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Sample records for cardiac adrenergic innervation

  1. Scintigraphic assessment of regional cardiac adrenergic innervation

    SciTech Connect

    Dae, M.W.; O'Connell, J.W.; Botvinick, E.H.; Ahearn, T.; Yee, E.; Huberty, J.P.; Mori, H.; Chin, M.C.; Hattner, R.S.; Herre, J.M.

    1989-03-01

    To assess the feasibility of noninvasively imaging the regional distribution of myocardial sympathetic innervation, we evaluated the distribution of sympathetic nerve endings, using 123I metaiodobenzylguanidine (MIBG), and compared this with the distribution of myocardial perfusion, using 201Tl. Twenty dogs were studied: 11 after regional denervation, and nine as controls. Regional denervation was done by left stellate ganglion removal, right stellate ganglion removal, and application of phenol to the epicardial surface. Computer-processed functional maps displayed the relative distribution of MIBG and thallium in multiple projections in vivo and excised heart slices in all animals. In six animals, dual isotope emission computed tomograms were acquired in vivo. Tissue samples taken from innervated and denervated regions of the MIBG images were analyzed for norepinephrine content to validate image findings. Normal controls showed homogeneous and parallel distributions of MIBG and thallium in the major left ventricular mass. In the left stellectomized hearts, MIBG was reduced relative to thallium in the posterior left ventricle; whereas in right stellectomized hearts, reduced MIBG was in the anterior left ventricle. Phenol-painted hearts showed a broad area of decreased MIBG extending beyond the area of phenol application. In both stellectomized and phenol-painted hearts, thallium distribution remained homogeneous and normal. Norepinephrine content was greater in regions showing normal MIBG (550 +/- 223 ng/g) compared with regions showing reduced MIBG (39 +/- 44 ng/g) (p less than 0.001), confirming regional denervation. Combined MIBG-thallium functional maps display the regional distribution of sympathetic innervation.

  2. Scintigraphic assessment of cardiac adrenergic innervation in patients with essential hypertension

    SciTech Connect

    Fujiwara, Y.; Hamada, M.; Shigematsu, Y.; Sumimoto, T.; Hamamoto, K.; Hiwada, K. )

    1991-01-01

    To assess the regional cardiac adrenergic innervation in patients with essential hypertension (EHT), simultaneous iodine-123 metaiodobenzylguanidine ((123I)MIBG) and thallium-201 (201Tl) myocardial imagings were performed in five patients with EHT, seven patients with hypertrophic cardiomyopathy (HCM), and seven normal subjects. Short axial images at rest were divided into five segments: anterior, septal, posterior, lateral, and apical segments. Percent regional uptake (%RU) of 201Tl except the septal segment in patients with EHT showed no significant difference. However, the %RU of (123I)MIBG at posterior, lateral, and apical segments was significantly lower than that at anterior and septal segments in EHT. This intraimage heterogeneity of (123I)MIBG was also observed in HCM. These results suggest that there is a difference in regional adrenergic innervation of the left ventricle with myocardial hypertrophy.

  3. Sleep-disordered breathing, impaired cardiac adrenergic innervation and prognosis in heart failure.

    PubMed

    Scala, Oriana; Paolillo, Stefania; Formisano, Roberto; Pellegrino, Teresa; Rengo, Giuseppe; Gargiulo, Paola; De Michele, Fausto; Starace, Antonio; Rapacciuolo, Antonio; Parisi, Valentina; Prastaro, Maria; Piscopo, Valentina; Dellegrottaglie, Santo; Bruzzese, Dario; De Martino, Fabiana; Parente, Antonio; Leosco, Dario; Trimarco, Bruno; Cuocolo, Alberto; Perrone-Filardi, Pasquale

    2016-06-23

    Unfavourable effects of sleep-disordered breathing (SDB) in heart failure (HF) are mainly mediated by impaired sympathetic activity. Few data are available on SDB and cardiac adrenergic impairment evaluated at myocardial level. The aim of the study was to assess the relationship between SDB, cardiac sympathetic innervation assessed by (123)I-metaiodobenzylguanidine ((123)I-MIBG) imaging and prognosis in HF. Observational, prospective study enrolling patients with HF and reduced systolic function. Patients underwent nocturnal cardiorespiratory monitoring to assess SDB presence by apnoea/hypopnoea index (AHI), and (123)I-MIBG imaging to calculate heart-to-mediastinum (H/M) ratios and washout rate. Patients were prospectively followed for 29±18 months for the combined endpoint of cardiovascular death and HF hospitalisation. Ninety-four patients (66.1±9.8 years; left ventricular ejection fraction 32±7%) were enrolled; 72 (77%) showed SDB and, compared with non-SDB, significantly reduced early (1.67±0.22 vs 1.77±0.13; p=0.019) and late H/M ratios (1.50±0.22 vs 1.61±0.23; p=0.038). Dividing patients into two groups according to SDB severity, patients with a moderate-severe disturbance (AHI >15; n=43) showed significantly worse survival for the composite study outcome (log-rank test, p=0.001) with respect to patients with mild or no disorder (AHI ≤15; n=51). Adding SDB variables to the already known prognostic role of (123)I-MIBG imaging, we observed a worse survival in patients with both SDB and H/M impairment. Patients with systolic HF and SDB show more impaired cardiac adrenergic innervation assessed by (123)I-MIBG imaging, and more adverse prognosis compared with HF patients without SDB. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  4. Autonomic cardiac innervation

    PubMed Central

    Hasan, Wohaib

    2013-01-01

    Autonomic cardiac neurons have a common origin in the neural crest but undergo distinct developmental differentiation as they mature toward their adult phenotype. Progenitor cells respond to repulsive cues during migration, followed by differentiation cues from paracrine sources that promote neurochemistry and differentiation. When autonomic axons start to innervate cardiac tissue, neurotrophic factors from vascular tissue are essential for maintenance of neurons before they reach their targets, upon which target-derived trophic factors take over final maturation, synaptic strength and postnatal survival. Although target-derived neurotrophins have a central role to play in development, alternative sources of neurotrophins may also modulate innervation. Both developing and adult sympathetic neurons express proNGF, and adult parasympathetic cardiac ganglion neurons also synthesize and release NGF. The physiological function of these “non-classical” cardiac sources of neurotrophins remains to be determined, especially in relation to autocrine/paracrine sustenance during development.   Cardiac autonomic nerves are closely spatially associated in cardiac plexuses, ganglia and pacemaker regions and so are sensitive to release of neurotransmitter, neuropeptides and trophic factors from adjacent nerves. As such, in many cardiac pathologies, it is an imbalance within the two arms of the autonomic system that is critical for disease progression. Although this crosstalk between sympathetic and parasympathetic nerves has been well established for adult nerves, it is unclear whether a degree of paracrine regulation occurs across the autonomic limbs during development. Aberrant nerve remodeling is a common occurrence in many adult cardiovascular pathologies, and the mechanisms regulating outgrowth or denervation are disparate. However, autonomic neurons display considerable plasticity in this regard with neurotrophins and inflammatory cytokines having a central regulatory

  5. [Development of the adrenergic innervation of the atrioventricular valves of certain vertebrates].

    PubMed

    Strinskaia, L A; Leont'eva, G R; Avakian, O M; Govyrin, V A

    1980-01-01

    Adrenergic innervation of the atrioventricular valves in the carp Cyprinus carpo, frog Rana temporaria, tortoise Emys orbicularis, hens and albino rats has been investigated by histochemical glyoxylic technique. It was shown that the adrenergic innervation of cardiac valves becomes more intense and more complex during progressive evolution of cardio-vascular activity. Adrenergic nerves realize the connection between annullus fibrosus, valve, chordal tendineal and papillary muscles. Chromaffin cells of the valve serve as an additional store of catecholamines. A possibility cannot be excluded that these cells supply with biogenic amines the papillary muscles regulating their activity.

  6. The human thoracic duct is functionally innervated by adrenergic nerves.

    PubMed

    Telinius, Niklas; Baandrup, Ulrik; Rumessen, Jüri; Pilegaard, Hans; Hjortdal, Vibeke; Aalkjaer, Christian; Boedtkjer, Donna Briggs

    2014-01-15

    Lymphatic vessels from animals have been shown to be innervated. While morphological studies have confirmed human lymphatic vessels are innervated, functional studies supporting this are lacking. The present study demonstrates a functional innervation of the human thoracic duct (TD) that is predominantly adrenergic. TDs harvested from 51 patients undergoing esophageal and cardia cancer surgery were either fixed for structural investigations or maintained in vitro for the functional assessment of innervation by isometric force measurements and electrical field stimulation (EFS). Electron microscopy and immunohistochemistry suggested scarce diffuse distribution of nerves in the entire vessel wall, but nerve-mediated contractions could be induced with EFS and were sensitive to the muscarinic receptor blocker atropine and the α-adrenoceptor blocker phentolamine. The combination of phentolamine and atropine resulted in a near-complete abolishment of EFS-induced contractions. The presence of sympathetic nerves was further confirmed by contractions induced by the sympathomimetic and catecholamine-releasing agent tyramine. Reactivity to the neurotransmitters norepinephrine, substance P, neuropeptide Y, acetylcholine, and methacholine was demonstrated by exogenous application to human TD ring segments. Norepinephrine provided the most consistent responses, whereas responses to the other agonists varied. We conclude that the human TD is functionally innervated with both cholinergic and adrenergic components, with the latter of the two dominating.

  7. Cardiac Innervation and Sudden Cardiac Death

    PubMed Central

    Fukuda, Keiichi; Kanazawa, Hideaki; Aizawa, Yoshiyasu; Ardell, Jeffrey L.; Shivkumar, Kalyanam

    2015-01-01

    Afferent and efferent cardiac neurotransmission via the cardiac nerves intricately modulates nearly all physiological functions of the heart (chronotropy, dromotropy, lusitropy and inotropy). Afferent information from the heart is transmitted to higher levels of the nervous system for processing (intrinsic cardiac nervous system, extracardiac-intrathoracic ganglia, spinal cord, brain stem and higher centers) which ultimately results in efferent cardiomotor neural impulses (via the sympathetic and parasympathetic nerves). This system forms interacting feedback loops that provide physiological stability for maintaining normal rhythm and life-sustaining circulation. This system also ensures that there is fine-tuned regulation of sympathetic-parasympathetic balance in the heart under normal and stressed states in the short (beat to beat), intermediate (minutes-hours) and long term (days-years). This important neurovisceral /autonomic nervous system also plays a major role in the pathophysiology and progression of heart disease, including heart failure and arrhythmias leading to sudden cardiac death (SCD). Transdifferentiation of neurons in heart failure, functional denervation, cardiac and extra-cardiac neural remodeling have also been identified and characterized during the progression of disease. Recent advances in understanding the cellular and molecular processes governing innervation and the functional control of the myocardium in health and disease provides a rational mechanistic basis for development of neuraxial therapies for preventing SCD and other arrhythmias. Advances in cellular, molecular, and bioengineering realms have underscored the emergence of this area as an important avenue of scientific inquiry and therapeutic intervention. PMID:26044253

  8. Cardiac innervation and sudden cardiac death.

    PubMed

    Fukuda, Keiichi; Kanazawa, Hideaki; Aizawa, Yoshiyasu; Ardell, Jeffrey L; Shivkumar, Kalyanam

    2015-06-05

    Afferent and efferent cardiac neurotransmission via the cardiac nerves intricately modulates nearly all physiological functions of the heart (chronotropy, dromotropy, lusitropy, and inotropy). Afferent information from the heart is transmitted to higher levels of the nervous system for processing (intrinsic cardiac nervous system, extracardiac-intrathoracic ganglia, spinal cord, brain stem, and higher centers), which ultimately results in efferent cardiomotor neural impulses (via the sympathetic and parasympathetic nerves). This system forms interacting feedback loops that provide physiological stability for maintaining normal rhythm and life-sustaining circulation. This system also ensures that there is fine-tuned regulation of sympathetic-parasympathetic balance in the heart under normal and stressed states in the short (beat to beat), intermediate (minutes to hours), and long term (days to years). This important neurovisceral/autonomic nervous system also plays a major role in the pathophysiology and progression of heart disease, including heart failure and arrhythmias leading to sudden cardiac death. Transdifferentiation of neurons in heart failure, functional denervation, cardiac and extracardiac neural remodeling has also been identified and characterized during the progression of disease. Recent advances in understanding the cellular and molecular processes governing innervation and the functional control of the myocardium in health and disease provide a rational mechanistic basis for the development of neuraxial therapies for preventing sudden cardiac death and other arrhythmias. Advances in cellular, molecular, and bioengineering realms have underscored the emergence of this area as an important avenue of scientific inquiry and therapeutic intervention. © 2015 American Heart Association, Inc.

  9. Autonomic cardiac innervation: development and adult plasticity.

    PubMed

    Hasan, Wohaib

    2013-01-01

    Autonomic cardiac neurons have a common origin in the neural crest but undergo distinct developmental differentiation as they mature toward their adult phenotype. Progenitor cells respond to repulsive cues during migration, followed by differentiation cues from paracrine sources that promote neurochemistry and differentiation. When autonomic axons start to innervate cardiac tissue, neurotrophic factors from vascular tissue are essential for maintenance of neurons before they reach their targets, upon which target-derived trophic factors take over final maturation, synaptic strength and postnatal survival. Although target-derived neurotrophins have a central role to play in development, alternative sources of neurotrophins may also modulate innervation. Both developing and adult sympathetic neurons express proNGF, and adult parasympathetic cardiac ganglion neurons also synthesize and release NGF. The physiological function of these "non-classical" cardiac sources of neurotrophins remains to be determined, especially in relation to autocrine/paracrine sustenance during development.   Cardiac autonomic nerves are closely spatially associated in cardiac plexuses, ganglia and pacemaker regions and so are sensitive to release of neurotransmitter, neuropeptides and trophic factors from adjacent nerves. As such, in many cardiac pathologies, it is an imbalance within the two arms of the autonomic system that is critical for disease progression. Although this crosstalk between sympathetic and parasympathetic nerves has been well established for adult nerves, it is unclear whether a degree of paracrine regulation occurs across the autonomic limbs during development. Aberrant nerve remodeling is a common occurrence in many adult cardiovascular pathologies, and the mechanisms regulating outgrowth or denervation are disparate. However, autonomic neurons display considerable plasticity in this regard with neurotrophins and inflammatory cytokines having a central regulatory

  10. Multiple innervation of normal and re-innervated parasympathetic neurones in the frog cardiac ganglion.

    PubMed Central

    Dennis, M J; Sargent, P B

    1978-01-01

    1. Multiple innervation of parasympathetic neurones was examined in normal and re-innervated frog cardiac ganglia. The number of synaptic inputs impinging upon individual ganglion cells was determined by recording intracellularly and stimulating the vagosympathetic nerves. 2. In unoperated cardiac ganglia most neurones (93%) received a large, suprathreshold synaptic input. Some ganglion cells received additional, small synaptic inputs. Roughly equal numbers of cells encountered were singly and doubly innervated, and only 8% received more than two inputs. 3. Re-innervation of cardiac ganglion cells began three weeks after bilateral crush of the vagosympathetic nerves. By 7 weeks more than 90% of the ganglion cells were re-innervated. At this stage the pattern of multiple innervation was significantly different than normal: doubly innervated neurones outnumbered singly innervated ones, and 31% of the cells encountered received more than two inputs. This pattern was stable for at least a year. 4. These results indicate that polyneuronal innervation of cardiac ganglion cells is more widespread after re-innervation than it is normally and, furthermore, that synapse elimination does not occur during re-innervation of these cells. Images Plate 1 PMID:212557

  11. Adrenergic and cholinergic innervation of the arteriovenous anastomosis in the rabbit's ear.

    PubMed

    Iijima, T; Tagawa, T

    1976-07-01

    The distribution of adrenergic and cholinergic nerves in the arteriovenous anastomosis in the rabbit's ear was studied light microscopically using specific histochemical techniques for catecholamines and acetylcholinesterase. Histochemical observations was made with whole stretch preparations and cryostat or paraffin sections. Both kinds of nerves showed similar distribution, though the adrenergic innervation was denser than the cholinergic one. The intermediate segments of the anastomoses, which were characterized by a very thick wall, had the most dense innervation. The small arteries and arterial segments had a moderate innervation whereas most of the small veins and venous segments had few nerve fibers. The segmental variation in the vasomotor nerve supply clearly suggests that the intermediate segment has the most active contractility. An unusually rich innervation in the anastomosis, therefore, indicates the significance of the neurogenic mechanisms in the vasomotor control of the anastomosis.

  12. Cardiac autonomic innervation of the western pygmy possum (Cercatetus concinnus) and golden bandicoot (Isoodon auratus).

    PubMed

    Zosky, Graeme R; O'Shea, James E

    2017-01-01

    Evidence for a functional ventricular parasympathetic innervation of the mammalian heart between and within taxa remains controversial. We have previously proposed that the presence of a functional parasympathetic innervation of the ventricle was indicative of heterothermy, and is essential for maintaining ventricular stability at low body temperature. However, it is possible that the presence of such an innervation is also representative of the primitive mammalian state. In this study, we aimed to determine whether a functional parasympathetic innervation of the ventricle, that is capable of actively reducing the force of contraction, is present across metatherian mammals. Using in vitro isolated cardiac preparations, we examined evidence for a functional ventricular parasympathetic innervation of the ventricle in two species of metatherian mammal, one heterotherm (Western pygmy possum; Cercatetus concinnus) and one homeotherm (Golden bandicoot; Isoodon auratus), from different families to complement existing data from a heterothermic dasyurid. Both C. concinnus and I. auratus had a potent biphasic response to transmural electrical stimulation in both atrial and ventricular preparations. Both the decrease and increase in the force of contraction in response to stimulation were almost entirely blocked by the cholinergic and adrenergic antagonists, atropine and propranolol, respectively. These observations provide clear evidence for a parasympathetic innervation of the ventricle that is capable of directly influencing the force of contraction across metatherian mammals with different thermoregulatory strategies. While this innervation may facilitate heterothermy, this suggests that the presence of such an innervation pattern is indicative of the primitive mammalian state.

  13. Development of adrenergic innervation in rat peripheral vessels: a fluorescence microscopic study.

    PubMed Central

    Todd, M E

    1980-01-01

    The postnatal development of adrenergic innervation was followed in peripheral blood vessels of Wistar rats. The femoral vessels and their branches, the superficial epigastric and saphenous vessels, and the tail artery, were investigated from birth to maturity. The proximal ends of the vessels were studied with fluorescence microscopy after the catecholamine was converted to a fluorophore by hot formaldehyde vapour, and ultrastructural morphology confirmed that the nerve varicosities mainly contained small vesicles with dense cores, typical of adrenergic innervation. Further confirmation was obtained with reserpine pre-pretreatment, the sodium borohydride specificity test, and experiments to alter the non-specific fluorescence of elastin. The nerves in the arteries were immediately adjacent to the external elastic lamina, and they retained this position throughout postnatal development. Of the three muscular arteries, the development of innervation was earlier and more intense in the saphenous and superficial epigastric arteries than in the tail artery. However, the tail artery surpassed the other two both in the total number of nerves and in the density of innervation per unit area beyond 12 days of age, and maintained this lead to maturity. The superficial epigastric artery had the smallest total number of nerves but had a greater density of innervation than the saphenous. The femoral artery did not develop any appreciable innervation. The femoral vein demonstrated the greatest amount of fluorescence of any of the veins, the others having considerably less innervation than their companion arteries. Images Fig. 2 Fig. 3 Fig. 7 Fig. 8 PMID:7440396

  14. SHP-2 deletion in postmigratory neural crest cells results in impaired cardiac sympathetic innervation

    PubMed Central

    Lajiness, Jacquelyn D.; Snider, Paige; Wang, Jian; Feng, Gen-Sheng; Krenz, Maike; Conway, Simon J.

    2014-01-01

    Autonomic innervation is an essential component of cardiovascular regulation that is first established from the neural crest (NC) lineage in utero and continues developing postnatally. Although in vitro studies have indicated that SH2-containing protein tyrosine phosphatase 2 (SHP-2) is a signaling factor critical for regulating sympathetic neuron differentiation, this has yet to be shown in the complex in vivo environment of cardiac autonomic innervation. Targeting SHP-2 within postmigratory NC lineages resulted in a fully penetrant mouse model of diminished sympathetic cardiac innervation and concomitant bradycardia. Immunohistochemistry of the sympathetic nerve marker tyrosine hydroxylase revealed a progressive loss of adrenergic ganglionic neurons and reduction of cardiac sympathetic axon density in Shp2 cKOs. Molecularly, Shp2 cKOs exhibit lineage-specific suppression of activated phospo-ERK1/2 signaling but not of other downstream targets of SHP-2 such as pAKT. Genetic restoration of the phosphorylated-extracellular signal-regulated kinase (pERK) deficiency via lineage-specific expression of constitutively active MEK1 was sufficient to rescue the sympathetic innervation deficit and its physiological consequences. These data indicate that SHP-2 signaling specifically through pERK in postmigratory NC lineages is essential for development and maintenance of sympathetic cardiac innervation postnatally. PMID:24706815

  15. Myocardial perfusion and adrenergic innervation in patients with RBBB and LAfB: the effect of altering the activation sequence with right ventricular apical pacing.

    PubMed

    Simantirakis, Emmanuel N; Prassopoulos, Vasilios K; Marketou, Maria E; Chrysostomakis, Stavros I; Koukouraki, Sophia I; Lekakis, John P; Karkavitsas, Nikolaos S; Vardas, Panos E

    2003-05-01

    The aim of this study was to investigate myocardial perfusion and adrenergic innervation in patients with intraventricular conduction disturbances and to detect any changes caused by alteration of the ventricular activation sequence as a result of right ventricular apical pacing. We studied 15 patients with right bundle branch block (RBBB) and left anterior fascicular block (LAFB), while 15 healthy individuals served as controls. All patients underwent planar and single-photon emission computed tomography (SPECT) myocardial imaging after intravenous infusion of 5mCi 123I-metaiodobenzylguanidine (123I-MIBG) and a SPECT thallium201 myocardial perfusion study before and 3 months after pacemaker implantation. The heart to mediastinum ratio was calculated during the 123I-MIBG study in order to assess the global cardiac sympathetic activity and was significantly smaller in patients than in controls (P < 0.001). Patients with RBBB and LAFB revealed regional adrenergic innervation defects, mostly in the inferior and posterior walls. After a medium-term pacing period, a redistribution of 123I-MIBG uptake was detected, with aggravation of adrenergic innervation defects in the apical and posterior walls and amelioration in septal and anterior walls. Five patients showed perfusion defects that remained unchanged after pacing. Two others displayed mild myocardial perfusion defects that did not exist before pacing. In conclusion, patients with RBBB and LAFB reveal global and regional disturbances of myocardial adrenergic innervation, which shows redistribution as a result of the altered propagation of the ventricular electrical activation. To a smaller degree these patients reveal myocardial perfusion disturbances in which pacing has a limited medium-term effect.

  16. Adrenergic innervation of the gills, pulmonary arterial plexus, and dorsal aorta in the neotenic salamander, Ambystoma tigrinum.

    PubMed

    Malvin, G M; Dail, W G

    1986-07-01

    The presence of adrenergic innervation was investigated in four different vascular segments of the neotenic tiger salamander, Ambystoma tigrinum, by histofluorescent staining for catecholamines. The segments were the respiratory section of the gill, the branchial shunt vessels, a vascular plexus in the pulmonary artery, and the dorsal aorta. No adrenergic fibers were detected in the respiratory section of the gill or the pulmonary arterial plexus. In contrast, the branchial shunt vessels contained both adrenergic varicosities and catecholamine-containing cell bodies. These cells resemble Type I cells of the mammalian carotid body and amphibian carotid labyrinth. Adrenergic innervation of the dorsal aorta was sparse and restricted to the adventitia. The results suggest that adrenergic nerves may directly regulate blood flow in the gill, and thus gas exchange, by controlling vascular resistance of the branchial shunts. The contractile state of the dorsal aorta may also be under adrenergic control. In addition, it is suggested that the adrenergic cells of the branchial shunts may serve a receptor function in being sensitive to arterial blood gases.

