a coupling interval equivalent to 90% repolarization (APD90) for ventricular action potentials. The largest transient current response occurred at shorter coupling intervals for Purkinje fibre (APD90– 20 ms) and atrial (APD90– 30 ms) action potentials. The magnitude of the sustained current response following premature stimulation was similar to that recorded during the first action potential for ventricular action potential waveforms. However, for Purkinje and atrial action potentials the sustained current response was significantly larger during the premature action potential than during the normally paced action potential. A Markov model that included three closed states, one open and one inactivated state with transitions permitted between the pre-open closed state and the inactivated state, successfully reproduced our results for the effects of premature stimuli, both during square pulse and action potential clamp waveforms. These properties of HERG K+ channels may help to suppress arrhythmias initiated by early afterdepolarizations and premature beats in the ventricles, Purkinje fibres or atria. PMID:11744759

Site-specific PEGylation of human thyroid stimulating hormone to prolong duration of action.

PubMed

Qiu, Huawei; Boudanova, Ekaterina; Park, Anna; Bird, Julie J; Honey, Denise M; Zarazinski, Christine; Greene, Ben; Kingsbury, Jonathan S; Boucher, Susan; Pollock, Julie; McPherson, John M; Pan, Clark Q

2013-03-20

Recombinant human thyroid stimulating hormone (rhTSH or Thyrogen) has been approved for thyroid cancer diagnostics and treatment under a multidose regimen due to its short circulating half-life. To reduce dosing frequency, PEGylation strategies were explored to increase the duration of action of rhTSH. Lysine and N-terminal PEGylation resulted in heterogeneous product profiles with 40% or lower reaction yields of monoPEGylated products. Eleven cysteine mutants were designed based on a structure model of the TSH-TSH receptor (TSHR) complex to create unique conjugation sites on both α and β subunits for site-specific conjugation. Sequential screening of mutant expression level, oligomerization tendency, and conjugation efficiency resulted in the identification of the αG22C rhTSH mutant for stable expression and scale-up PEGylation. The introduced cysteine in the αG22C rhTSH mutant was partially blocked when isolated from conditioned media and could only be effectively PEGylated after mild reduction with cysteine. This produced a higher reaction yield, ~85%, for the monoPEGylated product. Although the mutation had no effect on receptor binding, PEGylation of αG22C rhTSH led to a PEG size-dependent decrease in receptor binding. Nevertheless, the 40 kDa PEG αG22C rhTSH showed a prolonged duration of action compared to rhTSH in a rat pharmacodynamics model. Reverse-phase HPLC and N-terminal sequencing experiments confirmed site-specific modification at the engineered Cys 22 position on the α-subunit. This work is another demonstration of successful PEGylation of a cysteine-knot protein by an engineered cysteine mutation.

Elderly benzodiazepine users at increased risk of activity limitations: influence of chronicity, indications, and duration of action--the three-city cohort.

PubMed

Carrière, Isabelle; Mura, Thibault; Pérès, Karine; Norton, Joanna; Jaussent, Isabelle; Edjolo, Arlette; Rouaud, Olivier; Berr, Claudine; Ritchie, Karen; Ancelin, Marie Laure

2015-08-01

To examine the cross-sectional and longitudinal associations between benzodiazepine use and daily activity limitations, according to drug indications and duration of action. Prospective cohort study. Population-based three-city study. 6,600 participants aged 65 years and over included between 1999 and 2001 and followed after 2, 4, and 7 years. Benzodiazepine users were separated into hypnotic, short-acting anxiolytic, and long-acting anxiolytic users and compared with non users. Three outcomes were examined assessing restrictions in mobility, instrumental activities of daily living (IADLs) and social participation. In multivariate simple or mixed logistic models adjusted for sociodemographic variables, impairments and comorbidity, and for anxiety, insomnia, and depression, hypnotic benzodiazepines were moderately associated with mobility limitation prevalence and IADL limitation incidence. Short-acting and long-acting anxiolytics were associated with IADL limitation prevalence and with mobility limitation prevalence and incidence and long-acting anxiolytics were also associated with IADL limitation incidence. Chronic benzodiazepines users were at a marked risk of developing restrictions for the three outcomes; odds ratio: 1.71 (95% CI: 1.23-2.39) for mobility, 1.54 (95% CI: 1.14-2.10) for IADL, and 1.74 (95% CI: 1.23-2.47) for participation limitations. Benzodiazepine users are at increased risk of activity limitations regardless of the duration of action or indication. Chronic use of benzodiazepines should be avoided in order to extend disability-free survival. Copyright © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Evaluation of the acute electrophysiologic effects of intravenous dronedarone, an amiodarone-like agent, with special emphasis on ventricular repolarization and acquired torsade de pointes arrhythmias.

PubMed

Verduyn, S C; Vos, M A; Leunissen, H D; van Opstal, J M; Wellens, H J

1999-02-01

In the anesthetized dog with complete chronic AV block (CAVB), we evaluated and compared the acute electrophysiologic effects of dronedarone i.v. (Dron, 2 times 2.5 mg/kg/10 min) and amiodarone i.v. (Amio, 2 times 5 mg/kg/10 min). This canine model with a high sensitivity for acquired torsade de pointes (TdP) provides an ideal substrate to evaluate ventricular repolarization abnormalities. Six ECG leads and two endocardial monophasic action potential (MAP) recordings in the left and right ventricle (LV and RV) were simultaneously recorded to measure QT time, action-potential duration (APD), interventricular dispersion (deltaAPD = LV(APD) - RV(APD)), early afterdepolarizations (EADs), ectopic beats (EBs), and TdP. Measurements were made at the spontaneous idioventricular rhythm (IVR) and 1,000-ms steady-state pacing. To investigate its short-term, antiarrhythmic properties, Dron was given after almokalant (0.12 mg/kg)-induced TdP. Furthermore, in another set of experiments, oral Dron (20 mg/kg, b.i.d) was given for 3 weeks to conscious CAVB dogs. Dron, i.v., shortened ventricular repolarization (QT, 435 +/- 60 to 360 +/- 55; LV(APD) 395 +/- 75 to 335 +/- 60 ms; p < 0.05), whereas IVR and ventricular effective refractory period (VERP, 225 +/- 30 to 230 +/- 30 ms) remained similar. Therefore the VERP/QT ratio increased (0.55 +/- 0.04 to 0.61 +/- 0.03; p < 0.05). Similar results were obtained with Amio, i.v.. Almokalant-induced TdP was characterized by an increased repolarization duration, deltaAPD, and EADs. Dron, i.v., suppressed the EADs, EBs, and TdP by a reduction and homogenization of repolarization (LV(APD), 505 +/- 110 to 455 +/- 80 ms, and deltaAPD, 110 +/- 55 to 65 +/- 40 ms). Long-term oral Dron increased the PP interval, CL-IVR, and QT(c) time. In contrast to oral treatment, Dron i.v. shortens ventricular repolarization parameters, resulting in suppression of EAD-dependent acquired TdP. The increased VERP/QT ratio after Dron i.v. may indicate an important second antiarrhythmic property.

Defective calcium inactivation causes long QT in obese insulin-resistant rat.

PubMed

Lin, Yen-Chang; Huang, Jianying; Kan, Hong; Castranova, Vincent; Frisbee, Jefferson C; Yu, Han-Gang

2012-02-15

The majority of diabetic patients who are overweight or obese die of heart disease. We suspect that the obesity-induced insulin resistance may lead to abnormal cardiac electrophysiology. We tested this hypothesis by studying an obese insulin-resistant rat model, the obese Zucker rat (OZR). Compared with the age-matched control, lean Zucker rat (LZR), OZR of 16-17 wk old exhibited an increase in QTc interval, action potential duration, and cell capacitance. Furthermore, the L-type calcium current (I(CaL)) in OZR exhibited defective inactivation and lost the complete inactivation back to the closed state, leading to increased Ca(2+) influx. The current density of I(CaL) was reduced in OZR, whereas the threshold activation and the current-voltage relationship of I(CaL) were not significantly altered. L-type Ba(2+) current (I(BaL)) in OZR also exhibited defective inactivation, and steady-state inactivation was not significantly altered. However, the current-voltage relationship and activation threshold of I(BaL) in OZR exhibited a depolarized shift compared with LZR. The total and membrane protein expression levels of Cav1.2 [pore-forming subunit of L-type calcium channels (LTCC)], but not the insulin receptors, were decreased in OZR. The insulin receptor was found to be associated with the Cav1.2, which was weakened in OZR. The total protein expression of calmodulin was reduced, but that of Cavβ2 subunit was not altered in OZR. Together, these results suggested that the 16- to 17-wk-old OZR has 1) developed cardiac hypertrophy, 2) exhibited altered electrophysiology manifested by the prolonged QTc interval, 3) increased duration of action potential in isolated ventricular myocytes, 4) defective inactivation of I(CaL) and I(BaL), 5) weakened the association of LTCC with the insulin receptor, and 6) decreased protein expression of Cav1.2 and calmodulin. These results also provided mechanistic insights into a remodeled cardiac electrophysiology under the condition of insulin resistance, enhancing our understanding of long QT associated with obese type 2 diabetic patients.