  17. The maturation of neuromuscular function in a multiply innervated structure: development of the longitudinal smooth muscle of the foetal mammalian gut and its cholinergic excitatory, adrenergic inhibitory, and non-adrenergic inhibitory innervation

    PubMed Central

    Gershon, Michael D.; Thompson, Elizabeth Barnes

    1973-01-01

    1. The earliest components of the developing innervation of the rabbit intestine to be detected in this study were the cholinergic excitatory and the intrinsic inhibitory innervation. These developed simultaneously in the rabbit at 17 days of gestation. Both were also present in the mouse by the 16th day of gestation. Responsiveness of rabbit tissue to exogenous acetylcholine appeared together with the advent of a functional cholinergic innervation. Since excitatory responses were potentiated by eserine, the tissue was probably able to inactivate acetylcholine through hydrolysis mediated by cholinesterase. Early relaxant responses resisted blockade by adrenergic neurone blocking agents and by antagonists active at α- and β-adrenoceptors. 2. The development of the adrenergic innervation lagged far behind that of the other two components. Specific uptake of noradrenaline in the rabbit was detected for the first time at the 21st day of gestation and stores of noradrenaline could not be detected histochemically until 26-28 days. However, relaxant responses to stimulation of the perivascular sympathetic supply, such as characterize adult tissues, had not yet developed by the time of birth. Relaxation in response to perivascular stimulation could be seen 30 days after birth. 3. Morphologic studies indicated that the longitudinal layer of smooth muscle was very primitive when an effective innervation was established. Although contractile, the cells were still myoblasts. Neural elements also appeared primitive. Thus considerable morphological maturation follows the development both of a functioning contractile machinery and innervation in the foetal gut. 4. This study helps establish that the intrinsic inhibitory innervation of the gut is not adrenergic. ImagesPlate 1Plate 2Plate 3 PMID:4148880

  18. Adrenergic innervation of the developing chick heart: neural crest ablations to produce sympathetically aneural hearts

    SciTech Connect

    Kirby, M.; Stewart, D.

    1984-11-01

    Ablation of various regions of premigratory trunk neural crest which gives rise to the sympathetic trunks was used to remove sympathetic cardiac innervation. Neuronal uptake of (/sup 3/H)-norepinephrine was used as an index of neuronal development in the chick atrium. Following ablation of neural crest over somites 10-15 or 15-20, uptake was significantly decreased in the atrium at 16 and 17 days of development. Ablation of neural crest over somites 5-10 and 20-25 caused no decrease in (/sup 3/H)-norepinephrine uptake. Removal of neural crest over somites 5-25 or 10-20 caused approximately equal depletions of (/sup 3/H)-norepinephrine uptake in the atrium. Cardiac norepinephrine concentration was significantly depressed following ablation of neural crest over somites 5-25 but not over somites 10-20. Light-microscopic and histofluorescent preparations confirmed the absence of sympathetic trunks in the region of the normal origin of the sympathetic cardiac nerves following neural crest ablation over somites 10-20. The neural tube and dorsal root ganglia were damaged in the area of the neural-crest ablation; however, all of these structures were normal cranial and caudal to the lesioned area. Development of most of the embryos as well as the morphology of all of the hearts was normal following the lesion. These results indicate that it is possible to produce sympathetically aneural hearts by neural-crest ablation; however, sympathetic cardiac nerves account for an insignificant amount of cardiac norepinephrine.

  19. Positron emission tomographic imaging of cardiac sympathetic innervation and function

    SciTech Connect

    Goldstein, D.S.; Chang, P.C.; Eisenhofer, G.; Miletich, R.; Finn, R.; Bacher, J.; Kirk, K.L.; Bacharach, S.; Kopin, I.J. )

    1990-05-01

    Sites of uptake, storage, and metabolism of ({sup 18}F)fluorodopamine and excretion of ({sup 18}F)fluorodopamine and its metabolites were visualized using positron emission tomographic (PET) scanning after intravenous injection of the tracer into anesthetized dogs. Radioactivity was concentrated in the renal pelvis, heart, liver, spleen, salivary glands, and gall bladder. Uptake of 18F by the heart resulted in striking delineation of the left ventricular myocardium. Pretreatment with desipramine markedly decreased cardiac positron emission, consistent with dependence of the heart on neuronal uptake (uptake-1) for removal of circulating catecholamines. In reserpinized animals, cardiac positron emission was absent within 30 minutes after injection of ({sup 18}F)-6-fluorodopamine, demonstrating that the emission in untreated animals was from radioactive labeling of the sympathetic storage vesicles. Decreased positron emission from denervated salivary glands confirmed that the tracer was concentrated in sympathetic neurons. Radioactivity in the gall bladder and urinary system depicted the hepatic and renal excretion of the tracer and its metabolites. Administration of tyramine or nitroprusside increased and ganglionic blockade with trimethaphan decreased the rate of loss of myocardial radioactivity. The results show that PET scanning after administration of ({sup 18}F)fluorodopamine can be used to visualize sites of sympathetic innervation, follow the metabolism and renal and hepatic excretion of catecholamines, and examine cardiac sympathetic function.

  20. Pressure overload causes cardiac hypertrophy in beta1-adrenergic and beta2-adrenergic receptor double knockout mice.

    PubMed

    Palazzesi, Sergio; Musumeci, Marco; Catalano, Liviana; Patrizio, Mario; Stati, Tonino; Michienzi, Simona; Di Certo, Maria Grazia; Mattei, Elisabetta; Vitelli, Luigi; Marano, Giuseppe

    2006-03-01

    Cardiac hypertrophy arises as an adaptive response to increased afterload. Studies in knockout mice have shown that catecholamines, but not alpha1-adrenergic receptors, are necessary for such an adaptation to occur. However, whether beta-adrenergic receptors are critical for the development of cardiac hypertrophy in response to pressure overload is not known at this time. Pressure overload was induced by transverse aortic banding in beta1-adrenergic and beta2-adrenergic receptor double knockout (DbetaKO) mice, in which the predominant cardiac beta-adrenergic receptor subtypes are lacking. Chronic pressure overload for 4 weeks induced cardiac hypertrophy in both DbetaKO and wild-type mice. There were no significant differences between banded mice in left ventricular weight to body weight ratio, in the left ventricular wall thickness, in the cardiomyocyte size or in the expression levels of the load-sensitive cardiac genes such as ANF and beta-MHC. Additionally, the left ventricular systolic pressure, an index of afterload, and cardiac contractility, evaluated as dp/dtmax, the maximal slope of systolic pressure increment, and Ees, end-systolic elastance, were increased at a similar level in both wild-type and DbetaKO banded mice, and were significantly greater than in sham controls. Despite chronic activation of the cardiac beta-adrenergic system being sufficient to induce a pathological hypertrophy, we show that beta1-adrenergic and beta2-adrenergic receptors are not an obligatory component of the signaling pathway that links the increased afterload to the development of cardiac hypertrophy.

  1. The role of cardiac sympathetic innervation and skin thermoreceptors on cardiac responses during heat stress

    PubMed Central

    Umemoto, Yasunori; Kinoshita, Tokio; Kouda, Ken; Ito, Tomoyuki; Nakamura, Takeshi; Crandall, Craig G.; Tajima, Fumihiro

    2015-01-01

    The mechanism(s) for the changes in cardiac function during heat stress remain unknown. This study tested two unique hypotheses. First, sympathetic innervation to the heart is required for increases in cardiac systolic function during heat stress. This was accomplished by comparing responses during heat stress between paraplegics versus tetraplegics, with tetraplegics having reduced/absent cardiac sympathetic innervation. Second, stimulation of skin thermoreceptors contributes to cardiovascular adjustments that occur during heat stress in humans. This was accomplished by comparing responses during leg only heating between paraplegic versus able-bodied individuals. Nine healthy able-bodied, nine paraplegics, and eight tetraplegics participated in this study. Lower body (i.e., nonsensed area for para/tetraplegics) was heated until esophageal temperature had increased by ∼1.0°C. Echocardiographic indexes of diastolic and systolic function were performed before and at the end of heat stress. The heat stress increased cardiac output in all groups, but the magnitude of this increase was attenuated in the tetraplegics relative to the able-bodied (1.3 ± 0.4 vs. 2.3 ± 1.0 l/min; P < 0.05). Diastolic function was maintained in all groups. Indexes of left atrial and ventricular systolic function were enhanced in the able-bodied, but did not change in tetraplegics, while these changes in paraplegics were attenuated relative to the able-bodied. These data suggest that the cardiac sympathetic innervation is required to achieve normal increases in cardiac systolic function during heat stress but not required to maintain diastolic function during this exposure. Second, elevated systolic function during heat stress primarily occurs as a result of increases in internal temperature, although stimulation of skin thermoreceptors may contribute. PMID:25795714

  2. [Development of the theory of cardiac innervation during ontogenesis in health and disease].

    PubMed

    Shvalev, V N

    2010-01-01

    The paper describes the mediatory stage of prenatal development of cardiac innervation and the phenomenon of early involution of sympathetic nerve plexuses in postnatality, which has been established while analyzing early autopsies by neurohistochemical studies. lmmunocytochemical, luminescence, and ultrastructural techniques have defined changes in the stages of their formation and development of the above early involution. Complex (neurohistochemical and electrophysiological) studies quantified groups of age-related cardiac innervation changes in health. Cardiac rhythm variability was electrophysiologically studied in 43 subjects aged 18-71 years. Cardiac desympathization is shown to develop after 40 years of age. Age-related changes in cardiac regulatory mechanisms should be taken into account on studying visceral systems in coronary heart disease, atherosclerosis, and sudden cardiac death, and during cardiac transplantation. Immunohistochemical study has revealed an increase in nitric oxide expression in the human cardiac nervous apparatus.

  3. Vagal cardiac efferent innervation in F344 rats: Effects of chronic intermittent hypoxia.

    PubMed

    Cheng, Zixi Jack

    2017-03-01

    Chronic intermittent hypoxia (CIH), which is a physiological consequence of obstructive sleep apnea, reduces baroreflex control of heart rate (HR). Previously, we showed that the heart rate (HR) response to electrical stimulation of the vagal efferent nerve was significantly increased following CIH in F344 rats. Since vagal cardiac efferent from the nucleus ambiguus (NA) project to cardiac ganglia and regulate HR, we hypothesized that vagal cardiac efferent innervation of cardiac ganglia is reorganized. Young adult F344 rats were exposed either to room air (RA) or to intermittent hypoxia for 35-50days. Fluorescent tracer DiI was injected into the NA to label vagal efferent innervation of cardiac ganglia which had been counterstained by Fluoro-Gold (FG) injections (i.p). Confocal microscopy was used to examine vagal cardiac efferent axons and terminals in cardiac ganglia. NA axons entered cardiac ganglia and innervated principal neurons (PNs) with robust basket endings in both RA control and CIH animals. In addition, the percentage of PNs which were innervated by DiI-labeled fibers in ganglia was similar. In CIH rats, abnormally large swollen cardiac axon segments and disorganized terminals as well as leaky endings were observed. In general, vagal efferent terminal varicosities around PNs appeared larger and the number of varicosities was significantly increased. Interestingly, some cardiac axons had sprouting-like terminal structures in the cardiac ganglia as well as in cardiac muscle, which had not been found in RA control. Finally, CIH increased the size of PNs and reduced the ratio of nucleus to PN somata. Thus, CIH significantly remodeled the structure of vagal cardiac axons and terminals in cardiac ganglia as well as cardiac PNs.

  4. Supine low-frequency power of heart rate variability reflects baroreflex function, not cardiac sympathetic innervation.

    PubMed

    Moak, Jeffrey P; Goldstein, David S; Eldadah, Basil A; Saleem, Ahmed; Holmes, Courtney; Pechnik, Sandra; Sharabi, Yehonatan

    2007-12-01

    Power spectral analysis of heart rate variability (HRV) has been used to indicate cardiac autonomic function. High-frequency power relates to respiratory sinus arrhythmia and therefore to parasympathetic cardiovagal tone; however, the relationship of low-frequency (LF) power to cardiac sympathetic innervation and function has been controversial. Alternatively, LF power might reflect baroreflexive modulation of autonomic outflows. We studied normal volunteers and chronic autonomic failure syndrome patients with and without loss of cardiac noradrenergic nerves to examine the relationships of LF power with cardiac sympathetic innervation and baroreflex function. We compared LF power of HRV in patients with cardiac sympathetic denervation, as indicated by low myocardial concentrations of 6-[(18)F] fluorodopamine-derived radioactivity or low rates of norepinephrine entry into coronary sinus plasma (cardiac norepinephrine spillover) to values in patients with intact innervation, at baseline, during infusion of yohimbine, which increases exocytotic norepinephrine release from sympathetic nerves, or during infusion of tyramine, which increases non-exocytotic release. Baroreflex-cardiovagal slope (BRS) was calculated from the cardiac interbeat interval and systolic pressure during the Valsalva maneuver. LF power was unrelated to myocardial 6-[(18)F] fluorodopamine-derived radioactivity or cardiac norepinephrine spillover. In contrast, the log of LF power correlated positively with the log of BRS (r=0.72, P <0.0001). Patients with a low BRS (cardiac innervation. Tyramine and yohimbine increased LF power in subjects with normal BRS but not in those with low BRS. BRS at baseline predicted LF responses to tyramine and yohimbine. LF power reflects baroreflex function, not cardiac sympathetic innervation.

  5. High-fat diet induces protein kinase A and G-protein receptor kinase phosphorylation of β2 -adrenergic receptor and impairs cardiac adrenergic reserve in animal hearts.

    PubMed

    Fu, Qin; Hu, Yuting; Wang, Qingtong; Liu, Yongming; Li, Ning; Xu, Bing; Kim, Sungjin; Chiamvimonvat, Nipavan; Xiang, Yang K

    2017-03-15

    Patients with diabetes show a blunted cardiac inotropic response to β-adrenergic stimulation despite normal cardiac contractile reserve. Acute insulin stimulation impairs β-adrenergically induced contractile function in isolated cardiomyocytes and Langendorff-perfused hearts. In this study, we aimed to examine the potential effects of hyperinsulinaemia associated with high-fat diet (HFD) feeding on the cardiac β2 -adrenergic receptor signalling and the impacts on cardiac contractile function. We showed that 8 weeks of HFD feeding leads to reductions in cardiac functional reserve in response to β-adrenergic stimulation without significant alteration of cardiac structure and function, which is associated with significant changes in β2 -adrenergic receptor phosphorylation at protein kinase A and G-protein receptor kinase sites in the myocardium. The results suggest that clinical intervention might be applied to subjects in early diabetes without cardiac symptoms to prevent further cardiac complications. Patients with diabetes display reduced exercise capability and impaired cardiac contractile reserve in response to adrenergic stimulation. We have recently uncovered an insulin receptor and adrenergic receptor signal network in the heart. The aim of this study was to understand the impacts of high-fat diet (HFD) on the insulin-adrenergic receptor signal network in hearts. After 8 weeks of HFD feeding, mice exhibited diabetes, with elevated insulin and glucose concentrations associated with body weight gain. Mice fed an HFD had normal cardiac structure and function. However, the HFD-fed mice displayed a significant elevation of phosphorylation of the β2 -adrenergic receptor (β2 AR) at both the protein kinase A site serine 261/262 and the G-protein-coupled receptor kinase site serine 355/356 and impaired adrenergic reserve when compared with mice fed on normal chow. Isolated myocytes from HFD-fed mice also displayed a reduced contractile response to adrenergic

  6. Cardiac sympathetic innervation via middle cervical and stellate ganglia and antiarrhythmic mechanism of bilateral stellectomy.

    PubMed

    Irie, Tadanobu; Yamakawa, Kentaro; Hamon, David; Nakamura, Keijiro; Shivkumar, Kalyanam; Vaseghi, Marmar

    2017-03-01

    Cardiac sympathetic denervation (CSD) is reported to reduce the burden of ventricular tachyarrhythmias [ventricular tachycardia (VT)/ventricular fibrillation (VF)] in cardiomyopathy patients, but the mechanisms behind this benefit are unknown. In addition, the relative contribution to cardiac innervation of the middle cervical ganglion (MCG), which may contain cardiac neurons and is not removed during this procedure, is unclear. The purpose of this study was to compare sympathetic innervation of the heart via the MCG vs. stellate ganglia, assess effects of bilateral CSD on cardiac function and VT/VF, and determine changes in cardiac sympathetic innervation after CSD to elucidate mechanisms of benefit in 6 normal and 18 infarcted pigs. Electrophysiological and hemodynamic parameters were evaluated at baseline, during bilateral stellate stimulation, and during bilateral MCG stimulation in 6 normal and 12 infarcted animals. Bilateral CSD (removal of bilateral stellates and T2 ganglia) was then performed and MCG stimulation repeated. In addition, in 18 infarcted animals VT/VF inducibility was assessed before and after CSD. In infarcted hearts, MCG stimulation resulted in greater chronotropic and inotropic response than stellate ganglion stimulation. Bilateral CSD acutely reduced VT/VF inducibility by 50% in infarcted hearts and prolonged global activation recovery interval. CSD mitigated effects of MCG stimulation on dispersion of repolarization and T-peak to T-end interval in infarcted hearts, without causing hemodynamic compromise. These data demonstrate that the MCG provides significant cardiac sympathetic innervation before CSD and adequate sympathetic innervation after CSD, maintaining hemodynamic stability. Bilateral CSD reduces VT/VF inducibility by improving electrical stability in infarcted hearts in the setting of sympathetic activation.NEW & NOTEWORTHY Sympathetic activation in myocardial infarction leads to arrhythmias and worsens heart failure. Bilateral

  7. Cardiac myosin binding protein-C Ser302 phosphorylation regulates cardiac β-adrenergic reserve

    PubMed Central

    Mamidi, Ranganath; Gresham, Kenneth S.; Li, Jiayang; Stelzer, Julian E.

    2017-01-01

    Phosphorylation of cardiac myosin binding protein-C (MyBP-C) modulates cardiac contractile function; however, the specific roles of individual serines (Ser) within the M-domain that are targets for β-adrenergic signaling are not known. Recently, we demonstrated that significant accelerations in in vivo pressure development following β-agonist infusion can occur in transgenic (TG) mouse hearts expressing phospho-ablated Ser282 (that is, TGS282A) but not in hearts expressing phospho-ablation of all three serines [that is, Ser273, Ser282, and Ser302 (TG3SA)], suggesting an important modulatory role for other Ser residues. In this regard, there is evidence that Ser302 phosphorylation may be a key contributor to the β-agonist–induced positive inotropic responses in the myocardium, but its precise functional role has not been established. Thus, to determine the in vivo and in vitro functional roles of Ser302 phosphorylation, we generated TG mice expressing nonphosphorylatable Ser302 (that is, TGS302A). Left ventricular pressure-volume measurements revealed that TGS302A mice displayed no accelerations in the rate of systolic pressure rise and an inability to maintain systolic pressure following dobutamine infusion similar to TG3SA mice, implicating Ser302 phosphorylation as a critical regulator of enhanced systolic performance during β-adrenergic stress. Dynamic strain–induced cross-bridge (XB) measurements in skinned myocardium isolated from TGS302A hearts showed that the molecular basis for impaired β-adrenergic–mediated enhancements in systolic function is due to the absence of protein kinase A–mediated accelerations in the rate of cooperative XB recruitment. These results demonstrate that Ser302 phosphorylation regulates cardiac contractile reserve by enhancing contractile responses during β-adrenergic stress. PMID:28345052

  8. Studies on the importance of sympathetic innervation, adrenergic receptors, and a possible local catecholamine production in the development of patellar tendinopathy (tendinosis) in man.

    PubMed

    Danielson, Patrik; Alfredson, Håkan; Forsgren, Sture

    2007-04-01

    Changes in the patterns of production and in the effects of signal substances may be involved in the development of tendinosis, a chronic condition of pain in human tendons. There is no previous information concerning the patterns of sympathetic innervation in the human patellar tendon. In this study, biopsies of normal and tendinosis patellar tendons were investigated with immunohistochemical methods, including the use of antibodies against tyrosine hydroxylase (TH) and neuropeptide Y, and against alpha1-, alpha2A-, and beta1-adrenoreceptors. It was noticed that most of the sympathetic innervation was detected in the walls of the blood vessels entering the tendon through the paratendinous tissue, and that the tendon tissue proper of the normal and tendinosis tendons was very scarcely innervated. Immunoreactions for adrenergic receptors were noticed in nerve fascicles containing both sensory and sympathetic nerve fibers. High levels of these receptors were also detected in the blood vessel walls; alpha1-adrenoreceptor immunoreactions being clearly more pronounced in the tendinosis tendons than in the tendons of controls. Interestingly, immunoreactions for adrenergic receptors and TH were noted for the tendon cells (tenocytes), especially in tendinosis tendons. The findings give a morphological correlate for the occurrence of sympathetically mediated effects in the patellar tendon and autocrine/paracrine catecholamine mechanisms for the tenocytes, particularly, in tendinosis. The observation of adrenergic receptors on tenocytes is interesting, as stimulation of these receptors can lead to cell proliferation, degeneration, and apoptosis, events which are all known to occur in tendinosis. Furthermore, the results imply that a possible source of catecholamine production might be the tenocytes themselves

  9. Low frequency power of heart rate variability reflects baroreflex function, not cardiac sympathetic innervation.

    PubMed

    Rahman, Faisal; Pechnik, Sandra; Gross, Daniel; Sewell, LaToya; Goldstein, David S

    2011-06-01

    Power spectral analysis of heart rate variability is used to assess cardiac autonomic function. The relationship of low frequency (LF) power to cardiac sympathetic tone has been unclear. We reported previously that LF power may reflect baroreflex modulation. In this study we attempted to replicate our findings in additional subject cohorts, taking into account possible influences of respiration and using different methods to measure baroreflex-cardiovagal gain (BCG). We assessed relationships of LF power, including respiration-adjusted LF power (LFa), with cardiac sympathetic innervation and baroreflex function in subjects with or without neuroimaging evidence of cardiac sympathetic denervation. Values for LF power at baseline supine, seated, and during the Valsalva maneuver were compared between subject groups with low or normal myocardial concentrations of 6-[(18)F]fluorodopamine-derived radioactivity. BCG was calculated from the slope of cardiac interbeat interval vs. systolic pressure during Phase II of the Valsalva maneuver or after i.v. nitroglycerine injection (the Oxford technique). LF and LFa were unrelated to myocardial 6-[(18)F]fluorodopamine-derived radioactivity. During sitting rest and the Valsalva maneuver logs of LF and LFa correlated positively with the log of Phase II BCG (r = 0.61, p = 0.0005; r = 0.47, p = 0.009; r = 0.69, p < 0.0001; r = 0.60, p = 0.0006). Groups with Low BCG (≤ 3 ms/mmHg) had low LF and LFa regardless of cardiac innervation. The log of LF power during supine rest correlated with the log of Oxford BCG (r = 0.74, p < 0.0001). LF power, with or without respiratory adjustment, reflects baroreflex modulation and not cardiac sympathetic tone.

  10. Relationship of cardiac sympathetic nerve innervation and excitability to cardiac hypertrophy in very elderly male hypertensive patients.

    PubMed

    Li, Shijun; Zhang, Li; Guo, Yuanyuan; Li, Xiaoying

    2013-09-01

    Our study aimed to disclose the relationship of cardiac sympathetic nerve innervation and excitability to myocardial hypertrophy in very old elderly male hypertensive patients with low serum testosterone level. A total of 80 elderly male hypertensive patients aged from 80 to 95 years were recruited. Heart rate variability is determined by 24 h dynamic electrocardiogram and heart rate variability analysis system. Cardiac function and left ventricular mass index were determined using color Doppler ultrasound. Standard deviation of all normal sinus R-R intervals over 24 h (SDNN) significantly decreased in hypertensive cardiac hypertrophy patients as compared with those without cardiac hypertrophy. SDANN and Standard deviation of the average normal sinus R-R intervals for all 5-min segment index, time-domain index reflecting sympathetic nerve tension, obviously decreased and LFnu and LFnu/HFnu, frequency-domain index representing sympathetic nerve excitability, significantly increased in hypertensive cardiac hypertrophy patients as compared with those without cardiac hypertrophy. Myocardial norepinephrine content significantly increased while tyrosine hydroxylase expression significantly lowered in hypertensive cardiac hypertrophy patients, and a negative correlation between myocardial tyrosine hydroxylase expression and myocardial norepinephrine content was present. Serum total testosterone level decreased in hypertensive cardiac hypertrophy patients and was an independent risk factor for the increase in myocardial norepinephrine content and decrease in tyrosine hydroxylase expression. These data confirm that cardiac sympathetic nerve hypoinnervation and relative increase in cardiac sympathetic nerve excitability are closely related to cardiac hypertrophy in very old hypertensive patients. A lower serum total testosterone level was the independent risk factor of cardiac sympathetic nerve hypoinnervation and relative increase in excitability in very old male

  11. Cardiac function as related to adrenergic activity in hypertensive left ventricular hypertrophy.

    PubMed

    Agabiti-Rosei, E; Muiesan, M L; Romanelli, G; Castellano, M; Beschi, M; Alicandri, C; Muiesan, G

    1987-06-01

    Studies in experimental animals and in hypertensive patients have shown that changes in cardiac anatomy and function are not just a simple consequence of the increased pressure load. The activity of the sympathetic nervous system is one of the factors that may influence cardiac performance and also, possibly, the cardiac anatomy of hypertensive patients. Animal studies have strongly suggested a possible role of adrenergic factors in the development of left ventricular hypertrophy. In man, plasma catecholamines are usually higher in hypertensive patients with left ventricular hypertrophy, and a correlation between left ventricular mass and plasma noradrenaline has also been observed. The decrease of cardiac performance after acute beta blockade has been found to be directly related to basal plasma noradrenaline concentration. An impaired response to beta-adrenergic stimulation has been reported in hypertensive animals and has been confirmed in hypertensive patients with left ventricular hypertrophy.