Sex Differences in β-Adrenergic Responsiveness of Action Potentials and Intracellular Calcium Handling in Isolated Rabbit Hearts

PubMed Central

Hoeker, Gregory S.; Hood, Ashleigh R.; Katra, Rodolphe P.; Poelzing, Steven; Pogwizd, Steven M.

2014-01-01

Cardioprotection in females, as observed in the setting of heart failure, has been attributed to sex differences in intracellular calcium handling and its modulation by β-adrenergic signaling. However, further studies examining sex differences in β-adrenergic responsiveness have yielded inconsistent results and have mostly been limited to studies of contractility, ion channel function, or calcium handling alone. Given the close interaction of the action potential (AP) and intracellular calcium transient (CaT) through the process of excitation-contraction coupling, the need for studies exploring the relationship between agonist-induced AP and calcium handling changes in female and male hearts is evident. Thus, the aim of this study was to use optical mapping to examine sex differences in ventricular APs and CaTs measured simultaneously from Langendorff-perfused hearts isolated from naïve adult rabbits during β-adrenergic stimulation. The non-selective β-agonist isoproterenol (Iso) decreased AP duration (APD90), CaT duration (CaD80), and the decay constant of the CaT (τ) in a dose-dependent manner (1–316.2 nM), with a plateau at doses ≥31.6 nM. The Iso-induced changes in APD90 and τ (but not CaD80) were significantly smaller in female than male hearts. These sex differences were more significant at faster (5.5 Hz) than resting rates (3 Hz). Treatment with Iso led to the development of spontaneous calcium release (SCR) with a dose threshold of 31.6 nM. While SCR occurrence was similar in female (49%) and male (53%) hearts, the associated ectopic beats had a lower frequency of occurrence (16% versus 40%) and higher threshold (100 nM versus 31.6 nM) in female than male hearts (p<0.05). In conclusion, female hearts had a decreased capacity to respond to β-adrenergic stimulation, particularly under conditions of increased demand (i.e. faster pacing rates and “maximal” levels of Iso effects), however this reduced β-adrenergic responsiveness of female hearts was associated with reduced arrhythmic activity. PMID:25340795

Adenosine-Induced Atrial Fibrillation: Localized Reentrant Drivers in Lateral Right Atria due to Heterogeneous Expression of Adenosine A1 Receptors and GIRK4 Subunits in the Human Heart.

PubMed

Li, Ning; Csepe, Thomas A; Hansen, Brian J; Sul, Lidiya V; Kalyanasundaram, Anuradha; Zakharkin, Stanislav O; Zhao, Jichao; Guha, Avirup; Van Wagoner, David R; Kilic, Ahmet; Mohler, Peter J; Janssen, Paul M L; Biesiadecki, Brandon J; Hummel, John D; Weiss, Raul; Fedorov, Vadim V

2016-08-09

Adenosine provokes atrial fibrillation (AF) with a higher activation frequency in right atria (RA) versus left atria (LA) in patients, but the underlying molecular and functional substrates are unclear. We tested the hypothesis that adenosine-induced AF is driven by localized reentry in RA areas with highest expression of adenosine A1 receptor and its downstream GIRK (G protein-coupled inwardly rectifying potassium channels) channels (IK,Ado). We applied biatrial optical mapping and immunoblot mapping of various atrial regions to reveal the mechanism of adenosine-induced AF in explanted failing and nonfailing human hearts (n=37). Optical mapping of coronary-perfused atria (n=24) revealed that adenosine perfusion (10-100 µmol/L) produced more significant shortening of action potential durations in RA (from 290±45 to 239±41 ms, 17.3±10.4%; P<0.01) than LA (from 307±24 to 286±23 ms, 6.7±6.6%; P<0.01). In 10 hearts, adenosine induced AF (317±116 s) that, when sustained (≥2 minutes), was primarily maintained by 1 to 2 localized reentrant drivers in lateral RA. Tertiapin (10-100 nmol/L), a selective GIRK channel blocker, counteracted adenosine-induced action potential duration shortening and prevented AF induction. Immunoblotting showed that the superior/middle lateral RA had significantly higher adenosine A1 receptor (2.7±1.7-fold; P<0.01) and GIRK4 (1.7±0.8-fold; P<0.05) protein expression than lateral/posterior LA. This study revealed a 3-fold RA-to-LA adenosine A1 receptor protein expression gradient in the human heart, leading to significantly greater RA versus LA repolarization sensitivity in response to adenosine. Sustained adenosine-induced AF is maintained by reentrant drivers localized in lateral RA regions with the highest adenosine A1 receptor/GIRK4 expression. Selective atrial GIRK channel blockade may effectively treat AF during conditions with increased endogenous adenosine. © 2016 American Heart Association, Inc.