  12. Radionuclide imaging of cardiac sympathetic innervation in heart failure: unlocking untapped potential.

    PubMed

    Gupta, Shuchita; Amanullah, Aman

    2015-03-01

    Heart failure (HF) is associated with sympathetic overactivity, which contributes to disease progression and arrhythmia development. Cardiac sympathetic innervation imaging can be performed using radiotracers that are taken up in the presynaptic nerve terminal of sympathetic nerves. The commonly used radiotracers are (123)I-metaiodobenzylguanidine ((123)I-mIBG) for planar and single-photon emission computed tomography imaging, and (11)C-hydroxyephedrine for positron emission tomography imaging. Sympathetic innervation imaging has been used in assessing prognosis, response to treatment, risk of ventricular arrhythmias and sudden death and prediction of response to cardiac resynchronization therapy in patients with HF. Other potential applications of these techniques are in patients with chemotherapy-induced cardiomyopathy, predicting myocardial recovery in patients with left ventricular assist devices, and assessing reinnervation following cardiac transplantation. There is a lack of standardization with respect to technique of (123)I-mIBG imaging that needs to be overcome for the imaging modality to gain popularity in clinical practice.

  13. Acute vagal stimulation attenuates cardiac metabolic response to β-adrenergic stress

    PubMed Central

    Vimercati, Claudio; Qanud, Khaled; Ilsar, Itamar; Mitacchione, Gianfranco; Sarnari, Roberto; Mania, Daniella; Faulk, Ryan; Stanley, William C; Sabbah, Hani N; Recchia, Fabio A

    2012-01-01

    The effects of vagal stimulation (VS) on cardiac energy substrate metabolism are unknown. We tested the hypothesis that acute VS alters the balance between free fatty acid (FFA) and carbohydrate oxidation and opposes the metabolic effects of β-adrenergic stimulation. A clinical-type selective stimulator of the vagal efferent fibres was connected to the intact right vagus in chronically instrumented dogs. VS was set to reduce heart rate by 30 beats min−1, and the confounding effects of bradycardia were then eliminated by pacing the heart at 165 beats min−1. [3H]Oleate and [14C]glucose were infused to measure FFA and glucose oxidation. The heart was subjected to β-adrenergic stress by infusing dobutamine at 5, 10 and 15 μg kg−1 min−1 before and during VS. VS did not significantly affect baseline cardiac performance, haemodynamics or myocardial metabolism. However, at peak dobutamine stress, VS attenuated the increase in left ventricular pressure–diameter area from 235.9 ± 72.8 to 167.3 ± 55.8%, and in cardiac oxygen consumption from 173.9 ± 23.3 to 127.89 ± 6.2% (both P < 0.05), and thus mechanical efficiency was not enhanced. The increase in glucose oxidation fell from 289.3 ± 55.5 to 131.1 ± 20.9%(P < 0.05), while FFA oxidation was not increased by β-adrenergic stress and fell below baseline during VS only at the lowest dose of dobutamine. The functional and in part the metabolic changes were reversed by 0.1 mg kg−1 atropine i.v. Our data show that acute right VS does not affect baseline cardiac metabolism, but attenuates myocardial oxygen consumption and glucose oxidation in response to adrenergic stress, thus functioning as a cardio-selective antagonist to β-adrenergic activation. PMID:22966163

  14. Acute vagal stimulation attenuates cardiac metabolic response to β-adrenergic stress.

    PubMed

    Vimercati, Claudio; Qanud, Khaled; Ilsar, Itamar; Mitacchione, Gianfranco; Sarnari, Roberto; Mania, Daniella; Faulk, Ryan; Stanley, William C; Sabbah, Hani N; Recchia, Fabio A

    2012-12-01

    The effects of vagal stimulation (VS) on cardiac energy substrate metabolism are unknown. We tested the hypothesis that acute VS alters the balance between free fatty acid (FFA) and carbohydrate oxidation and opposes the metabolic effects of β-adrenergic stimulation. A clinical-type selective stimulator of the vagal efferent fibres was connected to the intact right vagus in chronically instrumented dogs. VS was set to reduce heart rate by 30 beats min(-1), and the confounding effects of bradycardia were then eliminated by pacing the heart at 165 beats min(-1). [(3)H]Oleate and [(14)C]glucose were infused to measure FFA and glucose oxidation. The heart was subjected to β-adrenergic stress by infusing dobutamine at 5, 10 and 15 μg kg(-1) min(-1) before and during VS. VS did not significantly affect baseline cardiac performance, haemodynamics or myocardial metabolism. However, at peak dobutamine stress, VS attenuated the increase in left ventricular pressure-diameter area from 235.9 ± 72.8 to 167.3 ± 55.8%, and in cardiac oxygen consumption from 173.9 ± 23.3 to 127.89 ± 6.2% (both P < 0.05), and thus mechanical efficiency was not enhanced. The increase in glucose oxidation fell from 289.3 ± 55.5 to 131.1 ± 20.9% (P < 0.05), while FFA oxidation was not increased by β-adrenergic stress and fell below baseline during VS only at the lowest dose of dobutamine. The functional and in part the metabolic changes were reversed by 0.1 mg kg(-1) atropine i.v. Our data show that acute right VS does not affect baseline cardiac metabolism, but attenuates myocardial oxygen consumption and glucose oxidation in response to adrenergic stress, thus functioning as a cardio-selective antagonist to β-adrenergic activation.

  15. Mediating delta-opioid-initiated heart protection via the beta2-adrenergic receptor: role of the intrinsic cardiac adrenergic cell.

    PubMed

    Huang, Ming-He; Wang, Hui-Qun; Roeske, William R; Birnbaum, Yochai; Wu, Yewen; Yang, Ning-Ping; Lin, Yu; Ye, Yumei; McAdoo, David J; Hughes, Michael G; Lick, Scott D; Boor, Paul J; Lui, Charles Y; Uretsky, Barry F

    2007-07-01

    Stimulation of cardiac beta(2)-adrenergic receptor (beta(2)-AR) or delta-opioid receptor (DOR) exerts a similar degree of cardioprotection against myocardial ischemia in experimental models. We hypothesized that delta-opioid-initiated cardioprotection is mediated by the intrinsic cardiac adrenergic (ICA) cell via enhanced epinephrine release. Using immunohistochemical and in situ hybridization methods, we detected in situ tyrosine hydroxylase (TH) mRNA and TH immunoreactivity that was colocalized with DOR immunoreactivity in ICA cells in human and rat hearts. Western blot analysis detected DOR protein in ICA cells isolated from rat ventricular myocytes. The physiology of DOR expression was examined by determining changes of cytosolic Ca(2+) concentration ([Ca(2+)](i)) transients in isolated rat ICA cells using fluorescence spectrophotometry. Exposing the selective delta-opioid agonist D-[Pen(2,5)]enkephalin (DPDPE) to ICA cells increased [Ca(2+)](i) transients in a concentration-dependent manner. Such an effect was abolished by the Ca(2+) channel blocker nifedipine. HPLC-electrochemical detection demonstrated a 2.4-fold increase in epinephrine release from ICA cells following DPDPE application. The significance of the ICA cell and its epinephrine release in delta-opioid-initiated cardioprotection was demonstrated in the rat myocardial infarction model and ICA cell-ventricular myocyte coculture. DPDPE administered before coronary artery occlusion or simulated ischemia-reperfusion reduced left ventricular infarct size by 54 +/- 15% or myocyte death by 26 +/- 4%, respectively. beta(2)-AR blockade markedly attenuated delta-opioid-initiated infarct size-limiting effect and abolished delta-opioid-initiated myocyte survival protection in rat ICA cell-myocyte coculture. Furthermore, delta-opioid agonist exerted no myocyte survival protection in the absence of cocultured ICA cells during ischemia-reperfusion. We conclude that delta-opioid-initiated myocardial infarct size

  16. β-Adrenergic Regulation of Cardiac Progenitor Cell Death Versus Survival and Proliferation

    PubMed Central

    Khan, Mohsin; Mohsin, Sadia; Avitabile, Daniele; Siddiqi, Sailay; Nguyen, Jonathan; Wallach, Kathleen; Quijada, Pearl; McGregor, Michael; Gude, Natalie; Alvarez, Roberto; Tilley, Douglas G.; Koch, Walter J.; Sussman, Mark A.

    2013-01-01

    Rationale Short-term β-adrenergic stimulation promotes contractility in response to stress but is ultimately detrimental in the failing heart because of accrual of cardiomyocyte death. Endogenous cardiac progenitor cell (CPC) activation may partially offset cardiomyocyte losses, but consequences of long-term β-adrenergic drive on CPC survival and proliferation are unknown. Objective We sought to determine the relationship between β-adrenergic activity and regulation of CPC function. Methods and Results Mouse and human CPCs express only β2 adrenergic receptor (β2-AR) in conjunction with stem cell marker c-kit. Activation of β2-AR signaling promotes proliferation associated with increased AKT, extracellular signal-regulated kinase 1/2, and endothelial NO synthase phosphorylation, upregulation of cyclin D1, and decreased levels of G protein–coupled receptor kinase 2. Conversely, silencing of β2-AR expression or treatment with β2-antagonist ICI 118, 551 impairs CPC proliferation and survival. β1-AR expression in CPC is induced by differentiation stimuli, sensitizing CPC to isoproterenol-induced cell death that is abrogated by metoprolol. Efficacy of β1-AR blockade by metoprolol to increase CPC survival and proliferation was confirmed in vivo by adoptive transfer of CPC into failing mouse myocardium. Conclusions β-adrenergic stimulation promotes expansion and survival of CPCs through β2-AR, but acquisition of β1-AR on commitment to the myocyte lineage results in loss of CPCs and early myocyte precursors. PMID:23243208

  17. Beta-adrenergic stimulation reverses the IKr–IKs dominant pattern during cardiac action potential

    PubMed Central

    Banyasz, Tamas; Jian, Zhong; Horvath, Balazs; Khabbaz, Shaden; Izu, Leighton T.; Chen-Izu, Ye

    2014-01-01

    β-adrenergic stimulation differentially modulates different K+ channels and thus fine-tunes cardiac action potential (AP) repolarization. However, it remains unclear how the proportion of IKs, IKr, and IK1 current in the same cell would be altered by β-adrenergic stimulation, which would change the relative contribution of individual K+ current to the total repolarization reserve. In this study we used an innovative AP-clamp Sequential Dissection technique to directly record the dynamic –IKs, IKr, IK1– currents during the AP in guinea pig ventricular myocytes under physiologically relevant conditions. Our data provide quantitative measures of the magnitude and time course of IKs, IKr, IK1 currents in the same cell under its own steady-state AP, in a physiological milieu, and with preserved Ca2+ homeostasis. We found that isoproterenol treatment significantly enhanced IKs, moderately increased IK1, but slightly decreased IKr in a dose-dependent manner. The dominance pattern of the K+ currents was IKr>IK1>IKs at the control condition, but reversed to IKradrenergic stimulation. We systematically determined the changes in the relative contribution of IKs, IKr, IK1 to cardiac repolarization during AP at different adrenergic states. In conclusion, the β-adrenergic stimulation fine-tunes the cardiac AP morphology by shifting the power of different K+ currents in a dose-dependent manner. This Knowledge is important for designing anti-arrhythmic drug strategies to treat the hearts exposed to various sympathetic tones. PMID:24535581

  18. Alpha 1-adrenergic blockade and sudden cardiac death.

    PubMed

    Vanoli, E; Hull, S S; Foreman, R D; Ferrari, A; Schwartz, P J

    1994-01-01

    The primary goal of the present study was to test whether selective pharmacologic blockade of alpha 1 receptors, and specifically of the subtype alpha 1a, could prevent ventricular fibrillation (VF) during acute myocardial ischemia. The development of new autonomic interventions is of clinical interest in view of the failure of traditional antiarrhythmic drugs to prevent sudden death. Experimental evidence indicates that alpha 1 receptors, and in particular the subtype alpha 1a, may be involved in the genesis of malignant arrhythmias during acute myocardial ischemia and reperfusion. Despite this evidence, questions have been raised about the actual antifibrillatory efficacy of alpha-adrenergic blockade in the acutely ischemic myocardium. The effects of prazosin and of abanoquil (UK 52,046), a highly selective alpha 1a receptor blocker, were tested and compared with propranolol in a conscious animal preparation for sudden death. Ten dogs with a 1-month-old anterior wall myocardial infarction were studied. These dogs had all developed, in control conditions, VF during a 2-minute occlusion of the circumflex coronary artery while exercising (n = 9) or lying on the table (n = 1). Afterwards, the dogs underwent additional tests with the following intravenously administered drugs: abanoquil (n = 10; 1 micrograms/kg), prazosin (n = 9; 0.1 mg/kg), and propranolol (n = 10; 1 mg/kg). Internal control analysis was used. All dogs tested had recurrence of VF with both alpha-adrenergic blockers. Propranolol significantly reduced heart rate during ischemia and prevented VF in 5 of 10 dogs tested (P < 0.05). When heart rate was kept constant by atrial pacing (n = 3), 2 of the 3 animals remained protected by propranolol. Just prior to onset of VF, heart rate was not significantly different in the control and in the abanoquil tests (237 +/- 45 and 253 +/- 34 beats/min, respectively), whereas it was higher (P < 0.05) with prazosin (288 +/- 40 beats/min). Alpha 1 and alpha 1a receptor

  19. PEG-coated gold nanoparticles attenuate β-adrenergic receptor-mediated cardiac hypertrophy

    PubMed Central

    Qiao, Yuhui; Zhu, Baoling; Tian, Aiju; Li, Zijian

    2017-01-01

    Gold nanoparticles (AuNPs) are widely used as a drug delivery vehicle, which can accumulate in the heart through blood circulation. Therefore, it is very important to understand the effect of AuNPs on the heart, especially under pathological conditions. In this study, we found that PEG-coated AuNPs attenuate β-adrenergic receptor (β-AR)-mediated acute cardiac hypertrophy and inflammation. However, both isoproterenol, a non-selective β-AR agonist, and AuNPs did not induce cardiac function change or cardiac fibrosis. AuNPs exerted an anti-cardiac hypertrophy effect by decreasing β1-AR expression and its downstream ERK1/2 hypertrophic pathway. Our results indicated that AuNPs might be safe and have the potential to be used as multi-functional materials (drug carrier systems and anti-cardiac hypertrophy agents). PMID:28740379

  20. Interleukin 1 and Tumor Necrosis Factor Inhibit Cardiac Myocyte β -adrenergic Responsiveness

    NASA Astrophysics Data System (ADS)

    Gulick, Tod; Chung, Mina K.; Pieper, Stephen J.; Lange, Louis G.; Schreiner, George F.

    1989-09-01

    Reversible congestive heart failure can accompany cardiac allograft rejection and inflammatory myocarditis, conditions associated with an immune cell infiltrate of the myocardium. To determine whether immune cell secretory products alter cardiac muscle metabolism without cytotoxicity, we cultured cardiac myocytes in the presence of culture supernatants from activated immune cells. We observed that these culture supernatants inhibit β -adrenergic agonist-mediated increases in cultured cardiac myocyte contractility and intracellular cAMP accumulation. The myocyte contractile response to increased extracellular Ca2+ concentration is unaltered by prior exposure to these culture supernatants, as is the increase in myocyte intracellular cAMP concentration in response to stimulation with forskolin, a direct adenyl cyclase activator. Inhibition occurs in the absence of alteration in β -adrenergic receptor density or ligand binding affinity. Suppressive activity is attributable to the macrophage-derived cytokines interleukin 1 and tumor necrosis factor. Thus, these observations describe a role for defined cytokines in regulating the hormonal responsiveness and function of contractile cells. The effects of interleukin 1 and tumor necrosis factor on intracellular cAMP accumulation may be a model for immune modulation of other cellular functions dependent upon cyclic nucleotide metabolism. The uncoupling of agonist-occupied receptors from adenyl cyclase suggests that β -receptor or guanine nucleotide binding protein function is altered by the direct or indirect action of cytokines on cardiac muscle cells.

  1. The alpha1-adrenergic receptors in cardiac hypertrophy: signaling mechanisms and functional implications.

    PubMed

    Cotecchia, Susanna; Del Vescovo, Cosmo Damiano; Colella, Matilde; Caso, Stefania; Diviani, Dario

    2015-10-01

    Cardiac hypertrophy is a complex remodeling process of the heart induced by physiological or pathological stimuli resulting in increased cardiomyocyte size and myocardial mass. Whereas cardiac hypertrophy can be an adaptive mechanism to stressful conditions of the heart, prolonged hypertrophy can lead to heart failure which represents the primary cause of human morbidity and mortality. Among G protein-coupled receptors, the α1-adrenergic receptors (α1-ARs) play an important role in the development of cardiac hypertrophy as demonstrated by numerous studies in the past decades, both in primary cardiomyocyte cultures and genetically modified mice. The results of these studies have provided evidence of a large variety of α1-AR-induced signaling events contributing to the defining molecular and cellular features of cardiac hypertrophy. Recently, novel signaling mechanisms have been identified and new hypotheses have emerged concerning the functional role of the α1-adrenergic receptors in the heart. This review will summarize the main signaling pathways activated by the α1-AR in the heart and their functional implications in cardiac hypertrophy. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Gender-related differences in β-adrenergic receptor-mediated cardiac remodeling.

    PubMed

    Zhu, Baoling; Liu, Kai; Yang, Chengzhi; Qiao, Yuhui; Li, Zijian

    2016-12-01

    Cardiac remodeling is the pathological basis of various cardiovascular diseases. In this study, we found gender-related differences in β-adrenergic receptor (AR)-mediated pathological cardiac remodeling. Cardiac remodeling model was established by subcutaneous injection of isoprenaline (ISO) for 14 days. Heart rate (HR), mean arterial pressure (MAP), and echocardiography were obtained on 7th and 14th days during ISO administration. Myocardial cross-sectional area and the ratio of heart mass to tibia length (HM/TL) were detected to assess cardiac hypertrophy. Picro-Sirius red staining (picric acid + Sirius red F3B) was used to evaluate cardiac fibrosis. Myocardial capillary density was assessed by immunohistochemistry for von Willebrand factor. Further, real-time PCR was used to measure the expression of β1-AR and β2-AR. Results showed that ISO induced cardiac remodeling, the extent of which was different between female and male mice. The extent of increase in cardiac wall thickness, myocardial cross-sectional area, and collagen deposition in females was less than that in males. However, no gender-related difference was observed in HR, MAP, cardiac function, and myocardial capillary density. The distinctive decrease of β2-AR expression, rather than a decrease of β1-AR expression, seemed to result in gender-related differences in cardiac remodeling.

  3. Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

    PubMed Central

    O’Connell, Timothy D.; Jensen, Brian C.; Baker, Anthony J.

    2014-01-01

    Adrenergic receptors (AR) are G-protein-coupled receptors (GPCRs) that have a crucial role in cardiac physiology in health and disease. Alpha1-ARs signal through Gαq, and signaling through Gq, for example, by endothelin and angiotensin receptors, is thought to be detrimental to the heart. In contrast, cardiac alpha1-ARs mediate important protective and adaptive functions in the heart, although alpha1-ARs are only a minor fraction of total cardiac ARs. Cardiac alpha1-ARs activate pleiotropic downstream signaling to prevent pathologic remodeling in heart failure. Mechanisms defined in animal and cell models include activation of adaptive hypertrophy, prevention of cardiac myocyte death, augmentation of contractility, and induction of ischemic preconditioning. Surprisingly, at the molecular level, alpha1-ARs localize to and signal at the nucleus in cardiac myocytes, and, unlike most GPCRs, activate “inside-out” signaling to cause cardioprotection. Contrary to past opinion, human cardiac alpha1-AR expression is similar to that in the mouse, where alpha1-AR effects are seen most convincingly in knockout models. Human clinical studies show that alpha1-blockade worsens heart failure in hypertension and does not improve outcomes in heart failure, implying a cardioprotective role for human alpha1-ARs. In summary, these findings identify novel functional and mechanistic aspects of cardiac alpha1-AR function and suggest that activation of cardiac alpha1-AR might be a viable therapeutic strategy in heart failure. PMID:24368739

  4. Beta2-adrenergic signaling affects the phenotype of human cardiac progenitor cells through EMT modulation.

    PubMed

    Pagano, Francesca; Angelini, Francesco; Siciliano, Camilla; Tasciotti, Julia; Mangino, Giorgio; De Falco, Elena; Carnevale, Roberto; Sciarretta, Sebastiano; Frati, Giacomo; Chimenti, Isotta

    2017-01-15

    Human cardiac progenitor cells (CPCs) offer great promises to cardiac cell therapy for heart failure. Many in vivo studies have shown their therapeutic benefits, paving the way for clinical translation. The 3D model of cardiospheres (CSs) represents a unique niche-like in vitro microenvironment, which includes CPCs and supporting cells. CSs have been shown to form through a process mediated by epithelial-to-mesenchymal transition (EMT). β2-Adrenergic signaling significantly affects stem/progenitor cells activation and mobilization in multiple tissues, and crosstalk between β2-adrenergic signaling and EMT processes has been reported. In the present study, we aimed at investigating the biological response of CSs to β2-adrenergic stimuli, focusing on EMT modulation in the 3D culture system of CSs. We treated human CSs and CS-derived cells (CDCs) with the β2-blocker butoxamine (BUT), using either untreated or β2 agonist (clenbuterol) treated CDCs as control. BUT-treated CS-forming cells displayed increased migration capacity and a significant increase in their CS-forming ability, consistently associated with increased expression of EMT-related genes, such as Snai1. Moreover, long-term BUT-treated CDCs contained a lower percentage of CD90+ cells, and this feature has been previously correlated with higher cardiogenic and therapeutic potential of the CDCs population. In addition, long-term BUT-treated CDCs had an increased ratio of collagen-III/collagen-I gene expression levels, and showed decreased release of inflammatory cytokines, overall supporting a less fibrosis-prone phenotype. In conclusion, β2 adrenergic receptor block positively affected the stemness vs commitment balance within CSs through the modulation of type1-EMT (so called "developmental"). These results further highlight type-1 EMT to be a key process affecting the features of resident cardiac progenitor cells, and mediating their response to the microenvironment.

  5. Beta adrenergic receptor blockade of feline myocardium. Cardiac mechanics, energetics, and beta adrenoceptor regulation.

    PubMed Central

    Cooper, G; Kent, R L; McGonigle, P; Watanabe, A M

    1986-01-01

    Myocardial oxygen consumption is regulated by interrelated mechanical and inotropic conditions; there is a parallel increase in the aerobic metabolism and inotropic state during beta-adrenergic stimulation under fixed mechanical conditions. In contrast, there is some evidence that beta-blockade may reduce oxygen consumption through effects independent of its influence on mechanical conditions and contractile state, and that prolonged beta-blockade may sensitize the myocardium to beta-adrenergic stimulation. To clarify these two points, the present study examined the relationship of myocardial energetics to mechanics and inotropism during acute beta-blockade and after the withdrawal of long-term beta-blockade, whereupon the basis for any effect observed was sought by characterizing the number, affinity, and affinity states of the beta-receptors as well as the coupling of activated beta-receptors to cyclic AMP generation. Studies of right ventricular papillary muscles from control and chronically beta-blocked cats demonstrated contractile and energetic properties as well as dose-response behavior and inotropic specificity suggestive of an increase in myocardial sensitivity to beta-adrenoceptor stimulation in the latter group. Assays of cardiac beta-adrenoceptors from further groups of control and pretreated cats, both in cardiac tissue and in isolated cardiac muscle cells, failed to define a difference between the two groups either in terms of receptor number and affinity or in terms of the proportion of receptors in the high-affinity state. However, coupling of the activated beta-adrenoceptors to cyclic AMP generation was enhanced in cardiac muscle cells from chronically beta-blocked cats. These data demonstrate that beta-adrenoceptor blockade (a) produces parallel effects on inotropic state and oxygen consumption without an independent effect on either and (b) increases myocardial sensitivity to beta-adrenergic stimulation after beta-blockade withdrawal, not by "up

  6. [Interrelation between cardiac pump function disturbances and cardiac contractility after beta-adrenergic hyperstimulation of the heart in rats].

    PubMed

    Kuz'menko, M O; Pavliuchenko, V B; Tumanovs'ka, L V; Dosenko, V Ie; Moĭbenko, O O

    2011-01-01

    The complex of structural and functional changes of myocardium was investigated in experiments with rats with chronic beta-adrenergic activation for 1 month. We observed substantial attenuation of myocardial pump function, particularly reduction of stroke volume by 38.50% (P < 0.01), cardiac output by 42.38% (P < 0.01), and ejection fraction by 35.61% (P < 0.01). Furthermore, 2-fold increase of end-diastolic left ventricular pressure (P < 0.01) and rise of active relaxation constant Tau by 12.91% (P < 0.05) were observed. This indicates on an impaired diastolic function of the heart that is associated with accumulation of connective tissue elements in myocardium and increase of its end-diastolic stiffness that finally leads to cardiac pump function disturbances. Surprisingly, myocardial contractility was considerably augmented not only after the treatment with beta-adrenergic agonist but also on the 26th day after drug cessation. This phenomenon is associated with elevation of dP/dt(max) by 49.9% (P < 0.01), 2.5-fold increase of end-systolic elastance (P < 0.01) as well as maximal myocardial elastance by 42.53% (P < 0.05). It can be explained by compensatory influence of increased contractility that nevertheless failed to maintain adequate cardiac pump function and furthermore it may result in depletion of cardiac energy resource.

  7. High‐fat diet induces protein kinase A and G‐protein receptor kinase phosphorylation of β2‐adrenergic receptor and impairs cardiac adrenergic reserve in animal hearts

    PubMed Central

    Hu, Yuting; Wang, Qingtong; Liu, Yongming; Li, Ning; Xu, Bing; Kim, Sungjin; Chiamvimonvat, Nipavan

    2017-01-01

    Key points Patients with diabetes show a blunted cardiac inotropic response to β‐adrenergic stimulation despite normal cardiac contractile reserve.Acute insulin stimulation impairs β‐adrenergically induced contractile function in isolated cardiomyocytes and Langendorff‐perfused hearts.In this study, we aimed to examine the potential effects of hyperinsulinaemia associated with high‐fat diet (HFD) feeding on the cardiac β2‐adrenergic receptor signalling and the impacts on cardiac contractile function.We showed that 8 weeks of HFD feeding leads to reductions in cardiac functional reserve in response to β‐adrenergic stimulation without significant alteration of cardiac structure and function, which is associated with significant changes in β2‐adrenergic receptor phosphorylation at protein kinase A and G‐protein receptor kinase sites in the myocardium.The results suggest that clinical intervention might be applied to subjects in early diabetes without cardiac symptoms to prevent further cardiac complications. Abstract Patients with diabetes display reduced exercise capability and impaired cardiac contractile reserve in response to adrenergic stimulation. We have recently uncovered an insulin receptor and adrenergic receptor signal network in the heart. The aim of this study was to understand the impacts of high‐fat diet (HFD) on the insulin–adrenergic receptor signal network in hearts. After 8 weeks of HFD feeding, mice exhibited diabetes, with elevated insulin and glucose concentrations associated with body weight gain. Mice fed an HFD had normal cardiac structure and function. However, the HFD‐fed mice displayed a significant elevation of phosphorylation of the β2‐adrenergic receptor (β2AR) at both the protein kinase A site serine 261/262 and the G‐protein‐coupled receptor kinase site serine 355/356 and impaired adrenergic reserve when compared with mice fed on normal chow. Isolated myocytes from HFD‐fed mice also displayed a

  8. ß-adrenoceptor blockers increase cardiac sympathetic innervation by inhibiting autoreceptor suppression of axon growth.

    PubMed

    Clarke, Gwenaëlle L; Bhattacherjee, Aritra; Tague, Sarah E; Hasan, Wohaib; Smith, Peter G

    2010-09-15

    β-Adrenoceptor antagonists are used widely to reduce cardiovascular sympathetic tone, but withdrawal is accompanied by sympathetic hyperactivity. Receptor supersensitivity accounts for some but not all aspects of this withdrawal syndrome. Therefore, we investigated effects of β-blockers on sympathetic innervation. Rats received infusions of adrenergic receptor blockers or saline for 1 week. The nonselective β-blocker propranolol and the β(1)-antagonist metoprolol both increased myocardial sympathetic axon density. At 2 d after propranolol discontinuation, β-receptor sensitivity and responsiveness to isoproterenol were similar to controls. However, tyramine-induced mobilization of norepinephrine stores produced elevated ventricular contractility consistent with enhanced sympathetic neuroeffector properties. In addition, rats undergoing discontinuation showed exaggerated increases in mean arterial pressure in response to air puff or noise startle. In sympathetic neuronal cell cultures, both propranolol and metoprolol increased axon outgrowth but the β(2)-blocker ICI 118551 did not. Norepinephrine synthesis suppression by α-methyl-p-tyrosine also increased sprouting and concurrent dobutamine administration reduced it, confirming that locally synthesized norepinephrine inhibits outgrowth via β(1)-adrenoceptors. Immunohistochemistry revealed β(1)-adrenoceptor protein on sympathetic axon terminations. In rats with coronary artery ligation, propranolol reversed heart failure-induced ventricular myocardial sympathetic axon depletion, but did not affect infarct-associated sympathetic hyperinnervation. We conclude that sympathetic neurons possess β(1)-autoreceptors that negatively regulate axon outgrowth. Chronic β-adrenoceptor blockade disrupts this feedback system, leading to ventricular sympathetic axon proliferation and increased neuroeffector gain, which are likely to contribute to β-blocker withdrawal syndrome.

  9. Identification of the Cardiac Beta-Adrenergic Receptor Protein: Solubilization and Purification by Affinity Chromatography

    PubMed Central

    Lefkowitz, Robert J.; Haber, Edgar; O'Hara, Donald

    1972-01-01

    A protein that binds catecholamines with a specificity parallel to that of their in vivo effects on cardiac contractility (isoproterenol > epinephrine or norepinephrine > dopamine > dihydroxyphenylalanine) was solubilized from a microsomal fraction of canine ventricular myocardium. The binding protein was purified 500 to 800-fold by solubilization and subsequent affinity chromatography with conjugates of norepinephrine linked to agarose beads. Purified β-adrenergic binding protein exists in two forms, corresponding to molecular weights of 40,000 and 160,000. The purified material has a single association constant, 2.3 × 105 liters/mol (as compared to two association constants, 107 and 106 liters/mol, for the binding protein in particulate form) but retains the identical binding specificity for β-adrenergic drugs and antagonists. Images PMID:4507606

  10. Cardiac beta-adrenergic receptors and coronary hemodynamics in the conscious dog during hypoxic hypoxia.

    NASA Technical Reports Server (NTRS)

    Erickson, H. H.; Stone, H. L.

    1972-01-01

    The mechanisms by which acute hypoxia (10% and 5% oxygen) mediates changes in coronary blood flow and cardiac function were investigated in the conscious dog. When the dogs breathed hypoxic gas mixtures through a tracheostomy, both arterial and coronary sinus oxygen tensions were significantly decreased. With 5% oxygen, there were significant increases in heart rate (25%), maximum left ventricular dP/dt (39%), left circumflex coronary artery blood flow (163%), and left ventricular oxygen consumption (52%), which were attenuated by beta-adrenergic blockage with propranolol. When electrical pacing was used to keep the ventricular rate constant during hypoxia, there was no significant difference in coronary blood flow before and after beta blockade. Beta-adrenergic receptor activity in the myocardium participates in the integrated response to hypoxia although it may not cause active vasodilation of the coronary vessels.

  11. Cardiac beta-adrenergic receptors and coronary hemodynamics in the conscious dog during hypoxic hypoxia.

    NASA Technical Reports Server (NTRS)

    Erickson, H. H.; Stone, H. L.

    1972-01-01

    The mechanisms by which acute hypoxia (10% and 5% oxygen) mediates changes in coronary blood flow and cardiac function were investigated in the conscious dog. When the dogs breathed hypoxic gas mixtures through a tracheostomy, both arterial and coronary sinus oxygen tensions were significantly decreased. With 5% oxygen, there were significant increases in heart rate (25%), maximum left ventricular dP/dt (39%), left circumflex coronary artery blood flow (163%), and left ventricular oxygen consumption (52%), which were attenuated by beta-adrenergic blockage with propranolol. When electrical pacing was used to keep the ventricular rate constant during hypoxia, there was no significant difference in coronary blood flow before and after beta blockade. Beta-adrenergic receptor activity in the myocardium participates in the integrated response to hypoxia although it may not cause active vasodilation of the coronary vessels.

  12. Restoration of β -Adrenergic Signaling in Failing Cardiac Ventricular Myocytes via Adenoviral-Mediated Gene Transfer

    NASA Astrophysics Data System (ADS)

    Akhter, Shahab A.; Skaer, Christine A.; Kypson, Alan P.; McDonald, Patricia H.; Peppel, Karsten C.; Glower, Donald D.; Lefkowitz, Robert J.; Koch, Walter J.

    1997-10-01

    Cardiovascular gene therapy is a novel approach to the treatment of diseases such as congestive heart failure (CHF). Gene transfer to the heart would allow for the replacement of defective or missing cellular proteins that may improve cardiac performance. Our laboratory has been focusing on the feasibility of restoring β -adrenergic signaling deficiencies that are a characteristic of chronic CHF. We have now studied isolated ventricular myocytes from rabbits that have been chronically paced to produce hemodynamic failure. We document molecular β -adrenergic signaling defects including down-regulation of myocardial β -adrenergic receptors (β -ARs), functional β -AR uncoupling, and an upregulation of the β -AR kinase (β ARK1). Adenoviral-mediated gene transfer of the human β 2-AR or an inhibitor of β ARK1 to these failing myocytes led to the restoration of β -AR signaling. These results demonstrate that defects present in this critical myocardial signaling pathway can be corrected in vitro using genetic modification and raise the possibility of novel inotropic therapies for CHF including the inhibition of β ARK1 activity in the heart.

  13. Cardiac sympathetic nerve stimulation does not attenuate dynamic vagal control of heart rate via alpha-adrenergic mechanism.

    PubMed

    Miyamoto, Tadayoshi; Kawada, Toru; Yanagiya, Yusuke; Inagaki, Masashi; Takaki, Hiroshi; Sugimachi, Masaru; Sunagawa, Kenji

    2004-08-01

    Complex sympathovagal interactions govern heart rate (HR). Activation of the postjunctional beta-adrenergic receptors on the sinus nodal cells augments the HR response to vagal stimulation, whereas exogenous activation of the presynaptic alpha-adrenergic receptors on the vagal nerve terminals attenuates vagal control of HR. Whether the alpha-adrenergic mechanism associated with cardiac postganglionic sympathetic nerve activation plays a significant role in modulation of the dynamic vagal control of HR remains unknown. The right vagal nerve was stimulated in seven anesthetized rabbits that had undergone sinoaortic denervation and vagotomy according to a binary white-noise signal (0-10 Hz) for 10 min; subsequently, the transfer function from vagal stimulation to HR was estimated. The effects of beta-adrenergic blockade with propranolol (1 mg/kg i.v.) and the combined effects of beta-adrenergic blockade and tonic cardiac sympathetic nerve stimulation at 5 Hz were examined. The transfer function from vagal stimulation to HR approximated a first-order, low-pass filter with pure delay. beta-Adrenergic blockade decreased the dynamic gain from 6.0 +/- 0.4 to 3.7 +/- 0.6 beats x min(-1) x Hz(-1) (P < 0.01) with no alteration of the corner frequency or pure delay. Under beta-adrenergic blockade conditions, tonic sympathetic stimulation did not further change the dynamic gain (3.8 +/- 0.5 beats x min(-1) x Hz(-1)). In conclusion, cardiac postganglionic sympathetic nerve stimulation did not affect the dynamic HR response to vagal stimulation via the alpha-adrenergic mechanism.

  14. Human cardiac beta1- or beta2-adrenergic receptor stimulation and the negative chronotropic effect of low-dose pirenzepine.

    PubMed

    Jakubetz, J; Schmuck, S; Wochatz, G; Ruhland, B; Poller, U; Radke, J; Brodde, O E

    2000-05-01

    The M1-muscarinic receptor antagonist pirenzepine in low doses (<1 mg intravenously) decreases heart rate. We investigated whether these effects of pirenzepine differ in volunteers with activated cardiac beta1-adrenergic receptors versus activated cardiac beta2-adrenergic receptors. In 17 male volunteers (25 +/- 1 years) we studied effects of pirenzepine infusion (0.5 mg intravenous bolus followed by continuous infusion of 0.15 microg/kg/min) on heart rate and heart rate-corrected duration of electromechanical systole (QS2c, as a measure of inotropism) that had been stimulated by activation of cardiac beta1-adrenergic receptors (bicycle exercise in the supine position for 60 minutes at 25 W) or cardiac beta2-adrenergic receptors (continuous intravenous infusion of 100 ng/kg/min terbutaline). Bicycle exercise and terbutaline infusion significantly increased heart rate and shortened QS2c. When pirenzepine was infused 20 minutes after the beginning of the exercise or terbutaline infusion, heart rate decreased in both settings by approximately the same extent (approximately -10 to -14 beats/min), although exercise and terbutaline infusion continued; however, QS2c was not affected. Pirenzepine (0.05 to 1 mg intravenous bolus)-induced decrease in heart rate was abolished after 6 days of transdermal scopolamine treatment of volunteers. Low-dose pirenzepine decreased heart rate by muscarinic receptor stimulation, because this was blocked by scopolamine. Moreover, low-dose pirenzepine did not differentiate between cardiac beta1- or beta2-adrenergic receptor stimulation; however, low-dose pirenzepine did not affect cardiac contractility as measured by QS2c. Low-dose pirenzepine therefore exerted a unique pattern of action in the human heart: it decreased heart rate (basal and beta1- and/or beta2-adrenergic receptor-stimulated) without affecting contractility.

  15. Automic innervation of dog coronary arteries.

    PubMed

    Denn, M J; Stone, H L

    1976-07-01

    The autonomic innervation of canine coronary arteries has been examined using the Falck and Owman technique for demonstrating catecholamines and a modification of the Koelle technique for the demonstration of cholinesterase. The experimental protocol included an examination of the neural innervation of the major coronary arteries: LCC, LAD, and RCA. A consistent, relatively dense adrenergic innervation was noted. A gradient in the degree of cholinergic innervation was: LAD less than RCA less than LCC. Light microscopic examination of the hearts of dogs subjected to either cervical vagotomy or total extrinsic cardiac denervation was performed. Additional surgical procedures included removal of the left stellate ganglion and a preferential stripping of the LCC. These studies demonstrated the intrinsic nature of parasympathetic coronary innervation. Following all surgical procedure no variations in density of cholinergic innervation were noted, indicating that these fibers are probably postganglionic parasympathetic fibers arising from intrinsic ganglia within the ventricles. These ganglia may be located at the base of the great vessels and send their fibers to the coronary vessels via the septal artery.

  16. Modeling beta-adrenergic control of cardiac myocyte contractility in silico

    NASA Technical Reports Server (NTRS)

    Saucerman, Jeffrey J.; Brunton, Laurence L.; Michailova, Anushka P.; McCulloch, Andrew D.; McCullough, A. D. (Principal Investigator)

    2003-01-01

    The beta-adrenergic signaling pathway regulates cardiac myocyte contractility through a combination of feedforward and feedback mechanisms. We used systems analysis to investigate how the components and topology of this signaling network permit neurohormonal control of excitation-contraction coupling in the rat ventricular myocyte. A kinetic model integrating beta-adrenergic signaling with excitation-contraction coupling was formulated, and each subsystem was validated with independent biochemical and physiological measurements. Model analysis was used to investigate quantitatively the effects of specific molecular perturbations. 3-Fold overexpression of adenylyl cyclase in the model allowed an 85% higher rate of cyclic AMP synthesis than an equivalent overexpression of beta 1-adrenergic receptor, and manipulating the affinity of Gs alpha for adenylyl cyclase was a more potent regulator of cyclic AMP production. The model predicted that less than 40% of adenylyl cyclase molecules may be stimulated under maximal receptor activation, and an experimental protocol is suggested for validating this prediction. The model also predicted that the endogenous heat-stable protein kinase inhibitor may enhance basal cyclic AMP buffering by 68% and increasing the apparent Hill coefficient of protein kinase A activation from 1.0 to 2.0. Finally, phosphorylation of the L-type calcium channel and phospholamban were found sufficient to predict the dominant changes in myocyte contractility, including a 2.6x increase in systolic calcium (inotropy) and a 28% decrease in calcium half-relaxation time (lusitropy). By performing systems analysis, the consequences of molecular perturbations in the beta-adrenergic signaling network may be understood within the context of integrative cellular physiology.

  17. Modeling beta-adrenergic control of cardiac myocyte contractility in silico

    NASA Technical Reports Server (NTRS)

    Saucerman, Jeffrey J.; Brunton, Laurence L.; Michailova, Anushka P.; McCulloch, Andrew D.; McCullough, A. D. (Principal Investigator)

    2003-01-01

    The beta-adrenergic signaling pathway regulates cardiac myocyte contractility through a combination of feedforward and feedback mechanisms. We used systems analysis to investigate how the components and topology of this signaling network permit neurohormonal control of excitation-contraction coupling in the rat ventricular myocyte. A kinetic model integrating beta-adrenergic signaling with excitation-contraction coupling was formulated, and each subsystem was validated with independent biochemical and physiological measurements. Model analysis was used to investigate quantitatively the effects of specific molecular perturbations. 3-Fold overexpression of adenylyl cyclase in the model allowed an 85% higher rate of cyclic AMP synthesis than an equivalent overexpression of beta 1-adrenergic receptor, and manipulating the affinity of Gs alpha for adenylyl cyclase was a more potent regulator of cyclic AMP production. The model predicted that less than 40% of adenylyl cyclase molecules may be stimulated under maximal receptor activation, and an experimental protocol is suggested for validating this prediction. The model also predicted that the endogenous heat-stable protein kinase inhibitor may enhance basal cyclic AMP buffering by 68% and increasing the apparent Hill coefficient of protein kinase A activation from 1.0 to 2.0. Finally, phosphorylation of the L-type calcium channel and phospholamban were found sufficient to predict the dominant changes in myocyte contractility, including a 2.6x increase in systolic calcium (inotropy) and a 28% decrease in calcium half-relaxation time (lusitropy). By performing systems analysis, the consequences of molecular perturbations in the beta-adrenergic signaling network may be understood within the context of integrative cellular physiology.

  18. Differences in affinity of cardiac beta-adrenergic receptors for (3H)dihydroalprenolol

    SciTech Connect

    Muntz, K.H.; Calianos, T.A.; Vandermolen, D.T.; Willerson, J.T.; Buja, L.M.

    1986-03-01

    We performed quantitative light microscopic autoradiography of (3H)dihydroalprenolol (DHA) binding to frozen sections of canine myocardium to test the hypothesis that there are differences in the density or affinity of beta-adrenergic receptors on various tissue compartments. In one study, with concentrations of (3H)DHA from 0.34 to 5.1 nM, specific binding to cardiac myocytes was saturable, whereas nonspecific binding was linear with ligand concentration. Arterioles had more specific grain counts than muscle cells (P less than 0.0001), and Scatchard analysis showed that the arterioles had a much higher affinity for (3H)DHA than myocytes. In a second study with lower concentrations of (3H)DHA (0.19-1.98 nM), binding to the arterioles saturated, whereas binding to the cardiac myocytes did not. Specific binding to arterioles was significantly higher (P less than 0.0001) than binding to myocytes at all concentrations of (3H)DHA. The dissociation constants for the subendocardial and subepicardial myocytes were 1.57 and 1.71 nM, respectively, while the dissociation constant for the arterioles was 0.26 nM. The maximum number of binding sites was 911 grains/0.9 X 10(-2) mm2 for subepicardial myocytes, 936 for subendocardial myocytes, and 986 for arterioles. The large nerves accompanying an epicardial artery also demonstrated specific (3H)DHA binding. Thus this study has demonstrated major differences in the distribution and affinity of beta-adrenergic receptors, which may help to explain various physiological responses to beta-adrenergic stimulation.

  19. Some membrane properties of the circular muscle of chicken rectum and its non-adrenergic non-cholinergic innervation.

    PubMed

    Komori, S; Ohashi, H

    1988-07-01

    1. Membrane properties and innervation of the circular muscle of chicken rectum were investigated by recording intracellularly electrotonic potentials evoked by passing current, and excitatory and inhibitory junction potentials (EJPs and IJPs) evoked by electrical stimulation of the extrinsic or intrinsic nerves. 2. The membrane potential was -55 +/- 0.6 mV (n = 95). Action potentials of long duration (1.2-4.0 s) discharged spontaneously, or were generated when the membrane depolarization due to either electrotonic potential or EJP reached the threshold. The drug D600 blocked the generation of action potentials. 3. Electrotonic potentials spread fairly well in the longitudinal direction of the muscle fibres but not in the transverse direction. The longitudinal space constant was 1.7 +/- 0.2 mm (n = 10) and the membrane time constant was 205 +/- 21 ms (n = 10). 4. Field stimulation of intramural nerves evoked an EJP followed by a long-lasting IJP (3-12 s in total duration) in most cells, and an EJP alone or an IJP alone in a small number of cells. The EJP and IJP were preserved in the simultaneous presence of atropine and guanethidine, but abolished with tetrodotoxin. 5. Stimulation of Remak's nerve trunk or its branches produced EJPs which were atropine resistant and guanethidine resistant just like the EJP elicited by intramural nerve stimulation. The extrinsic nerve stimulation was ineffective in eliciting IJPs. 6. The EJP amplitude declined in a linear manner as the distance from the stimulating site of intramural nerves was increased. The decline was much greater along the transverse axis than the longitudinal axis of circular muscle fibres. 7. The reversal potential for the EJP was estimated by extrapolation to be about - 15.3 +/- 0.3 mV (n = 7). 8. Apamin did not inhibit the IJP. During the hyperpolarization of a single IJP or summed IJPs, electrotonic potentials remained unchanged or slightly decreased in amplitude.

  20. North American ginseng (Panax quinquefolius) suppresses β-adrenergic-dependent signalling, hypertrophy, and cardiac dysfunction.

    PubMed

    Tang, Xilan; Gan, Xiaohong Tracey; Rajapurohitam, Venkatesh; Huang, Cathy Xiaoling; Xue, Jenny; Lui, Edmund M K; Karmazyn, Morris

    2016-12-01

    There is increasing evidence for a beneficial effect of ginseng on cardiac pathology. Here, we determined whether North American ginseng can modulate the deleterious effects of the β-adrenoceptor agonist isoproterenol on cardiac hypertrophy and function using in vitro and in vivo approaches. Isoproterenol was administered for 2 weeks at either 25 mg/kg per day or 50 mg/kg per day (ISO25 or ISO50) via a subcutaneously implanted osmotic mini-pump to either control rats or those receiving ginseng (0.9 g/L in the drinking water ad libitum). Isoproterenol produced time- and dose-dependent left ventricular dysfunction, although these effects were attenuated by ginseng. Improved cardiac functions were associated with reduced heart masses, as well as prevention in the upregulation of the hypertrophy-related fetal gene expression. Lung masses were similarly attenuated, suggesting reduced pulmonary congestion. In in vitro studies, ginseng (10 μg/mL) completely suppressed the hypertrophic response to 1 μmol/L isoproterenol in terms of myocyte surface area, as well as reduction in the upregulation of fetal gene expression. These effects were associated with attenuation in both protein kinase A and cAMP response element-binding protein phosphorylation. Ginseng attenuates adverse cardiac adrenergic responses and, therefore, may be an effective therapy to reduce hypertrophy and heart failure associated with excessive catecholamine production.

  1. Radiotracers for Cardiac Sympathetic Innervation: Transport Kinetics and Binding Affinities for the Human Norepinephrine Transporter

    PubMed Central

    Raffel, David M.; Chen, Wei; Jung, Yong-Woon; Jang, Keun Sam; Gu, Guie; Cozzi, Nicholas V.

    2013-01-01

    Introduction Most radiotracers for imaging of cardiac sympathetic innervation are substrates of the norepinephrine transporter (NET). The goal of this study was to characterize the NET transport kinetics and binding affinities of several sympathetic nerve radiotracers, including [11C]-(−)-meta-hydroxyephedrine, [11C]-(−)-epinephrine, and a series of [11C]-labeled phenethylguanidines under development in our laboratory. For comparison, the NET transport kinetics and binding affinities of some [3H]-labeled biogenic amines were also determined. Methods Transport kinetics studies were performed using rat C6 glioma cells stably transfected with the human norepinephrine transporter (C6-hNET cells). For each radiolabeled NET substrate, saturation transport assays with C6-hNET cells measured the Michaelis-Menten transport constants Km and Vmax for NET transport. Competitive inhibition binding assays with homogenized C6-hNET cells and [3H]mazindol provided estimates of binding affinities (KI) for NET. Results Km, Vmax and KI values were determined for each NET substrate with a high degree of reproducibility. Interestingly, C6-hNET transport rates for ‘tracer concentrations’ of substrate, given by the ratio Vmax/Km, were found to be highly correlated with neuronal transport rates measured previously in isolated rat hearts (r2 = 0.96). This suggests that the transport constants Km and Vmax measured using the C6-hNET cells accurately reflect in vivo transport kinetics. Conclusion The results of these studies show how structural changes in NET substrates influence NET binding and transport constants, providing valuable insights that can be used in the design of new tracers with more optimal kinetics for quantifying regional sympathetic nerve density. PMID:23306137

  2. IL-18 cleavage triggers cardiac inflammation and fibrosis upon β-adrenergic insult.

    PubMed

    Xiao, Han; Li, Hao; Wang, Jing-Jing; Zhang, Jian-Shu; Shen, Jing; An, Xiang-Bo; Zhang, Cong-Cong; Wu, Ji-Min; Song, Yao; Wang, Xin-Yu; Yu, Hai-Yi; Deng, Xiang-Ning; Li, Zi-Jian; Xu, Ming; Lu, Zhi-Zhen; Du, Jie; Gao, Wei; Zhang, Ai-Hua; Feng, Yue; Zhang, You-Yi

    2017-05-26

    Rapid over-activation of β-adrenergic receptor (β-AR) upon stress leads to cardiac inflammation, a prevailing factor that underlies heart injury. However, mechanisms by which acute β-AR stimulation induce cardiac inflammation still remain unknown. Here, we set out to identify the crucial role of inflammasome/interleukin (IL)-18 in initiating and maintaining cardiac inflammatory cascades upon β-AR insult. Male C57BL/6 mice were injected with a single dose of β-AR agonist, isoproterenol (ISO, 5 mg/kg body weight) or saline subcutaneously. Cytokine array profiling demonstrated that chemokines dominated the initial cytokines upregulation specifically within the heart upon β-AR insult, which promoted early macrophage infiltration. Further investigation revealed that the rapid inflammasome-dependent activation of IL-18, but not IL-1β, was the critical up-stream regulator for elevated chemokine expression in the myocardium upon ISO induced β1-AR-ROS signalling. Indeed, a positive correlation was observed between the serum levels of norepinephrine and IL-18 in patients with chest pain. Genetic deletion of IL-18 or the up-stream inflammasome component NLRP3 significantly attenuated ISO-induced chemokine expression and macrophage infiltration. In addition, IL-18 neutralizing antibodies selectively abated ISO-induced chemokines, proinflammatory cytokines and adhesion molecules but not growth factors. Moreover, blocking IL-18 early after ISO treatment effectively attenuated cardiac inflammation and fibrosis. Inflammasome-dependent activation of IL-18 within the myocardium upon acute β-AR over-activation triggers cytokine cascades, macrophage infiltration and pathological cardiac remodelling. Blocking IL-18 at the early stage of β-AR insult can successfully prevent inflammatory responses and cardiac injuries.

  3. MiRNA-1/133a Clusters Regulate Adrenergic Control of Cardiac Repolarization

    PubMed Central

    Wystub, Katharina; Bachmann, Angela; Wietelmann, Astrid; Sasse, Philipp; Fleischmann, Bernd K.; Braun, Thomas; Boettger, Thomas

    2014-01-01

    The electrical properties of the heart are primarily determined by the activity of ion channels and the activity of these molecules is permanently modulated and adjusted to the physiological needs by adrenergic signaling. miRNAs are known to control the expression of many proteins and to fulfill distinct functions in the mammalian heart, though the in vivo effects of miRNAs on the electrical activity of the heart are poorly characterized. The miRNAs miR-1 and miR-133a are the most abundant miRNAs of the heart and are expressed from two miR-1/133a genomic clusters. Genetic modulation of miR-1/133a cluster expression without concomitant severe disturbance of general cardiomyocyte physiology revealed that these miRNA clusters govern cardiac muscle repolarization. Reduction of miR-1/133a dosage induced a longQT phenotype in mice especially at low heart rates. Longer action potentials in cardiomyocytes are caused by modulation of the impact of β-adrenergic signaling on the activity of the depolarizing L-type calcium channel. Pharmacological intervention to attenuate β-adrenergic signaling or L-type calcium channel activity in vivo abrogated the longQT phenotype that is caused by modulation of miR-1/133a activity. Thus, we identify the miR-1/133a miRNA clusters to be important to prevent a longQT-phenotype in the mammalian heart. PMID:25415383

  4. Dependence of deoxycorticosterone/salt hypertension in the rat on the activity of adrenergic cardiac nerves.

    PubMed

    Bell, C; McLachlan, E M

    1979-08-01

    1. Chronic hypertension was induced in Wistar rats with intact kidneys by subcutaneous implantation of 50 mg of deoxycorticosterone acetate (DOCA) in wax and addition of sodium chloride (9 g/l) to the drinking water. 2. The development of DOCA/salt hypertension, as monitored by tail-cuff plethysmography, was prevented by: (a) destruction of the peripheral adrenergic nerves with neonatal administration of guanethidine (80 mg/kg subcutaneously for the first 14 days postnatally); (b) bilateral stellate ganglionectomy; (c) oral administration of the beta-adrenoreceptor antagonists propranolol or atenolol (1 mg day-1 kg-1) during the period of DOCA/salt treatment. 3. The dose of DOCA used was sufficient to inhibit the atrial Uptake2 pathway completely: this process appears to participate in termination of action of neurally released noradrenaline in the heart. 4. It is suggested that this model of DOCA/salt hypertension is due to adrenergic enhancement of cardiac output in the presence of an increased sodium load. The enhancement may be partly due to deficient myocardial inactivation of noradrenaline.

  5. Mechanism of the attenuated cardiac response to beta-adrenergic stimulation in chronic hypoxia.

    PubMed

    Maher, J T; Deniiston, J C; Wolfe, D L; Cymerman, A

    1978-05-01

    A blunting of the chronotropic and inotropic responses of the heart to beta-adrenergic stimulation occurs following chronic exposure to hypobaric hypoxia. To pursue the mechanism(s) involved, observations were made in six intact, conscious goats at sea level and in another six goats maintained in a decompression chamber at 445 Torr (approximately 4,300m) for 10 days (Pao2 = 43 Torr). No significant group differences in cardiac frequency and various indices of myocardial performance (peak dP/dt, time-to-peak dP/dt, Vmax) were demonstrable either before or after cholinergic blockade with intravenous atropine methyl bromide, 1 mg/kg. Following hemodynamic studies, thoracotomies were performed and full-thickness biopsies were obtained from the free wall of each of the cardiac chambers. Neither monoamine oxidase activity nor norepinephrine level of any region of the heart was altered by chronic hypoxia. However, a twofold increase (P less than 0.001) in catechol O-methyltransferase activity above sea-level values was found in both the atria and ventricles of the hypoxic animals. Thus, the attenuation in cardiac responsiveness to beta-adrenoceptor stimulation in chronic hypoxia appears unrelated to the level of vagal activity, but may be attributable to enhanced enzymatic inactivation of catecholamines.

  6. Purification and molecular characterization of the cardiac beta-adrenergic receptor

    SciTech Connect

    Robinson, D.A.; Venter, J.C.; Fraser, C.M.

    1986-05-01

    The porcine ventricle cardiac beta-adrenergic receptor (..beta..AR) is predominantly of the ..beta../sub 2/ subtype. Sucrose density gradient purified porcine ventricle membranes exhibit a high ..beta..AR density of 1 pmol per mg and a K/sub d/ for /sup 125/I-iodocyanopindolol of 180 pM. Digitonin solubilized receptor exhibits ligand binding characteristics identical to those of membrane bound receptor. Stability studies indicate that the solubilized cardiac ..beta..AR has a t/sub 1/2/ of 92 hours. Solubilized receptor is stabilized by occupation with antagonists. Isoelectric focusing indicates a pI = 5.0, in agreement with results obtained for both ..beta../sub 1/AR and ..beta../sub 2/AR isolated from other sources. The cardiac ..beta../sub 1/AR has been purified to homogeneity by affinity chromatography and size exclusion HPLC (2 TSK 2000, 1 TSK 3000). Autoradiograms of purified, radioiodinated receptor preparations subjected to SDS-PAGE revealed a single band with an apparent subunit molecular mass (M/sub r/) of 68 kDa. This subunit M/sub r/ was confirmed in membranes photoaffinity labeled with /sup 125/I-iodocyanopindolol diazirine. A single band was specifically labeled, as evidenced by blocking of photoincorporation by (-) and (+) propranolol with typical ..beta..AR stereoselectivity.

  7. Nuclear Compartmentalization of α1-Adrenergic Receptor Signaling in Adult Cardiac Myocytes

    PubMed Central

    Wu, Steven C.

    2015-01-01

    Abstract: Although convention dictates that G protein-coupled receptors localize to and signal at the plasma membrane, accumulating evidence suggests that G protein-coupled receptors localize to and signal at intracellular membranes, most notably the nucleus. In fact, there is now significant evidence indicating that endogenous alpha-1 adrenergic receptors (α1-ARs) localize to and signal at the nuclei in adult cardiac myocytes. Cumulatively, the data suggest that α1-ARs localize to the inner nuclear membrane, activate intranuclear signaling, and regulate physiologic function in adult cardiac myocytes. Although α1-ARs signal through Gαq, unlike other Gq-coupled receptors, α1-ARs mediate important cardioprotective functions including adaptive/physiologic hypertrophy, protection from cell death (survival signaling), positive inotropy, and preconditioning. Also unlike other Gq-coupled receptors, most, if not all, functional α1-ARs localize to the nuclei in adult cardiac myocytes, as opposed to the sarcolemma. Together, α1-AR nuclear localization and cardioprotection might suggest a novel model for compartmentalization of Gq-coupled receptor signaling in which nuclear Gq-coupled receptor signaling is cardioprotective. PMID:25264754

  8. Pressor response to intravenous tyramine is a marker of cardiac, but not vascular, adrenergic function

    NASA Technical Reports Server (NTRS)

    Meck, Janice V.; Martin, David S.; D'Aunno, Dominick S.; Waters, Wendy W.

    2003-01-01

    Intravenous injections of the indirect sympathetic amine, tyramine, are used as a test of peripheral adrenergic function. The authors measured the time course of increases in ejection fraction, heart rate, systolic and diastolic pressure, popliteal artery flow, and greater saphenous vein diameter before and after an injection of 4.0 mg/m(2) body surface area of tyramine in normal human subjects. The tyramine caused moderate, significant increases in systolic pressure and significant decreases in total peripheral resistance. The earliest changes were a 30% increase in ejection fraction and a 16% increase in systolic pressure, followed by a 60% increase in popliteal artery flow and a later 11% increase in greater saphenous vein diameter. There were no changes in diastolic pressure or heart rate. These results suggest that pressor responses during tyramine injections are primarily due to an inotropic response that increases cardiac output and pressure and causes a reflex decrease in vascular resistance. Thus, tyramine pressor tests are a measure of cardiac, but not vascular, sympathetic function.

  9. Pressor response to intravenous tyramine is a marker of cardiac, but not vascular, adrenergic function

    NASA Technical Reports Server (NTRS)

    Meck, Janice V.; Martin, David S.; D'Aunno, Dominick S.; Waters, Wendy W.

    2003-01-01

    Intravenous injections of the indirect sympathetic amine, tyramine, are used as a test of peripheral adrenergic function. The authors measured the time course of increases in ejection fraction, heart rate, systolic and diastolic pressure, popliteal artery flow, and greater saphenous vein diameter before and after an injection of 4.0 mg/m(2) body surface area of tyramine in normal human subjects. The tyramine caused moderate, significant increases in systolic pressure and significant decreases in total peripheral resistance. The earliest changes were a 30% increase in ejection fraction and a 16% increase in systolic pressure, followed by a 60% increase in popliteal artery flow and a later 11% increase in greater saphenous vein diameter. There were no changes in diastolic pressure or heart rate. These results suggest that pressor responses during tyramine injections are primarily due to an inotropic response that increases cardiac output and pressure and causes a reflex decrease in vascular resistance. Thus, tyramine pressor tests are a measure of cardiac, but not vascular, sympathetic function.

  10. Beta-adrenergic stimulation reverses the I Kr-I Ks dominant pattern during cardiac action potential.

    PubMed

    Banyasz, Tamas; Jian, Zhong; Horvath, Balazs; Khabbaz, Shaden; Izu, Leighton T; Chen-Izu, Ye

    2014-11-01

    β-Adrenergic stimulation differentially modulates different K(+) channels and thus fine-tunes cardiac action potential (AP) repolarization. However, it remains unclear how the proportion of I Ks, I Kr, and I K1 currents in the same cell would be altered by β-adrenergic stimulation, which would change the relative contribution of individual K(+) current to the total repolarization reserve. In this study, we used an innovative AP-clamp sequential dissection technique to directly record the dynamic I Ks, I Kr, and I K1 currents during the AP in guinea pig ventricular myocytes under physiologically relevant conditions. Our data provide quantitative measures of the magnitude and time course of I Ks, I Kr, and I K1 currents in the same cell under its own steady-state AP, in a physiological milieu, and with preserved Ca(2+) homeostasis. We found that isoproterenol treatment significantly enhanced I Ks, moderately increased I K1, but slightly decreased I Kr in a dose-dependent manner. The dominance pattern of the K(+) currents was I Kr > I K1 > I Ks at the control condition, but reversed to I Kr < I K1 < I Ks following β-adrenergic stimulation. We systematically determined the changes in the relative contribution of I Ks, I Kr, and I K1 to cardiac repolarization during AP at different adrenergic states. In conclusion, the β-adrenergic stimulation fine-tunes the cardiac AP morphology by shifting the power of different K(+) currents in a dose-dependent manner. This knowledge is important for designing antiarrhythmic drug strategies to treat hearts exposed to various sympathetic tones.

  11. Regional cardiac adrenergic function using I-123 meta-iodobenzylguanidine tomographic imaging after acute myocardial infarction

    SciTech Connect

    McGhie, A.I.; Corbett, J.R.; Akers, M.S.; Kulkarni, P.; Sills, M.N.; Kremers, M.; Buja, L.M.; Durant-Reville, M.; Parkey, R.W.; Willerson, J.T. )

    1991-02-01

    The effect of acute myocardial infarction (AMI) on regional cardiac adrenergic function was studied in 27 patients mean +/- standard deviation 10 +/- 4 days after AMI. Regional adrenergic function was evaluated noninvasively with I-123 meta-iodobenzylguanidine (MIBG) using a dedicated 3-detector tomograph. Four hours after its administration, there was reduced MIBG uptake in the region of infarction, 0.38 +/- 0.31 counts/pixel/mCi x 103 compared with 0.60 +/- 0.30 counts/pixel/mCi x 103 and 0.92 +/- 0.35 counts/pixel/mCi x 103 in the zones bordering and distant from the infarct area, respectively, p less than 0.001. In all patients, the area of reduced MIBG uptake after 4 hours was more extensive that the associated thallium-201 perfusion defect with defect scores of 52 +/- 22 and 23 +/- 18%, respectively, p less than 0.001. After anterior wall AMI, the 4-hour MIBG defect score was 70 +/- 13% and the degree of mismatch between myocardial perfusion and MIBG uptake was 30 +/- 9% compared with 39 +/- 17 and 21 +/- 17% after inferior AMI, p less than 0.001 and p = 0.016, respectively. The 4-hour MIBG defect score correlated inversely with the predischarge left ventricular ejection fraction, r = -0.73, p less than 0.001. Patients with ventricular arrhythmia of greater than or equal to 1 ventricular premature complexes per hour, paired ventricular premature complexes or ventricular tachycardia detected during the late hospital phase had higher 4-hour MIBG defect scores, 62.5 +/- 15.0%, than patients with no detectable complex ventricular ectopic activity and a ventricular premature complex frequency of less than 1 per hour, 44.6 +/- 23.4%, p = 0.036.

  12. Adrenergic responsiveness is reduced, while baseline cardiac function is preserved in old adult conscious monkeys

    NASA Technical Reports Server (NTRS)

    Sato, N.; Kiuchi, K.; Shen, Y. T.; Vatner, S. F.; Vatner, D. E.

    1995-01-01

    To examine the physiological deficit to adrenergic stimulation with aging, five younger adult (3 +/- 1 yr old) and nine older adult (17 +/- 1 yr old) healthy monkeys were studied after instrumentation with a left ventricular (LV) pressure gauge, aortic and left atrial catheters, and aortic flow probes to measure cardiac output directly. There were no significant changes in baseline hemodynamics in conscious older monkeys. For example, an index of contractility, the first derivative of LV pressure (LV dP/dt) was similar (3,191 +/- 240, young vs. 3,225 +/- 71 mmHg/s, old) as well as in isovolumic relaxation, tau (24.3 +/- 1.7 ms, young vs. 23.0 +/- 1.0 ms, old) was similar. However, inotropic, lusitropic, and chronotropic responses to isoproterenol (Iso; 0.1 micrograms/kg), norepinephrine (NE; 0.4 micrograms/kg), and forskolin (For; 75 nmol/kg) were significantly (P < 0.05) depressed in older monkeys. For example. Iso increased LV dP/dt by by 146 +/- 14% in younger monkeys and by only 70 +/- 5% in older monkeys. Iso also reduced tau more in younger monkeys (-28 +/- 7%) compared with older monkeys (-13 +/- 3%). Furthermore, peripheral vascular responsiveness to Iso, NE, For, and phenylephrine (PE; 5 micrograms/kg) was significantly (P < 0.05) reduced in older monkeys. For example, phenylephrine (5 micrograms/kg) increased total peripheral resistence by 69 +/- 4% in younger monkeys and by only 45 +/- 3% in older monkeys. Thus in older monkeys without associated cardiovascular disease, baseline hemodynamics are preserved, but adrenergic receptor responsiveness is reduced systemically, not just in the heart.

  13. Adrenergic responsiveness is reduced, while baseline cardiac function is preserved in old adult conscious monkeys

    NASA Technical Reports Server (NTRS)

    Sato, N.; Kiuchi, K.; Shen, Y. T.; Vatner, S. F.; Vatner, D. E.

    1995-01-01

    To examine the physiological deficit to adrenergic stimulation with aging, five younger adult (3 +/- 1 yr old) and nine older adult (17 +/- 1 yr old) healthy monkeys were studied after instrumentation with a left ventricular (LV) pressure gauge, aortic and left atrial catheters, and aortic flow probes to measure cardiac output directly. There were no significant changes in baseline hemodynamics in conscious older monkeys. For example, an index of contractility, the first derivative of LV pressure (LV dP/dt) was similar (3,191 +/- 240, young vs. 3,225 +/- 71 mmHg/s, old) as well as in isovolumic relaxation, tau (24.3 +/- 1.7 ms, young vs. 23.0 +/- 1.0 ms, old) was similar. However, inotropic, lusitropic, and chronotropic responses to isoproterenol (Iso; 0.1 micrograms/kg), norepinephrine (NE; 0.4 micrograms/kg), and forskolin (For; 75 nmol/kg) were significantly (P < 0.05) depressed in older monkeys. For example. Iso increased LV dP/dt by by 146 +/- 14% in younger monkeys and by only 70 +/- 5% in older monkeys. Iso also reduced tau more in younger monkeys (-28 +/- 7%) compared with older monkeys (-13 +/- 3%). Furthermore, peripheral vascular responsiveness to Iso, NE, For, and phenylephrine (PE; 5 micrograms/kg) was significantly (P < 0.05) reduced in older monkeys. For example, phenylephrine (5 micrograms/kg) increased total peripheral resistence by 69 +/- 4% in younger monkeys and by only 45 +/- 3% in older monkeys. Thus in older monkeys without associated cardiovascular disease, baseline hemodynamics are preserved, but adrenergic receptor responsiveness is reduced systemically, not just in the heart.

  14. beta-Adrenergic activation reveals impaired cardiac calcium handling at early stage of diabetes.

    PubMed

    op den Buijs, Jorn; Miklós, Zsuzsanna; van Riel, Natal A W; Prestia, Christina M; Szenczi, Orsolya; Tóth, András; Van der Vusse, Ger J; Szabó, Csaba; Ligeti, László; Ivanics, Tamás

    2005-01-21

    Cardiac function is known to be impaired in diabetes. Alterations in intracellular calcium handling have been suggested to play a pivotal role. This study aimed to test the hypothesis that beta-adrenergic activation can reveal the functional derangements of intracellular calcium handling of the 4-week diabetic heart. Langendorff perfused hearts of 4-week streptozotocin-induced diabetic rats were subjected to the beta-adrenoceptor agonist isoproterenol. Cyclic changes in [Ca(2+)](i) levels were measured throughout the cardiac cycle using Indo-1 fluorescent dye. Based on the computational analysis of the [Ca(2+)](i) transient the kinetic parameters of the sarcoplasmic reticulum Ca(2+)-ATPase and the ryanodine receptor were determined by minimizing the squared error between the simulated and the experimentally obtained [Ca(2+)](i) transient. Under unchallenged conditions, hemodynamic parameters were comparable between control and diabetic hearts. Isoproterenol administration stimulated hemodynamic function to a greater extent in control than in diabetic hearts, which was exemplified by more pronounced increases in rate of pressure development and decline. Under unchallenged conditions, [Ca(2+)](i) amplitude and rate of rise and decline of [Ca(2+)](i) as measured throughout the cardiac cycle were comparable between diabetic and control hearts. Differences became apparent under beta-adrenoceptor stimulation. Upon beta-activation the rate-pressure product showed a blunted response, which was accompanied by a diminished rise in [Ca(2+)](i) amplitude in diabetic hearts. Computational analysis revealed a reduced function of the sarcoplasmic reticulum Ca(2+)-ATPase and Ca(2+)-release channel in response to beta-adrenoceptor challenge. Alterations in Ca(2+)(i) handling may play a causative role in depressed hemodynamic performance of the challenged heart at an early stage of diabetes.

  15. MRP4 and CFTR in the regulation of cAMP and β-adrenergic contraction in cardiac myocytes.

    PubMed

    Sellers, Zachary M; Naren, Anjaparavanda P; Xiang, Yang; Best, Philip M

    2012-04-15

    Spatiotemporal regulation of cAMP in cardiac myocytes is integral to regulating the diverse functions downstream of β-adrenergic stimulation. The activities of cAMP phosphodiesterases modulate critical and well-studied cellular processes. Recently, in epithelial and smooth muscle cells, it was found that the multi-drug resistant protein 4 (MRP4) acts as a cAMP efflux pump to regulate intracellular cAMP levels and alter effector function, including activation of the cAMP-stimulated Cl(-) channel, CFTR (cystic fibrosis transmembrane conductance regulator). In the current study we investigated the potential role of MRP4 in regulating intracellular cAMP and β-adrenergic stimulated contraction rate in cardiac myocytes. Cultured neonatal ventricular myocytes were used for all experiments. In addition to wildtype mice, β(1)-, β(2)-, and β(1)/β(2)-adrenoceptor, and CFTR knockout mice were used. MRP4 expression was probed via Western blot, intracellular cAMP was measured by fluorescence resonance energy transfer, while the functional role of MRP4 was assayed via monitoring of isoproterenol-stimulated contraction rate. We found that MRP4 is expressed in mouse neonatal ventricular myocytes. A pharmacological inhibitor of MRP4, MK571, potentiated submaximal isoproterenol-stimulated cAMP accumulation and cardiomyocyte contraction rate via β(1)-adrenoceptors. CFTR expression was critical for submaximal isoproterenol-stimulated contraction rate. Interestingly, MRP4-dependent changes in contraction rate were CFTR-dependent, however, PDE4-dependent potentiation of contraction rate was CFTR-independent. We have shown, for the first time, a role for MRP4 in the regulation of cAMP in cardiac myocytes and involvement of CFTR in β-adrenergic stimulated contraction. Together with phosphodiesterases, MRP4 must be considered when examining cAMP regulation in cardiac myocytes. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. MRP4 and CFTR in the regulation of cAMP and β-adrenergic contraction in cardiac myocytes

    PubMed Central

    Sellers, Zachary M.; Naren, Anjaparavanda P.; Xiang, Yang; Best, Philip M.

    2012-01-01

    Spatiotemporal regulation of cAMP in cardiac myocytes is integral to regulating the diverse functions downstream of β-adrenergic stimulation. The activities of cAMP phosphodiesterases modulate critical and well-studied cellular processes. Recently, in epithelial and smooth muscle cells, it was found that the multi-drug resistant protein 4 (MRP4) acts as a cAMP efflux pump to regulate intracellular cAMP levels and alter effector function, including activation of the cAMP-stimulated Cl− channel, CFTR (cystic fibrosis transmembrane conductance regulator). In the current study we investigated the potential role of MRP4 in regulating intracellular cAMP and β-adrenergic stimulated contraction rate in cardiac myocytes. Cultured neonatal ventricular myocytes were used for all experiments. In addition to wildtype mice, β1-, β2-, β1/β2-adrenoceptor, and CFTR knockout mice were used. MRP4 expression was probed via Western blot, intracellular cAMP was measured by fluorescence resonance energy transfer, while the functional role of MRP4 was assayed via monitoring of isoproterenol-stimulated contraction rate. We found that MRP4 is expressed in mouse neonatal ventricular myocytes. A pharmacological inhibitor of MRP4, MK571, potentiated submaximal isoproterenol-stimulated cAMP accumulation and cardiomyocyte contraction rate via β1-adrenoceptors. CFTR expression was critical for submaximal isoproterenol-stimulated contraction rate. Interestingly, MRP4-dependent changes in contraction rate were CFTR-dependent, however, PDE4-dependent potentiation of contraction rate was CFTR-independent. We have shown, for the first time, a role for MRP4 in the regulation of cAMP in cardiac myocytes and involvement of CFTR in β-adrenergic stimulated contraction. Together with phosphodiesterases, MRP4 must be considered when examining cAMP regulation in cardiac myocytes. PMID:22381067

  17. Phosphoregulation of Cardiac Inotropy via Myosin Binding Protein-C During Increased Pacing Frequency or β1-Adrenergic Stimulation

    PubMed Central

    Tong, Carl W.; Wu, Xin; Liu, Yang; Rosas, Paola C.; Sadayappan, Sakthivel; Hudmon, Andy; Muthuchamy, Mariappan; Powers, Patricia A.; Valdivia, Héctor H.; Moss, Richard L.

    2015-01-01

    Background Mammalian hearts exhibit positive inotropic responses to β-adrenergic stimulation as a consequence of protein kinase A (PKA)-mediated phosphorylation or as a result of increased beat frequency (the Bowditch effect). Several membrane and myofibrillar proteins are phosphorylated under these conditions, but the relative contributions of these to increased contractility are not known. Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) by PKA accelerates the kinetics of force development in permeabilized heart muscle, but its role in vivo is unknown. Such understanding is important, since adrenergic responsiveness of the heart and the Bowditch effect are both depressed in heart failure. Methods and Results The roles of cMyBP-C phosphorylation were studied using mice in which either WT or nonphosphorylatable forms of cMyBP-C [ser273ala, ser282ala, ser302ala: cMyBP-C(t3SA)] were expressed at similar levels on a cMyBP-C null background. Force and [Ca2+]in measurements in isolated papillary muscles showed that the increased force and twitch kinetics due to increased pacing or β1-adrenergic stimulation were nearly absent in cMyBP-C(t3SA) myocardium, even though [Ca2+]intransients under each condition were similar to WT. Biochemical measurements confirmed that PKA phosphorylated ser273, ser282 and ser302 in WT cMyBP-C. In contrast, CaMKIIδ, which is activated by increased pacing, phosphorylated ser302 principally, ser282 to a lesser degree, and ser273 not at all. Conclusions Phosphorylation of cMyBP-C increases the force and kinetics of twitches in living cardiac muscle. Further, cMyBP-C is a principal mediator of increased contractility observed with β-adrenergic stimulation or increased pacing, due to PKA and CaMKIIδ phosphorylations of cMyB-C. PMID:25740838

  18. Phosphoregulation of Cardiac Inotropy via Myosin Binding Protein-C During Increased Pacing Frequency or β1-Adrenergic Stimulation.

    PubMed

    Tong, Carl W; Wu, Xin; Liu, Yang; Rosas, Paola C; Sadayappan, Sakthivel; Hudmon, Andy; Muthuchamy, Mariappan; Powers, Patricia A; Valdivia, Héctor H; Moss, Richard L

    2015-05-01

    Mammalian hearts exhibit positive inotropic responses to β-adrenergic stimulation as a consequence of protein kinase A-mediated phosphorylation or as a result of increased beat frequency (the Bowditch effect). Several membrane and myofibrillar proteins are phosphorylated under these conditions, but the relative contributions of these to increased contractility are not known. Phosphorylation of cardiac myosin-binding protein-C (cMyBP-C) by protein kinase A accelerates the kinetics of force development in permeabilized heart muscle, but its role in vivo is unknown. Such understanding is important because adrenergic responsiveness of the heart and the Bowditch effect are both depressed in heart failure. The roles of cMyBP-C phosphorylation were studied using mice in which either WT or nonphosphorylatable forms of cMyBP-C [ser273ala, ser282ala, ser302ala: cMyBP-C(t3SA)] were expressed at similar levels on a cMyBP-C null background. Force and [Ca(2+)]in measurements in isolated papillary muscles showed that the increased force and twitch kinetics because increased pacing or β1-adrenergic stimulation were nearly absent in cMyBP-C(t3SA) myocardium, even though [Ca(2+)]in transients under each condition were similar to WT. Biochemical measurements confirmed that protein kinase A phosphorylated ser273, ser282, and ser302 in WT cMyBP-C. In contrast, CaMKIIδ, which is activated by increased pacing, phosphorylated ser302 principally, ser282 to a lesser degree, and ser273 not at all. Phosphorylation of cMyBP-C increases the force and kinetics of twitches in living cardiac muscle. Further, cMyBP-C is a principal mediator of increased contractility observed with β-adrenergic stimulation or increased pacing because of protein kinase A and CaMKIIδ phosphorylations of cMyB-C. © 2015 American Heart Association, Inc.

  19. CXCR4 and CXCR7 play distinct roles in cardiac lineage specification and pharmacologic β-adrenergic response.

    PubMed

    Ceholski, Delaine K; Turnbull, Irene C; Pothula, Venu; Lecce, Laura; Jarrah, Andrew A; Kho, Changwon; Lee, Ahyoung; Hadri, Lahouaria; Costa, Kevin D; Hajjar, Roger J; Tarzami, Sima T

    2017-08-01

    CXCR4 and CXCR7 are prominent G protein-coupled receptors (GPCRs) for chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). This study demonstrates that CXCR4 and CXCR7 induce differential effects during cardiac lineage differentiation and β-adrenergic response in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using lentiviral vectors to ablate CXCR4 and/or CXCR7 expression, hiPSC-CMs were tested for phenotypic and functional properties due to gene knockdown. Gene expression and flow cytometry confirmed the pluripotent and cardiomyocyte phenotype of undifferentiated and differentiated hiPSCs, respectively. Although reduction of CXCR4 and CXCR7 expression resulted in a delayed cardiac phenotype, only knockdown of CXCR4 delayed the spontaneous beating of hiPSC-CMs. Knockdown of CXCR4 and CXCR7 differentially altered calcium transients and β-adrenergic response in hiPSC-CMs. In engineered cardiac tissues, depletion of CXCR4 or CXCR7 had opposing effects on developed force and chronotropic response to β-agonists. This work demonstrates distinct roles for the SDF-1/CXCR4 or CXCR7 network in hiPSC-derived ventricular cardiomyocyte specification, maturation and function. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  20. Adrenergic Repression of the Epigenetic Reader MeCP2 Facilitates Cardiac Adaptation in Chronic Heart Failure

    PubMed Central

    Mayer, Sandra C.; Gilsbach, Ralf; Preissl, Sebastian; Monroy Ordonez, Elsa Beatriz; Schnick, Tilman; Beetz, Nadine; Lother, Achim; Rommel, Carolin; Ihle, Hannah; Bugger, Heiko; Rühle, Frank; Schrepper, Andrea; Schwarzer, Michael; Heilmann, Claudia; Bönisch, Ulrike; Gupta, Shashi Kumar; Wilpert, Jochen; Kretz, Oliver; von Elverfeldt, Dominik; Orth, Joachim; Aktories, Klaus; Beyersdorf, Friedhelm; Bode, Christoph; Stiller, Brigitte; Krüger, Markus; Thum, Thomas; Doenst, Torsten; Stoll, Monika

    2015-01-01

    Rationale: In chronic heart failure, increased adrenergic activation contributes to structural remodeling and altered gene expression. Although adrenergic signaling alters histone modifications, it is unknown, whether it also affects other epigenetic processes, including DNA methylation and its recognition. Objective: The aim of this study was to identify the mechanism of regulation of the methyl-CpG–binding protein 2 (MeCP2) and its functional significance during cardiac pressure overload and unloading. Methods and Results: MeCP2 was identified as a reversibly repressed gene in mouse hearts after transverse aortic constriction and was normalized after removal of the constriction. Similarly, MeCP2 repression in human failing hearts resolved after unloading by a left ventricular assist device. The cluster miR-212/132 was upregulated after transverse aortic constriction or on activation of α1- and β1-adrenoceptors and miR-212/132 led to repression of MeCP2. Prevention of MeCP2 repression by a cardiomyocyte-specific, doxycycline-regulatable transgenic mouse model aggravated cardiac hypertrophy, fibrosis, and contractile dysfunction after transverse aortic constriction. Ablation of MeCP2 in cardiomyocytes facilitated recovery of failing hearts after reversible transverse aortic constriction. Genome-wide expression analysis, chromatin immunoprecipitation experiments, and DNA methylation analysis identified mitochondrial genes and their transcriptional regulators as MeCP2 target genes. Coincident with its repression, MeCP2 was removed from its target genes, whereas DNA methylation of MeCP2 target genes remained stable during pressure overload. Conclusions: These data connect adrenergic activation with a microRNA—MeCP2 epigenetic pathway that is important for cardiac adaptation during the development and recovery from heart failure. PMID:26195221

  1. Adrenergic Repression of the Epigenetic Reader MeCP2 Facilitates Cardiac Adaptation in Chronic Heart Failure.

    PubMed

    Mayer, Sandra C; Gilsbach, Ralf; Preissl, Sebastian; Monroy Ordonez, Elsa Beatriz; Schnick, Tilman; Beetz, Nadine; Lother, Achim; Rommel, Carolin; Ihle, Hannah; Bugger, Heiko; Rühle, Frank; Schrepper, Andrea; Schwarzer, Michael; Heilmann, Claudia; Bönisch, Ulrike; Gupta, Shashi Kumar; Wilpert, Jochen; Kretz, Oliver; von Elverfeldt, Dominik; Orth, Joachim; Aktories, Klaus; Beyersdorf, Friedhelm; Bode, Christoph; Stiller, Brigitte; Krüger, Markus; Thum, Thomas; Doenst, Torsten; Stoll, Monika; Hein, Lutz

    2015-09-11

    In chronic heart failure, increased adrenergic activation contributes to structural remodeling and altered gene expression. Although adrenergic signaling alters histone modifications, it is unknown, whether it also affects other epigenetic processes, including DNA methylation and its recognition. The aim of this study was to identify the mechanism of regulation of the methyl-CpG-binding protein 2 (MeCP2) and its functional significance during cardiac pressure overload and unloading. MeCP2 was identified as a reversibly repressed gene in mouse hearts after transverse aortic constriction and was normalized after removal of the constriction. Similarly, MeCP2 repression in human failing hearts resolved after unloading by a left ventricular assist device. The cluster miR-212/132 was upregulated after transverse aortic constriction or on activation of α1- and β1-adrenoceptors and miR-212/132 led to repression of MeCP2. Prevention of MeCP2 repression by a cardiomyocyte-specific, doxycycline-regulatable transgenic mouse model aggravated cardiac hypertrophy, fibrosis, and contractile dysfunction after transverse aortic constriction. Ablation of MeCP2 in cardiomyocytes facilitated recovery of failing hearts after reversible transverse aortic constriction. Genome-wide expression analysis, chromatin immunoprecipitation experiments, and DNA methylation analysis identified mitochondrial genes and their transcriptional regulators as MeCP2 target genes. Coincident with its repression, MeCP2 was removed from its target genes, whereas DNA methylation of MeCP2 target genes remained stable during pressure overload. These data connect adrenergic activation with a microRNA-MeCP2 epigenetic pathway that is important for cardiac adaptation during the development and recovery from heart failure. © 2015 The Authors.

  2. THE EFFECTS OF ADRENERGIC AND ADRENOLYTIC AGENTS ON THE APPEARANCE OF CARDIAC ARRHYTHMIAS DURING EXPERIMENTAL HYPOTHERMIA,

    DTIC Science & Technology

    The object of this study was to compare the influence of the adrenergic drugs epinephrine and norepinephrine and the adrenolytic drug phentolamine on...fibrillation. Phentolamine was without significant effect on heart rate, blood pressure, and terminal temperature.

  3. Exacerbated cardiac fibrosis induced by β-adrenergic activation in old mice due to decreased AMPK activity.

    PubMed

    Wang, Jingjing; Song, Yao; Li, Hao; Shen, Qiang; Shen, Jing; An, Xiangbo; Wu, Jimin; Zhang, Jianshu; Wu, Yunong; Xiao, Han; Zhang, Youyi

    2016-11-01

    Senescent hearts exhibit defective responses to β-adrenergic receptor (β-AR) over-activation upon stress, leading to more severe pathological cardiac remodelling. However, the underlying mechanisms remain unclear. Here, we investigated the role of adenosine monophosphate-activated protein kinase (AMPK) in protecting against ageing-associated cardiac remodelling in mice upon β-AR over-activation. 10-week-old (young) and 18-month-old (old) mice were subcutaneously injected with the β-AR agonist isoproterenol (ISO; 5 mg/kg). More extensive cardiac fibrosis was found in old mice upon ISO exposure than in young mice. Meanwhile, ISO treatment decreased AMPK activity and increased β-arrestin 1, but not β-arrestin 2, expression, and the effects of ISO on AMPK and β-arrestin 1 were greater in old mice than in young mice. Similarly, young AMPKα2-knockout (KO) mice showed more extensive cardiac fibrosis upon ISO exposure than that was observed in age-matched wild-type (WT) littermates. The extent of cardiac fibrosis in WT old mice was similar to that in young KO mice. Additionally, AMPK activities were decreased and β-arrestin 1 expression increased in KO mice. In contrast, the AMPK activator metformin decreased β-arrestin 1 expression and attenuated cardiac fibrosis in both young and old mice upon ISO exposure. In conclusion, more severe cardiac fibrosis is induced by ISO in old mice than in young mice. A decrease in AMPK activity, which further increases β-arrestin 1 expression, is the central mechanism underlying the ageing-related cardiac fibrosis induced by ISO. The AMPK activator metformin is a promising therapeutic agent for treating ageing-related cardiac remodelling upon β-AR over-activation.

  4. β1-Adrenergic blockers exert antioxidant effects, reduce matrix metalloproteinase activity, and improve renovascular hypertension-induced cardiac hypertrophy.

    PubMed

    Rizzi, Elen; Guimaraes, Danielle A; Ceron, Carla S; Prado, Cibele M; Pinheiro, Lucas C; Martins-Oliveira, Alisson; Gerlach, Raquel F; Tanus-Santos, Jose E

    2014-08-01

    Hypertension induces left-ventricular hypertrophy (LVH) by mechanisms involving oxidative stress and unbalanced cardiac matrix metalloproteinase (MMP) activity. We hypothesized that β1-adrenergic receptor blockers with antioxidant properties (nebivolol) could reverse hypertension-induced LVH more effectively than conventional β1-blockers (metoprolol) when used at doses that exert similar antihypertensive effects. Two-kidney one-clip (2K1C) hypertension was induced in male Wistar rats. Six weeks after surgery, hypertensive and sham rats were treated with nebivolol (10 mg kg(-1)day(-1)) or metoprolol (20 mg kg(-1)day(-1)) for 4 weeks. Systolic blood pressure was monitored weekly by tail-cuff plethysmography. LV structural changes and fibrosis were studied in hematoxylin/eosin- and picrosirius-stained sections, respectively. Cardiac MMP levels and activity were determined by in situ zymography, gel zymography, and immunofluorescence. Dihydroethidium and lucigenin-derived chemiluminescence assays were used to assess cardiac reactive oxygen species (ROS) production. Nitrotyrosine levels were determined in LV samples by immunohistochemistry and green fluorescence and were evaluated using the ImageJ software. Cardiac protein kinase B/Akt (AKT) phosphorylation state was assessed by Western blot. Both β-blockers exerted similar antihypertensive effects and attenuated hypertension-induced cardiac remodeling. Both drugs reduced myocyte hypertrophy and collagen deposition in 2K1C rats. These effects were associated with lower cardiac ROS and nitrotyrosine levels and attenuation of hypertension-induced increases in cardiac MMP-2 levels and in situ gelatinolytic activity after treatment with both β-blockers. Whereas hypertension increased AKT phosphorylation, no effects were found with β-blockers. In conclusion, we found evidence that two β1-blockers with different properties attenuate hypertension-induced LV hypertrophy and cardiac collagen deposition in association with

  5. Comparative anatomy and evolution of the cardiac innervation in New World monkeys (Platyrrhini, e. Geoffroy, 1812).

    PubMed

    Kawashima, Tomokazu; Thorington, Richard W; Whatton, James F

    2009-05-01

    The morphology of the autonomic cardiac nervous system (ACNS) was examined in 24 sides of 12 New World monkeys (Platyrrhini) of all four families to document the morphology systematically and to study the evolutionary changes of the ACNS in this primate lineage. We report the following: (1) Although several trivial intra- and inter-specific variations are present, a family-dependent morphology of the ACNS does not exist in New World monkeys. (2) The sympathetic ganglia in New World monkeys consist of the superior cervical, the middle cervical, and the cervicothoracic which is composed of the inferior cervical and first and second thoracic, and the thoracic ganglia starting with the third thoracic. The general cardiac nervous system is the sympathetic middle and inferior cardiac nerves and all parasympathetic vagal cardiac branches. (3) The morphology of the ACNS in the New World monkeys is almost consistent regardless of the number of vertebrae, the cardiac position and deviation (axis), and the great arterial branching pattern of the aortic arch, and it is very similar to that in the Old World monkeys, with only one difference: the superior cervical ganglion in the New World monkeys tends to be relatively smaller, higher, and provides a narrower contribution to the spinal nerves than in the Old World monkeys. The ACNS morphology exhibits significant evolutionary changes within the primate lineage from New and Old World monkeys to humans. The comparative morphology within the lineage is concordant with the phylogeny, suggesting that the primate ACNS preserves its evolutionary history in close alignment with phylogeny.

  6. The role of adrenergic stimulation in maintaining maximum cardiac performance in rainbow trout (Oncorhynchus mykiss) during hypoxia, hyperkalemia and acidosis at 10 degrees C.

    PubMed

    Hanson, Linda M; Obradovich, Shannon; Mouniargi, Janet; Farrell, Anthony P

    2006-07-01

    As rainbow trout approach exhaustion during prolonged exercise, they maintain maximum cardiac output despite the fact their venous blood, which bathes the heart, becomes hypoxic, acidotic and hyperkalemic. Because these factors are individually recognized to have detrimental inotropic and chronotropic effects on cardiac performance, we hypothesized that adrenergic stimulation is critical in maintaining maximum cardiac performance under these collectively adverse conditions in vivo. To test this hypothesis, maximum cardiac performance in the presence and absence of maximal adrenergic stimulation was assessed with in situ rainbow trout hearts using relevant hyperkalemic (5.0 mmol l(-1) K+), acidotic (pH 7.5) and hypoxic challenges. With tonic adrenergic stimulation (5.0 nmol l(-1) adrenaline), hearts produced only 44.8+/-14.6% of their normal maximum cardiac output when exposed under normoxic conditions (20 kPa) to the hyperkalemic, acidotic perfusate, indicating that in vivo there was no refuge from cardiac impairment even if venous blood was fully oxygenated. By contrast, maximum adrenergic stimulation (500 nmol l(-1) adrenaline), fully protected maximum cardiac performance under hyperkalemic and acidotic conditions over a wide range of oxygen availability, from normoxia to 2.0 kPa, a venous oxygen tension close to routine values in vivo. Extending the level of hypoxia to 1.3 kPa resulted in a 43.6+/-2.8% decrease in maximum cardiac output, with hearts failing when tested at 1.0 kPa. Our results suggest that adrenergic stimulation of the trout heart is critical in maintaining maximum performance during prolonged swimming tests, and probably during all forms of exhaustive activity and recovery, when venous blood is hyperkalemic, acidotic and hypoxic.

  7. β-Adrenergic Receptor-Mediated Cardiac Contractility is Inhibited via Vasopressin Type 1A-Receptor-Dependent Signaling

    PubMed Central

    Tilley, Douglas G.; Zhu, Weizhong; Myers, Valerie D.; Barr, Larry A.; Gao, Erhe; Li, Xue; Song, Jianliang; Carter, Rhonda L.; Makarewich, Catherine A.; Yu, Daohai; Troupes, Constantine D.; Grisanti, Laurel A.; Coleman, Ryan C.; Koch, Walter J.; Houser, Steven R.; Cheung, Joseph Y.; Feldman, Arthur M.

    2014-01-01

    Background Enhanced arginine vasopressin (AVP) levels are associated with increased mortality during end-stage human heart failure (HF), and cardiac AVP type 1A receptor (V1AR) expression becomes increased. Additionally, mice with cardiac-restricted V1AR overexpression develop cardiomyopathy and decreased β-adrenergic receptor (βAR) responsiveness. This led us to hypothesize that V1AR signaling regulated βAR responsiveness and in doing so contributes to HF development. Methods and Results Transaortic constriction resulted in decreased cardiac function and βAR density and increased cardiac V1AR expression, effects reversed by a V1AR-selective antagonist. Molecularly, V1AR stimulation led to decreased βAR ligand affinity, as well as βAR-induced Ca2+ mobilization and cAMP generation in isolated adult cardiomyocytes, effects recapitulated via ex vivo Langendorff analysis. V1AR-mediated regulation of βAR responsiveness was demonstrated to occur in a previously unrecognized Gq protein-independent/GRK-dependent manner. Conclusions This newly discovered relationship between cardiac V1AR and βAR may be informative for the treatment of patients with acute decompensated HF and elevated AVP. PMID:25205804

  8. Dynamic molecular imaging of cardiac innervation using a dual headpinhole SPECT system

    SciTech Connect

    Hu, Jicun; Boutchko, Rostyslav; Sitek, Arkadiusz; Reutter, BryanW.; Huesman, Ronald H.; Gullberg, Grant T.

    2008-03-29

    Typically 123I-MIBG is used for the study of innervation andfunction of the sympathetic nervous system in heart failure. The protocolinvolves two studies: first a planar or SPECT scan is performed tomeasure initial uptake of the tracer, followed some 3-4 hours later byanother study measuring the wash-out of the tracer from the heart. A fastwash-out is indicative of a compromised heart. In this work, a dual headpinhole SPECT system was used for imaging the distribution and kineticsof 123I-MIBG in the myocardium of spontaneous hypertensive rats (SHR) andnormotensive Wistar Kyoto (WKY) rats. The system geometry was calibratedbased on a nonlinear point projection fitting method using a three-pointsource phantom. The angle variation effect of the parameters was modeledwith a sinusoidal function. A dynamic acquisition was performed byinjecting 123I-MIBG into rats immediately after starting the dataacquisition. The detectors rotated continuously performing a 360o dataacquisition every 90 seconds. We applied the factor analysis (FA)methodand region of interest (ROI) sampling method to obtain time activitycurves (TACs)in the blood pool and myocardium and then appliedtwo-compartment modeling to estimate the kinetic parameters. Since theinitial injection bolus is too fast for obtaining a consistenttomographic data set in the first few minutes of the study, we appliedthe FA method directly to projections during the first rotation. Then thetime active curves for blood and myocardial tissue were obtained from ROIsampling. The method was applied to determine if there were differencesin the kinetics between SHR and WKY rats and requires less time byreplacing the delayed scan at 3-4 hours after injection with a dynamicacquisition over 90 to 120 minutes. The results of a faster washout and asmaller distribution volume of 123IMIBG near the end of life in the SHRmodel of hypertrophic cardiomyopthy may be indicative of a failing heartin late stages of heart failure.

  9. Focal myocardial infarction induces global remodeling of cardiac sympathetic innervation: neural remodeling in a spatial context

    PubMed Central

    Ajijola, Olujimi A.; Yagishita, Daigo; Patel, Krishan J.; Vaseghi, Marmar; Zhou, Wei; Yamakawa, Kentaro; So, Eileen; Lux, Robert L.; Mahajan, Aman

    2013-01-01

    Myocardial infarction (MI) induces neural and electrical remodeling at scar border zones. The impact of focal MI on global functional neural remodeling is not well understood. Sympathetic stimulation was performed in swine with anteroapical infarcts (MI; n = 9) and control swine (n = 9). A 56-electrode sock was placed over both ventricles to record electrograms at baseline and during left, right, and bilateral stellate ganglion stimulation. Activation recovery intervals (ARIs) were measured from electrograms. Global and regional ARI shortening, dispersion of repolarization, and activation propagation were assessed before and during sympathetic stimulation. At baseline, mean ARI was shorter in MI hearts than control hearts (365 ± 8 vs. 436 ± 9 ms, P < 0.0001), dispersion of repolarization was greater in MI versus control hearts (734 ± 123 vs. 362 ± 32 ms2, P = 0.02), and the infarcted region in MI hearts showed longer ARIs than noninfarcted regions (406 ± 14 vs. 365 ± 8 ms, P = 0.027). In control animals, percent ARI shortening was greater on anterior than posterior walls during right stellate ganglion stimulation (P = 0.0001), whereas left stellate ganglion stimulation showed the reverse (P = 0.0003). In infarcted animals, this pattern was completely lost. In 50% of the animals studied, sympathetic stimulation, compared with baseline, significantly altered the direction of activation propagation emanating from the intramyocardial scar during pacing. In conclusion, focal distal anterior MI alters regional and global pattern of sympathetic innervation, resulting in shorter ARIs in infarcted hearts, greater repolarization dispersion, and altered activation propagation. These conditions may underlie the mechanisms by which arrhythmias are initiated when sympathetic tone is enhanced. PMID:23893167

  10. The unusual adrenergic-like excitatory action of acetylcholine on the ventricular cardiac muscle of the horned shark, Heterodontus portusjacksoni.

    PubMed

    Thompson, A P; O'Shea, J E

    1997-01-01

    The atypical excitatory effect of acetylcholine on cardiac ventricular muscle was investigated in the horned shark, Heterodontus portusjacksoni. Electrically paced ventricular strips produced a massive 391.45% (+/-26.39%) increase in basal force of contraction in response to exogenously applied acetylcholine. The response was similar in nature to that produced by applied adrenaline, which caused a 382.52% (+/-72.47%) increase. The response to acetylcholine was blocked by the muscarinic cholinoceptor antagonist atropine and the competitive beta-adrenoceptor antagonist propranolol and was reduced by bretylium, an agent known to inhibit the release of catecholamines from adrenergic nerves. These findings strongly suggest that acetylcholine mediates a localised release of a catecholamine via muscarinic cholinoceptors in shark heart. A cholinergically controlled catecholamine store has been proposed (cholinergic-adreno complex), implying that elasmobranchs may be capable of finer control of cardiac output than has previously been suspected. This complex may represent a transitional adrenergic state between humoral and neuronal regulation. The spontaneously beating atrium showed no evidence of such an excitatory response to applied acetylcholine but produced an atropine-sensitive slowing, a response typical of other vertebrates.

  11. Effect of age on upregulation of the cardiac adrenergic beta receptors

    SciTech Connect

    Tumer, N.; Houck, W.T.; Roberts, J.

    1990-03-01

    Radioligand binding studies were performed to determine whether upregulation of postjunctional beta receptors occurs in sympathectomized hearts of aged animals. Fischer 344 rats 6, 12, and 24 months of age (n = 10) were used in these experiments. To produce sympathectomy, rats were injected with 6-hydroxydopamine hydrobromide (6-OHDA; 2 x 50 mg/kg iv) on days 1 and 8; the animals were decapitated on day 15. The depletion of norepinephrine in the heart was about 86% in each age group. 125I-Iodopindolol (IPIN), a beta adrenergic receptor antagonist, was employed to determine the affinity and total number of beta adrenergic receptors in the ventricles of the rat heart. The maximal number of binding sites (Bmax) was significantly elevated by 37%, 48%, and 50% in hearts from sympathectomized 6-, 12-, and 24-month-old rats, respectively. These results indicate that beta receptor mechanisms in older hearts can respond to procedures that cause upregulation of the beta adrenergic receptors.

  12. Increased dependency of cardiac pacemaker activity on extracellular Ca after adrenergic blockade in the frog heart.

    PubMed

    Fukuda, Y

    1986-01-01

    The frog sinus venosus shows spontaneous regular pacemaker activity, even in the absence of extracellular Ca2+. When an alpha-adrenergic blocking agent (phentolamine) is applied, the rate of pacemaker activity, height of action potential, rate of slow diastolic depolarization, and the maximum diastolic potential become strongly dependent upon the extracellular Ca2+ concentration.

  13. Three-dimensional 123I-meta-iodobenzylguanidine cardiac innervation maps to assess substrate and successful ablation sites for ventricular tachycardia: feasibility study for a novel paradigm of innervation imaging.

    PubMed

    Klein, Thomas; Abdulghani, Mohammed; Smith, Mark; Huang, Rui; Asoglu, Ramazan; Remo, Benjamin F; Turgeman, Aharon; Mesubi, Olurotimi; Sidhu, Sunjeet; Synowski, Stephen; Saliaris, Anastasios; See, Vincent; Shorofsky, Stephen; Chen, Wengen; Dilsizian, Vasken; Dickfeld, Timm

    2015-06-01

    Innervation is a critical component of arrhythmogenesis and may present an important trigger/substrate modifier not used in current ventricular tachycardia (VT) ablation strategies. Fifteen patients referred for ischemic VT ablation underwent preprocedural cardiac (123)I- meta-iodobenzylguanidine ((123)I-mIBG) imaging, which was used to create 3-dimensional (3D) innervation models and registered to high-density voltage maps. 3D (123)I-mIBG innervation maps demonstrated areas of complete denervation and (123)I-mIBG transition zone in all patients, which corresponded to 0% to 31% and 32% to 52% uptake. (123)I-mIBG denervated areas were ≈2.5-fold larger than bipolar voltage-defined scar (median, 24.6% [Q1-Q3, 18.3%-34.4%] versus 10.6% [Q1-Q3, 3.9%-16.4%]; P<0.001) and included the inferior wall in all patients, with no difference in the transition/border zone (11.4% [Q1-Q3, 9.5%-13.2%] versus 16.6% [Q1-Q3, 12.0%-18.8%]; P=0.07). Bipolar/unipolar voltages varied widely within areas of denervation (0.8 mV [Q1-Q3, 0.3-1.7 mV] and 4.0 mV [Q1-Q3, 2.9-5.6 mV]) and (123)I-mIBG transition zones (0.8 mV [Q1-Q3, 0.4-1.8 mV] and 4.6 mV [Q1-Q3, 3.2-6.3 mV]). Bipolar voltages in denervated areas and (123)I-mIBG transition zones were <0.5 mV, 0.5 to 1.5 mV, and >1.5 mV in 35%, 36%, and 29%, as well as 35%, 35%, and 30%, respectively (P>0.05). Successful ablation sites were within bipolar voltage-defined scar (7%), border zone (57%), and areas of normal voltage (36%), but all ablation sites were abnormally innervated (denervation/(123)I-mIBG transition zone in 50% each). (123)I-mIBG innervation defects are larger than bipolar voltage-defined scar and cannot be detected with standard voltage criteria. Thirty-six percent of successful VT ablation sites demonstrated normal voltages (>1.5 mV), but all ablation sites were within the areas of abnormal innervation. (123)I-mIBG innervation maps may provide critical information about triggers/substrate modifiers and could improve

  14. How effortful is cognitive control? Insights from a novel method measuring single-trial evoked beta-adrenergic cardiac reactivity.

    PubMed

    Kuipers, Mithras; Richter, Michael; Scheepers, Daan; Immink, Maarten A; Sjak-Shie, Elio; van Steenbergen, Henk

    2017-09-01

    The ability to adjust attentional focus to varying levels of task demands depends on the adaptive recruitment of cognitive control processes. The present study investigated for the first time whether the mobilization of cognitive control during response-conflict trials in a flanker task is associated with effort-related sympathetic activity as measured by changes in the RZ-interval at a single-trial level, thus providing an alternative to the pre-ejection period (PEP) which can only be reliably measured in ensemble-averaged data. We predicted that response conflict leads to a physiological orienting response (i.e. heart rate slowing) and increases in effort as reflected by changes in myocardial beta-adrenergic activity (i.e. decreased RZ interval). Our results indeed showed that response conflict led to cardiac deceleration and decreased RZ interval. However, the temporal overlap of the observed heart rate and RZ interval changes suggests that the effect on the latter reflects a change in cardiac pre-load (Frank-Starling mechanism). Our study was thus unable to provide evidence for the expected link between cognitive control and cardiovascular effort. However, it demonstrated that our single-trial analysis enables the assessment of transient changes in cardiac sympathetic activity, thus providing a promising tool for future studies that aim to investigate effort at a single-trial level. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Synergistic prognostic values of cardiac sympathetic innervation with left ventricular hypertrophy and left atrial size in heart failure patients without reduced left ventricular ejection fraction: a cohort study

    PubMed Central

    Doi, Takahiro; Nakata, Tomoaki; Hashimoto, Akiyoshi; Yuda, Satoshi; Wakabayashi, Takeru; Kouzu, Hidemichi; Kaneko, Naofumi; Hase, Mamoru; Tsuchihashi, Kazufumi; Miura, Tetsuji

    2012-01-01

    Objectives This study tested whether cardiac sympathetic innervation assessed by metaiodobenzylguanidine (MIBG) activity has long-term prognostic value in combination with left ventricular hypertrophy (LVH) and left atrial size in heart failure (HF) patients without reduced left ventricular ejection fraction (LVEF). Design A single-centre prospective cohort study. Setting/participants With primary endpoints of cardiac death and rehospitalisation due to HF progression, 178 consecutive symptomatic HF patients with 74% men, mean age of 56 years and mean LVEF of 64.5% were followed up for 80 months. The entry criteria consisted of LVEF more than 50%, completion of predischarge clinical evaluations including cardiac MIBG and echocardiographic studies and at least more than 1-year follow-up when survived. Results Thirty-four patients with cardiac evens had larger left atrial dimension (LAD), increased LV mass index, reduced MIBG activity quantified as heart-to-mediastinum ratio (HMR) than did the others. Multivariable Cox analysis showed that LAD and HMR were significant predictors (HR of 1.080 (95% CI 1.00 to 1.16, p=0.044) and 0.107 (95% CI 0.01 to 0.61, p=0.012, respectively). Thresholds of HMR (1.65) and LAD (37 mm) were closely related to identification of high-risk patients. In particular, HMR was a significant determinant of cardiac events in both patients with and without LV hypertrophy. Reduced HMR with enlarged LAD or LV hypertrophy identified patients at most increased risk; overall log-rank value, 11.5, p=0.0032 for LAD and 17.5, p=0.0002, respectively. Conclusions In HF patients without reduced LV ejection fraction, impairment of cardiac sympathetic innervation is related to cardiac outcomes independently and synergistically with LA size and LV hypertrophy. Cardiac sympathetic innervation assessment can contribute to better risk-stratification in combination with evaluation of LA size and LV mass but is needed to be evaluated for establishing aetiology

  16. Overexpression Myocardial Inducible Nitric Oxide Synthase Exacerbates Cardiac Dysfunction and Beta-Adrenergic Desensitization in Experimental Hypothyroidism☆,☆☆

    PubMed Central

    Shao, Qun; Cheng, Heng-Jie; Callahan, Michael F.; Kitzman, Dalane W; Li, Wei-Min; Cheng, Che Ping

    2015-01-01

    Background Altered nitric oxide synthase (NOS) has been implicated in the pathophysiology of heart failure (HF). Recent evidence links hypothyroidism to the pathology of HF. However, the precise mechanisms are incompletely understood. The alterations and functional effects of cardiac NOS in hypothyroidism are unknown. We tested the hypothesis that hypothyroidism increases cadiomyocyte inducible NOS (iNOS) expression, which plays an important role in hypothyroidism-induced depression of cardiomyocyte contractile properties, [Ca2+]i transient ([Ca2+]iT), and β-adrenergic hyporesponsiveness. Methods and Results We simultaneously evaluated LV functional performance and compared myocyte three NOS, β-adrenergic receptors (AR) and SERCA2a expressions and assessed cardiomyocyte contractile and [Ca2+]iT responses to β-AR stimulation with and without pretreatment of iNOS inhibitor (1400W, 10−5 mol/L) in 26 controls and 26 rats with hypothyroidism induced by methimazole (~30 mg/kg/day for 8 weeks in the drinking water). Compared with controls, in hypothyroidism, total serum T3 and T4 were significantly reduced followed by significantly decreased LV contractility (EES) with increased LV time constant of relaxation. These LV abnormalities were accompanied by concomitant significant decreases in myocyte contraction (dL/dtmax), relaxation (dR/dtmax), and [Ca2+]iT. In hypothyroidism, isoproterenol (10−8 M) produced significantly smaller increases in dL/dtmax, dR/dtmax and [Ca2+]iT. These changes were associated with decreased β1-AR and SERCA2a, but significantly increased iNOS. Moreover, only in hypothyroidism, pretreatment with iNOS inhibitor significantly improved basal and isoproterenol-stimulated myocyte contraction, relaxation and [Ca2+]iT. Conclusions Hypothyroidism produces intrinsic defects of LV myocyte force-generating capacity and relaxation with β-AR desensitization. Up-regulation of cadiomyocyte iNOS may promote progressive cardiac dysfunction in

  17. Vgl-4, a novel member of the vestigial-like family of transcription cofactors, regulates alpha1-adrenergic activation of gene expression in cardiac myocytes.

    PubMed

    Chen, Hsiao-Huei; Mullett, Steven J; Stewart, Alexandre F R

    2004-07-16

    Cardiac and skeletal muscle genes are regulated by the transcriptional enhancer factor (TEF-1) family of transcription factors. In skeletal muscle, TEF-1 factors interact with a skeletal muscle-specific cofactor called Vestigial-like 2 (Vgl-2) that is related to the Drosophila protein Vestigial. Here, we characterize Vgl-4, the only member of the Vestigial-like family expressed in the heart. Unlike other members of the Vgl family that have a single TEF-1 interaction domain called the tondu (TDU) motif, Vgl-4 has two TDU motifs in its carboxyl-terminal domain. Like other Vgl factors, Vgl-4 physically interacts with TEF-1 in an immunoprecipitation assay. Vgl-4 functionally interacts with TEF-1 and also with myocyte enhancer factor 2 in a mammalian two-hybrid assay. Overexpression of Vgl-4 in cardiac myocytes interfered with the basal expression and alpha1-adrenergic receptor-dependent activation of a TEF-1-dependent skeletal alpha-actin promoter. In cardiac myocytes cultured in serum and in serum-free medium, a myc-tagged Vgl-4 protein was located in the nucleus and cytoplasm but was exported from the nucleus when cells were treated with alpha1-adrenergic receptor agonist. A chimeric nuclear-retained Vgl-4 protein inhibited alpha1-adrenergic receptor-dependent activation. In contrast, deletion of the TDU motifs of Vgl-4 prevented Vgl-4 nuclear localization, relieved Vgl-4 interference of basal activity, and enhanced alpha1-adrenergic up-regulation of the skeletal alpha-actin promoter. Nuclear export of Vgl-4 is dependent on the nuclear exportin CRM-1. These results suggest that Vgl-4 modulates the activity of TEF-1 factors and counteracts alpha1-adrenergic activation of gene expression in cardiac myocytes.

  18. Mechanism of alpha-2 adrenergic modulation of canine cardiac Purkinje action potential.

    PubMed

    Lee, H C; Cai, J J; Arnar, D O; Shibata, E F; Martins, J B

    1996-08-01

    We reported recently that stimulation of postjunctional alpha-2 adrenergic receptors prolongs the action potential durations (APD) of isolated canine Purkinje fibers. With standard microelectrode techniques, we examined the ionic mechanism through which alpha-2 adrenergic stimulation prolonged Purkinje APD, by measuring the effects of inhibitors of the various plateau currents on the alpha-2-mediated prolongation of APD. The alpha-2-specific agonist UK 14,304 (0.1 microM) prolonged the Purkinje APD at 50% repolarization and the APD at 90% repolarization, and these effects were inhibited by yohimbine (0.1 microM). The Purkinje APD at 50% repolarization and the APD at 90% repolarization were prolonged significantly with the transient outward potassium current inhibitor 4-aminopyridine (1 mM), the rapid component of delayed rectifier potassium current inhibitor d-sotalol (10 microM), the slow component of delayed rectifier potassium current inhibitor indapamide (0.1 microM) and the chloride current inhibitor mefenamic acid (10 nM) and were shortened significantly with the calcium current inhibitor nifedipine (0.3 microM). Prolongation of Purkinje APD at 50% repolarization and APD at 90% repolarization by UK 14,304 remained intact in the presence of d-sotalol, indapamide, mefenamic acid and nifedipine. All of these UK 14,304 effects were significantly reversed by yohimbine. Only in the presence of 4-aminopyridine did UK 14,304 fail to prolong Purkinje APD. The phase 1 magnitudes of Purkinje action potentials were also significantly inhibited by UK 14,304. This effect was completely abolished only in the presence of 4-aminopyridine. These results suggest that inhibition of the 4-aminopyridine-sensitive transient outward potassium current is the major ionic mechanism by which alpha-2 adrenergic stimulation prolongs Purkinje APD.

  19. Cardiomyocyte Circadian Oscillations Are Cell-Autonomous, Amplified by β-Adrenergic Signaling, and Synchronized in Cardiac Ventricle Tissue

    PubMed Central

    Welsh, David K.

    2016-01-01

    Circadian clocks impact vital cardiac parameters such as blood pressure and heart rate, and adverse cardiac events such as myocardial infarction and sudden cardiac death. In mammals, the central circadian pacemaker, located in the suprachiasmatic nucleus of the hypothalamus, synchronizes cellular circadian clocks in the heart and many other tissues throughout the body. Cardiac ventricle explants maintain autonomous contractions and robust circadian oscillations of clock gene expression in culture. In the present study, we examined the relationship between intrinsic myocardial function and circadian rhythms in cultures from mouse heart. We cultured ventricular explants or dispersed cardiomyocytes from neonatal mice expressing a PER2::LUC bioluminescent reporter of circadian clock gene expression. We found that isoproterenol, a β-adrenoceptor agonist known to increase heart rate and contractility, also amplifies PER2 circadian rhythms in ventricular explants. We found robust, cell-autonomous PER2 circadian rhythms in dispersed cardiomyocytes. Single-cell rhythms were initially synchronized in ventricular explants but desynchronized in dispersed cells. In addition, we developed a method for long-term, simultaneous monitoring of clock gene expression, contraction rate, and basal intracellular Ca2+ level in cardiomyocytes using PER2::LUC in combination with GCaMP3, a genetically encoded fluorescent Ca2+ reporter. In contrast to robust PER2 circadian rhythms in cardiomyocytes, we detected no rhythms in contraction rate and only weak rhythms in basal Ca2+ level. In summary, we found that PER2 circadian rhythms of cardiomyocytes are cell-autonomous, amplified by adrenergic signaling, and synchronized by intercellular communication in ventricle explants, but we detected no robust circadian rhythms in contraction rate or basal Ca2+. PMID:27459195

  20. Delta-opioid augments cardiac contraction through β-adrenergic and CGRP-receptor co-signaling.

    PubMed

    Nguyen, Vince T; Wu, Yewen; Guillory, Ashley N; McConnell, Bradley K; Fujise, Kenichi; Huang, Ming-He

    2012-01-01

    Cardiac epinephrine and calcitonin gene-related peptide (CGRP) are produced by intrinsic cardiac adrenergic cells (ICA cells) residing in human and animal hearts. ICA cells are neuroparicine cells expressing δ-opioid receptors (DOR). We hypothesized that δ-opioid stimulation of ICA cells enhances epinephrine and CGRP release, which results in the augmentation of heart contraction. Rats were injected with DOR-agonist DPDPE (100 μg/kg) with or without 10-min pretreatment with either β-adrenergic receptor (β-AR) blocker propranolol (2mg/kg) or CGRP-receptor (CGRPR) blocker CGRP(8-37) (300 μg/kg), or their combination. Hemodynamics were monitored with echocardiogram and systolic blood pressure (SBP) was monitored via a tail arterial catheter. Changes in left ventricular fraction-shortening (LVFS) and heart rate (HR) were observed at 5-min after DPDPE infusion. At 5-min DPDPE induced a 36 ± 18% (p<0.001) increase of the LVFS, which continues to increase to 51 ± 24% (p<0.0001) by 10 min, and 68 ± 19% (p<0.001) by 20 min. The increase in LVFS was accompanied by the decrease of HR by 9±5% (p<0.01) by 5 min and 11 ± 6% (p<0.001) by 15 min post DPDPE infusion. This magnitude of HR reduction was observed for the remainder of the 20 min. Despite the HR-reduction, cardiac output was increased by 17 ± 8% (p<0.05) and 28±5% (p<0.001) by 5- and 20-min post DPDPE administration, respectively. There was a modest (9 ± 9%, p=0.03) decrease in SBP that was not apparent until 20 min post DPDPE infusion. The positive inotropism of DPDPE was abrogated in animals pretreated with propranolol, CGRP(8-37), or combined propranolol+CGRP(8-37). Furthermore, in whole animal and cardiomyocyte cell culture preparations, DPDPE induced myocardial protein-kinase A (PKA) activation which was abrogated in the animals pretreated with propranolol+CGRP(8-37). DOR agonists augment myocardial contraction through enhanced β-AR and CGRPR co-signaling. Copyright © 2011 Elsevier Inc. All rights

  1. Alpha-1-adrenergic receptors in heart failure: the adaptive arm of the cardiac response to chronic catecholamine stimulation.

    PubMed

    Jensen, Brian C; OʼConnell, Timothy D; Simpson, Paul C

    2014-04-01

    Alpha-1-adrenergic receptors (ARs) are G protein-coupled receptors activated by catecholamines. The alpha-1A and alpha-1B subtypes are expressed in mouse and human myocardium, whereas the alpha-1D protein is found only in coronary arteries. There are far fewer alpha-1-ARs than beta-ARs in the nonfailing heart, but their abundance is maintained or increased in the setting of heart failure, which is characterized by pronounced chronic elevation of catecholamines and beta-AR dysfunction. Decades of evidence from gain and loss-of-function studies in isolated cardiac myocytes and numerous animal models demonstrate important adaptive functions for cardiac alpha-1-ARs to include physiological hypertrophy, positive inotropy, ischemic preconditioning, and protection from cell death. Clinical trial data indicate that blocking alpha-1-ARs is associated with incident heart failure in patients with hypertension. Collectively, these findings suggest that alpha-1-AR activation might mitigate the well-recognized toxic effects of beta-ARs in the hyperadrenergic setting of chronic heart failure. Thus, exogenous cardioselective activation of alpha-1-ARs might represent a novel and viable approach to the treatment of heart failure.

  2. Alpha-1-Adrenergic Receptors in Heart Failure: The Adaptive Arm of the Cardiac Response to Chronic Catecholamine Stimulation

    PubMed Central

    Jensen, Brian C.; O'Connell, Timothy D.; Simpson, Paul C.

    2013-01-01

    Alpha-1-adrenergic receptors are G-protein coupled receptors (GPCRs) activated by catecholamines. The alpha-1A and alpha-1B subtypes are expressed in mouse and human myocardium, whereas the alpha-1D protein is found only in coronary arteries. There are far fewer alpha-1-ARs than beta-ARs in the non-failing heart, but their abundance is maintained or increased in the setting of heart failure, which is characterized by pronounced chronic elevation of catecholamines and b□eta-AR dysfunction. Decades of evidence from gain- and loss-of-function studies in isolated cardiac myocytes and numerous animal models demonstrate important adaptive functions for cardiac alpha-1-ARs, to include physiological hypertrophy, positive inotropy, ischemic preconditioning, and protection from cell death. Clinical trial data indicate that blocking alpha-1-ARs is associated with incident heart failure in patients with hypertension. Collectively, these findings suggest that alpha-1-AR activation might mitigate the well-recognized toxic effects of beta-ARs in the hyperadrenergic setting of chronic heart failure. Thus, exogenous cardioselective activation of alpha-1-ARs might represent a novel and viable approach to the treatment of heart failure. PMID:24145181

  3. GRK2 blockade with βARKct is essential for cardiac β2-adrenergic receptor signaling towards increased contractility

    PubMed Central

    2013-01-01

    Background β1- and β2–adrenergic receptors (ARs) play distinct roles in the heart, e.g. β1AR is pro-contractile and pro-apoptotic but β2AR anti-apoptotic and only weakly pro-contractile. G protein coupled receptor kinase (GRK)-2 desensitizes and opposes βAR pro-contractile signaling by phosphorylating the receptor and inducing beta-arrestin (βarr) binding. We posited herein that GRK2 blockade might enhance the pro-contractile signaling of the β2AR subtype in the heart. We tested the effects of cardiac-targeted GRK2 inhibition in vivo exclusively on β2AR signaling under normal conditions and in heart failure (HF). Results We crossed β1AR knockout (B1KO) mice with cardiac-specific transgenic mice expressing the βARKct, a known GRK2 inhibitor, and studied the offspring under normal conditions and in post-myocardial infarction (MI). βARKct expression in vivo proved essential for β2AR-dependent contractile function, as β2AR stimulation with isoproterenol fails to increase contractility in either healthy or post-MI B1KO mice and it only does so in the presence of βARKct. The main underlying mechanism for this is blockade of the interaction of phosphodiesterase (PDE) type 4D with the cardiac β2AR, which is normally mediated by the actions of GRK2 and βarrs on the receptor. The molecular “brake” that PDE4D poses on β2AR signaling to contractility stimulation is thus “released”. Regarding the other beneficial functions of cardiac β2AR, βARKct increased overall survival of the post-MI B1KO mice progressing to HF, via a decrease in cardiac apoptosis and an increase in wound healing-associated inflammation early (at 24 hrs) post-MI. However, these effects disappear by 4 weeks post-MI, and, in their place, upregulation of the other major GRK in the heart, GRK5, is observed. Conclusions GRK2 inhibition in vivo with βARKct is absolutely essential for cardiac β2AR pro-contractile signaling and function. In addition, β2AR anti-apoptotic signaling in

  4. GRK2 blockade with βARKct is essential for cardiac β2-adrenergic receptor signaling towards increased contractility.

    PubMed

    Salazar, Norma C; Vallejos, Ximena; Siryk, Ashley; Rengo, Giuseppe; Cannavo, Alessandro; Liccardo, Daniela; De Lucia, Claudio; Gao, Erhe; Leosco, Dario; Koch, Walter J; Lymperopoulos, Anastasios

    2013-08-28

    β1- and β2-adrenergic receptors (ARs) play distinct roles in the heart, e.g. β1AR is pro-contractile and pro-apoptotic but β2AR anti-apoptotic and only weakly pro-contractile. G protein coupled receptor kinase (GRK)-2 desensitizes and opposes βAR pro-contractile signaling by phosphorylating the receptor and inducing beta-arrestin (βarr) binding. We posited herein that GRK2 blockade might enhance the pro-contractile signaling of the β2AR subtype in the heart. We tested the effects of cardiac-targeted GRK2 inhibition in vivo exclusively on β2AR signaling under normal conditions and in heart failure (HF). We crossed β1AR knockout (B1KO) mice with cardiac-specific transgenic mice expressing the βARKct, a known GRK2 inhibitor, and studied the offspring under normal conditions and in post-myocardial infarction (MI). βARKct expression in vivo proved essential for β2AR-dependent contractile function, as β2AR stimulation with isoproterenol fails to increase contractility in either healthy or post-MI B1KO mice and it only does so in the presence of βARKct. The main underlying mechanism for this is blockade of the interaction of phosphodiesterase (PDE) type 4D with the cardiac β2AR, which is normally mediated by the actions of GRK2 and βarrs on the receptor. The molecular "brake" that PDE4D poses on β2AR signaling to contractility stimulation is thus "released". Regarding the other beneficial functions of cardiac β2AR, βARKct increased overall survival of the post-MI B1KO mice progressing to HF, via a decrease in cardiac apoptosis and an increase in wound healing-associated inflammation early (at 24 hrs) post-MI. However, these effects disappear by 4 weeks post-MI, and, in their place, upregulation of the other major GRK in the heart, GRK5, is observed. GRK2 inhibition in vivo with βARKct is absolutely essential for cardiac β2AR pro-contractile signaling and function. In addition, β2AR anti-apoptotic signaling in post-MI HF is augmented by

  5. AKAP13 Rho-GEF and PKD-Binding Domain Deficient Mice Develop Normally but Have an Abnormal Response to β-Adrenergic-Induced Cardiac Hypertrophy

    PubMed Central

    Spindler, Matthew J.; Burmeister, Brian T.; Huang, Yu; Hsiao, Edward C.; Salomonis, Nathan; Scott, Mark J.; Srivastava, Deepak; Carnegie, Graeme K.; Conklin, Bruce R.

    2013-01-01

    Background A-kinase anchoring proteins (AKAPs) are scaffolding molecules that coordinate and integrate G-protein signaling events to regulate development, physiology, and disease. One family member, AKAP13, encodes for multiple protein isoforms that contain binding sites for protein kinase A (PKA) and D (PKD) and an active Rho-guanine nucleotide exchange factor (Rho-GEF) domain. In mice, AKAP13 is required for development as null embryos die by embryonic day 10.5 with cardiovascular phenotypes. Additionally, the AKAP13 Rho-GEF and PKD-binding domains mediate cardiomyocyte hypertrophy in cell culture. However, the requirements for the Rho-GEF and PKD-binding domains during development and cardiac hypertrophy are unknown. Methodology/Principal Findings To determine if these AKAP13 protein domains are required for development, we used gene-trap events to create mutant mice that lacked the Rho-GEF and/or the protein kinase D-binding domains. Surprisingly, heterozygous matings produced mutant mice at Mendelian ratios that had normal viability and fertility. The adult mutant mice also had normal cardiac structure and electrocardiograms. To determine the role of these domains during β-adrenergic-induced cardiac hypertrophy, we stressed the mice with isoproterenol. We found that heart size was increased similarly in mice lacking the Rho-GEF and PKD-binding domains and wild-type controls. However, the mutant hearts had abnormal cardiac contractility as measured by fractional shortening and ejection fraction. Conclusions These results indicate that the Rho-GEF and PKD-binding domains of AKAP13 are not required for mouse development, normal cardiac architecture, or β-adrenergic-induced cardiac hypertrophic remodeling. However, these domains regulate aspects of β-adrenergic-induced cardiac hypertrophy. PMID:23658642

  6. β-adrenergic Responsiveness in the Type 2 Diabetic Heart: Effects on Cardiac Reserve.

    PubMed

    Wilson, Genevieve A; Wilson, Luke C; Lamberts, Regis R; Majeed, Kamran; Lal, Sudish; Wilkins, Gerard T; Baldi, James C

    2016-12-14

    Type 2 diabetes (T2D) is associated with reduced cardiac reserve and aerobic capacity. Altered myocardial autonomic nervous regulation has been demonstrated in humans with diabetes (indirectly) and animal models (directly).

  7. Cardiac Dysfunction Induced by Obesity Is Not Related to β-Adrenergic System Impairment at the Receptor-Signalling Pathway

    PubMed Central

    Sant’Ana, Paula Grippa; de Campos, Dijon Henrique Salomé; de Tomasi, Loreta Casquel; Luvizotto, Renata de Azevedo Mello; Cicogna, Antonio Carlos; Leopoldo, André Soares; Lima-Leopoldo, Ana Paula

    2015-01-01

    Obesity has been shown to impair myocardial performance. Some factors have been suggested as responsible for possible cardiac abnormalities in models of obesity, among them beta-adrenergic (βA) system, an important mechanism of regulation of myocardial contraction and relaxation. The objective of present study was to evaluate the involvement of βA system components in myocardial dysfunction induced by obesity. Thirty-day-old male Wistar rats were distributed in control (C, n = 25) and obese (Ob, n = 25) groups. The C group was fed a standard diet and Ob group was fed four unsaturated high-fat diets for 15 weeks. Cardiac function was evaluated by isolated papillary muscle preparation and βA system evaluated by using cumulative concentrations of isoproterenol and Western blot. After 15 weeks, the Ob rats developed higher adiposity index than C rats and several comorbidities; however, were not associated with changes in systolic blood pressure. Obesity caused structural changes and the myocardial responsiveness to post-rest contraction stimulus and increased extracellular calcium (Ca2+) was compromised. There were no changes in cardiac function between groups after βA stimulation. The obesity was not accompanied by changes in protein expression of G protein subunit alpha (Gsα) and βA receptors (β1AR and β2AR). In conclusion, the myocardial dysfunction caused by unsaturated high-fat diet-induced obesity, after 15 weeks, is not related to βAR system impairment at the receptor-signalling pathway. PMID:26390297

  8. Restraint stress exacerbates cardiac and adipose tissue pathology via β-adrenergic signaling in rats with metabolic syndrome.

    PubMed

    Matsuura, Natsumi; Nagasawa, Kai; Minagawa, Yuji; Ito, Shogo; Sano, Yusuke; Yamada, Yuichiro; Hattori, Takuya; Watanabe, Shogo; Murohara, Toyoaki; Nagata, Kohzo

    2015-05-15

    Restraint stress stimulates sympathetic nerve activity and can affect adiposity and metabolism. However, the effects of restraint stress on cardiovascular and metabolic disorders in metabolic syndrome (MetS) have remained unclear. We investigated the effects of chronic restraint stress and β-adrenergic receptor (β-AR) blockade on cardiac and adipose tissue pathology and metabolic disorders in a rat model of MetS. DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats. Rats were exposed to restraint stress (restraint cage, 2 h/day) for 4 wk from 9 wk of age with or without daily subcutaneous administration of the β-AR blocker propranolol (2 mg/kg). Age-matched homozygous lean littermates of DS/obese rats (DahlS.Z-Lepr(+)/Lepr(+) rats) served as control animals. Chronic restraint stress exacerbated hypertension as well as left ventricular hypertrophy, fibrosis, diastolic dysfunction, and oxidative stress in a manner sensitive to propranolol treatment. Restraint stress attenuated body weight gain in DS/obese rats, and this effect tended to be reversed by propranolol (P = 0.0682). Restraint stress or propranolol did not affect visceral or subcutaneous fat mass. However, restraint stress potentiated cardiac and visceral adipose tissue inflammation in DS/obese rats, and these effects were ameliorated by propranolol. Restraint stress also exacerbated glucose intolerance, insulin resistance, and abnormal lipid metabolism in a manner sensitive to propranolol. In addition, restraint stress increased urinary norepinephrine excretion, and propranolol attenuated this effect. Our results thus implicate β-ARs in the exacerbation of cardiac and adipose tissue pathology and abnormal glucose and lipid metabolism induced by restraint stress in this model of MetS.

  9. Tubulin polymerization disrupts cardiac β-adrenergic regulation of late INa

    PubMed Central

    Dybkova, Nataliya; Wagner, Stefan; Backs, Johannes; Hund, Thomas J.; Mohler, Peter J.; Sowa, Thomas; Nikolaev, Viacheslav O.; Maier, Lars S.

    2014-01-01

    Aims The anticancer drug paclitaxel (TXL) that polymerizes microtubules is associated with arrhythmias and sinus node dysfunction. TXL can alter membrane expression of Na channels (NaV1.5) and Na current (INa), but the mechanisms are unknown. Calcium/calmodulin-dependent protein kinase II (CaMKII) can be activated by β-adrenergic stimulation and regulates INa gating. We tested whether TXL interferes with isoproterenol (ISO)-induced activation of CaMKII and consequent INa regulation. Methods and results In wild-type mouse myocytes, the addition of ISO (1 µmol/L) resulted in increased CaMKII auto-phosphorylation (western blotting). This increase was completely abolished after pre-treatment with TXL (100 µmol/L, 1.5 h). The mechanism was further investigated in human embryonic kidney cells. TXL inhibited the ISO-induced β-arrestin translocation. Interestingly, both knockdown of β-arrestin2 expression using small interfering RNA and inhibition of exchange protein directly activated by cAMP (Epac) blocked the ISO-induced CaMKII auto-phosphorylation similar to TXL. The generation of cAMP, however, was unaltered (Epac1-camps). CaMKII-dependent Na channel function was measured using patch-clamp technique in isolated cardiomyoctes. ISO stimulation failed to induce CaMKII-dependent enhancement of late INa and Na channel inactivation (negative voltage shift in steady-state activation and enhanced intermediate inactivation) after pre-incubation with TXL. Consistent with this, TXL also inhibited ISO-induced CaMKII-specific Na channel phosphorylation (at serine 571 of NaV1.5). Conclusion Pre-incubation with TXL disrupts the ISO-dependent CaMKII activation and consequent Na channel regulation. This may be important for patients receiving TXL treatments, but also relevant for conditions of increased CaMKII expression and enhanced β-adrenergic stimulation like in heart failure. PMID:24812278

  10. Increased intracellular magnesium attenuates β-adrenergic stimulation of the cardiac Ca(V)1.2 channel.

    PubMed

    Brunet, Sylvain; Scheuer, Todd; Catterall, William A

    2013-01-01

    Increases in intracellular Mg(2+) (Mg(2+)(i)), as observed in transient cardiac ischemia, decrease L-type Ca(2+) current of mammalian ventricular myocytes (VMs). However, cardiac ischemia is associated with an increase in sympathetic tone, which could stimulate L-type Ca(2+) current. Therefore, the effect of Mg(2+)(i) on L-type Ca(2+) current in the context of increased sympathetic tone was unclear. We tested the impact of increased Mg(2+)(i) on the β-adrenergic stimulation of L-type Ca(2+) current. Exposure of acutely dissociated adult VMs to higher Mg(2+)(i) concentrations decreased isoproterenol stimulation of the L-type Ca(2+) current from 75 ± 13% with 0.8 mM Mg(2+)(i) to 20 ± 8% with 2.4 mM Mg(2+)(i). We activated this signaling cascade at different steps to determine the site or sites of Mg(2+)(i) action. Exposure of VMs to increased Mg(2+)(i) attenuated the stimulation of L-type Ca(2+) current induced by activation of adenylyl cyclase with forskolin, inhibition of cyclic nucleotide phosphodiesterases with isobutylmethylxanthine, and inhibition of phosphoprotein phosphatases I and IIA with calyculin A. These experiments ruled out significant effects of Mg(2+)(i) on these upstream steps in the signaling cascade and suggested that Mg(2+)(i) acts directly on Ca(V)1.2 channels. One possible site of action is the EF-hand in the proximal C-terminal domain, just downstream in the signaling cascade from the site of regulation of Ca(V)1.2 channels by protein phosphorylation on the C terminus. Consistent with this hypothesis, Mg(2+)(i) had no effect on enhancement of Ca(V)1.2 channel activity by the dihydropyridine agonist (S)-BayK8644, which activates Ca(V)1.2 channels by binding to a site formed by the transmembrane domains of the channel. Collectively, our results suggest that, in transient ischemia, increased Mg(2+)(i) reduces stimulation of L-type Ca(2+) current by the β-adrenergic receptor by directly acting on Ca(V)1.2 channels in a cell-autonomous manner

  11. Developmental changes in the role of a pertussis toxin sensitive guanine nucleotide binding protein in the rat cardiac alpha sub 1 -adrenergic system

    SciTech Connect

    Han, H.M.

    1989-01-01

    During development, the cardiac alpha{sub 1}-adrenergic chronotropic response changes from positive in the neonate to negative in the adult. This thesis examined the possibility of a developmental change in coupling of a PT-sensitive G-protein to the alpha{sub 1}-adrenergic receptor. Radioligand binding experiments performed with the iodinated alpha{sub 1}-selective radioligand ({sup 125}I)-I-2-({beta}-(4-hydroxphenyl)ethylaminomethyl)tetralone (({sup 125}I)-IBE 2254) demonstrated that the alpha{sub 1}-adrenergic receptor is coupled to a G-protein in both neonatal and adult rat hearts. However, in the neonate the alpha{sub 1}-adrenergic receptor is coupled to a PT-insensitive G-protein, whereas in the adult the alpha{sub 1}-adrenergic receptor is coupled to both a PT-insensitive and a PT-sensitive G-protein. Consistent with the results from binding experiments, PT did not have any effect on the alpha{sub 1}-mediated positive chronotropic response in the neonate, whereas in the adult the alpha{sub 1}-mediated negative chronotropic response was completely converted to a positive one after PT-treatment. This thesis also examined the possibility of an alteration in coupling of the alpha{sub 1}-adrenergic receptor to its effector under certain circumstances such as high potassium (K{sup +}) depolarization in nerve-muscle (NM) co-cultures, a system which has been previously shown to be a convenient in vitro model to study the mature inhibitory alpha{sub 1}-response.

  12. Dynamic mass redistribution analysis of endogenous β-adrenergic receptor signaling in neonatal rat cardiac fibroblasts.

    PubMed

    Carter, Rhonda L; Grisanti, Laurel A; Yu, Justine E; Repas, Ashley A; Woodall, Meryl; Ibetti, Jessica; Koch, Walter J; Jacobson, Marlene A; Tilley, Douglas G

    2014-02-01

    Label-free systems for the agnostic assessment of cellular responses to receptor stimulation have been shown to provide a sensitive method to dissect receptor signaling. β-adenergic receptors (βAR) are important regulators of normal and pathologic cardiac function and are expressed in cardiomyocytes as well as cardiac fibroblasts, where relatively fewer studies have explored their signaling responses. Using label-free whole cell dynamic mass redistribution (DMR) assays we investigated the response patterns to stimulation of endogenous βAR in primary neonatal rat cardiac fibroblasts (NRCF). Catecholamine stimulation of the cells induced a negative DMR deflection resulting in a concentration-dependent pharmacological response that was competitively blocked by βAR blockade and non-competitively blocked by irreversible uncoupling of Gs proteins. Pharmacological profiling of subtype-selective βAR agonists and antagonists revealed a dominant role of β2AR in mediating the DMR responses, consistent with the relative expression levels of β2AR and β1AR in NRCF. Additionally, βAR-mediated cAMP generation was assessed via a fluorescence biosensor, revealing similar kinetics between DMR responses and cAMP generation. As such, βAR-dependent DMR responses were enhanced via inhibition of cAMP degradation, as well as dynamin-mediated receptor internalization. Finally, we assessed G protein-independent βAR signaling through epidermal growth factor receptor (EGFR). While inhibition of EGFR reduced the DMR response to βAR stimulation, our results demonstrate that G protein-dependent signaling produces a majority of the biological response to βAR stimulation in NRCF. Altogether, measurement of DMR responses in primary cardiac fibroblasts provides a sensitive readout for investigating endogenous βAR signaling via both G protein-dependent and -independent pathways.

  13. β-adrenergic effects on cardiac myofilaments and contraction in an integrated rabbit ventricular myocyte model

    PubMed Central

    Negroni, Jorge A.; Morotti, Stefano; Lascano, Elena C.; Gomes, Aldrin V.; Grandi, Eleonora; Puglisi, José L; Bers, Donald M.

    2015-01-01

    A five-state model of myofilament contraction was integrated into a well-established rabbit ventricular myocyte model of ion channels, Ca2+ transporters and kinase signaling to analyze the relative contribution of different phosphorylation targets to the overall mechanical response driven by β-adrenergic stimulation (β-AS). β-AS effect on sarcoplasmic reticulum Ca2+ handling, Ca2+, K+ and Cl− currents, and Na+/K+-ATPase properties were included based on experimental data. The inotropic effect on the myofilaments was represented as reduced myofilament Ca2+ sensitivity (XBCa) and titin stiffness, and increased cross-bridge (XB) cycling rate (XBcy). Assuming independent roles of XBCa and XBcy, the model reproduced experimental β-AS responses on action potentials and Ca2+ transient amplitude and kinetics. It also replicated the behavior of force-Ca2+, release-restretch, length-step, stiffness-frequency and force-velocity relationships, and increased force and shortening in isometric and isotonic twitch contractions. The β-AS effect was then switched off from individual targets to analyze their relative impact on contractility. Preventing β-AS effects on L-type Ca2+ channels or phospholamban limited Ca2+ transients and contractile responses in parallel, while blocking phospholemman and K+ channel (IKs) effects enhanced Ca2+ and inotropy. Removal of β-AS effects from XBCa enhanced contractile force while decreasing peak Ca2+ (due to greater Ca2+ buffering), but had less effect on shortening. Conversely, preventing β-AS effects on XBcy preserved Ca2+ transient effects, but blunted inotropy (both isometric force and especially shortening). Removal of titin effects had little impact on contraction. Finally, exclusion of β-AS from XBCa and XBcy while preserving effects on other targets resulted in preserved peak isometric force response (with slower kinetics) but nearly abolished enhanced shortening. β-AS effects on XBCa vs. XBcy have greater impact on isometric

  14. β-adrenergic effects on cardiac myofilaments and contraction in an integrated rabbit ventricular myocyte model.

    PubMed

    Negroni, Jorge A; Morotti, Stefano; Lascano, Elena C; Gomes, Aldrin V; Grandi, Eleonora; Puglisi, José L; Bers, Donald M

    2015-04-01

    A five-state model of myofilament contraction was integrated into a well-established rabbit ventricular myocyte model of ion channels, Ca(2+) transporters and kinase signaling to analyze the relative contribution of different phosphorylation targets to the overall mechanical response driven by β-adrenergic stimulation (β-AS). β-AS effect on sarcoplasmic reticulum Ca(2+) handling, Ca(2+), K(+) and Cl(-) currents, and Na(+)/K(+)-ATPase properties was included based on experimental data. The inotropic effect on the myofilaments was represented as reduced myofilament Ca(2+) sensitivity (XBCa) and titin stiffness, and increased cross-bridge (XB) cycling rate (XBcy). Assuming independent roles of XBCa and XBcy, the model reproduced experimental β-AS responses on action potentials and Ca(2+) transient amplitude and kinetics. It also replicated the behavior of force-Ca(2+), release-restretch, length-step, stiffness-frequency and force-velocity relationships, and increased force and shortening in isometric and isotonic twitch contractions. The β-AS effect was then switched off from individual targets to analyze their relative impact on contractility. Preventing β-AS effects on L-type Ca(2+) channels or phospholamban limited Ca(2+) transients and contractile responses in parallel, while blocking phospholemman and K(+) channel (IKs) effects enhanced Ca(2+) and inotropy. Removal of β-AS effects from XBCa enhanced contractile force while decreasing peak Ca(2+) (due to greater Ca(2+) buffering), but had less effect on shortening. Conversely, preventing β-AS effects on XBcy preserved Ca(2+) transient effects, but blunted inotropy (both isometric force and especially shortening). Removal of titin effects had little impact on contraction. Finally, exclusion of β-AS from XBCa and XBcy while preserving effects on other targets resulted in preserved peak isometric force response (with slower kinetics) but nearly abolished enhanced shortening. β-AS effects on XBCa and XBcy

  15. Remodelling of cardiac sympathetic re-innervation with thoracic spinal cord stimulation improves left ventricular function in a porcine model of heart failure.

    PubMed

    Liao, Song-Yan; Liu, Yuan; Zuo, Mingliang; Zhang, Yuelin; Yue, Wensheng; Au, Ka-Wing; Lai, Wing-Hon; Wu, Yangsong; Shuto, Chika; Chen, Peter; Siu, Chung-Wah; Schwartz, Peter J; Tse, Hung-Fat

    2015-12-01

    Thoracic spinal cord stimulation (SCS) has been shown to improve left ventricular ejection fraction (LVEF) in heart failure (HF). Nevertheless, the optimal duration (intermittent vs. continuous) of stimulation and the mechanisms of action remain unclear. We performed chronic thoracic SCS at the level of T1-T3 (50 Hz, pulse width 0.2 ms) in 30 adult pigs with HF induced by myocardial infarction and rapid ventricular pacing for 4 weeks. All the animals were treated with daily oral metoprolol succinate (25 mg) plus ramipril (2.5 mg), and randomized to a control group (n = 10), intermittent SCS (4 h ×3, n = 10) or continuous SCS (24 h, n = 10) for 10 weeks. Serial measurements of LVEF and +dP/dt and serum levels of norepinephrine and B-type natriuretic peptide (BNP) were measured. After sacrifice, immunohistological studies of myocardial sympathetic and parasympathetic nerve sprouting and innervation were performed. Echocardiogram revealed a significant increase in LVEF and +dP/dt at 10 weeks in both the intermittent and continuous SCS group compared with controls (P < 0.05). In both SCS groups, there was diffuse sympathetic nerve sprouting over the infarct, peri-infarct, and normal regions compared with only the peri-infarct and infarct regions in the control group. In addition, sympathetic innervation at the peri-infarct and infarct regions was increased following SCS, but decreased in the control group. Myocardium norepinephrine spillover and serum BNP at 10 weeks was significantly decreased only in the continuous SCS group (P < 0.05). In a porcine model of HF, SCS induces significant remodelling of cardiac sympathetic innervation over the peri-infarct and infarct regions and is associated with improved LV function and reduced myocardial norepinephrine spillover. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  16. cAMP compartmentation is responsible for a local activation of cardiac Ca2+ channels by beta-adrenergic agonists.

    PubMed Central

    Jurevicius, J; Fischmeister, R

    1996-01-01

    The role of cAMP subcellular compartmentation in the progress of beta-adrenergic stimulation of cardiac L-type calcium current (ICa) was investigated by using a method based on the use of whole-cell patch-clamp recording and a double capillary for extracellular microperfusion. Frog ventricular cells were sealed at both ends to two patch-clamp pipettes and positioned approximately halfway between the mouths of two capillaries that were separated by a 5-micron thin wall. ICa could be inhibited in one half or the other by omitting Ca2+ from one solution or the other. Exposing half of the cell to a saturating concentration of isoprenaline (ISO, 1 microM) produced a nonmaximal increase in ICa (347 +/- 70%; n = 4) since a subsequent application of ISO to the other part induced an additional effect of nearly similar amplitude to reach a 673 +/- 130% increase. However, half-cell exposure to forskolin (FSK, 30 microM) induced a maximal stimulation of ICa (561 +/- 55%; n = 4). This effect was not the result of adenylyl cyclase activation due to FSK diffusion in the nonexposed part of the cell. To determine the distant effects of ISO and FSK on ICa, the drugs were applied in a zero-Ca solution. Adding Ca2+ to the drug-containing solutions allowed us to record the local effect of the drugs. Dose-response curves for the local and distant effects of ISO and FSK on ICa were used as an index of cAMP concentration changes near the sarcolemma. We found that ISO induced a 40-fold, but FSK induced only a 4-fold, higher cAMP concentration close to the Ca2+ channels, in the part of the cell exposed to the drugs, than it did in the rest of the cell. cAMP compartmentation was greatly reduced after inhibition of phosphodiesterase activity with 3-isobutyl-methylxanthine, suggesting the colocalization of enzymes involved in the cAMP cascade. We conclude that beta-adrenergic receptors are functionally coupled to nearby Ca2+ channels via local elevations of cAMP. PMID:8552625

  17. Maximal exercise limitation in functionally overreached triathletes: role of cardiac adrenergic stimulation.

    PubMed

    Le Meur, Yann; Louis, Julien; Aubry, Anaël; Guéneron, Jacques; Pichon, Aurélien; Schaal, Karine; Corcuff, Jean-Benoît; Hatem, Stéphane N; Isnard, Richard; Hausswirth, Christophe

    2014-08-01

    Functional overreaching (F-OR) induced by heavy load endurance training programs has been associated with reduced heart rate values both at rest and during exercise. Because this phenomenon may reflect an impairment of cardiac response, this research was conducted to test this hypothesis. Thirty-five experienced male triathletes were tested (11 control and 24 overload subjects) before overloading (Pre), immediately after overloading (Mid), and after a 2-wk taper period (Post). Physiological responses were assessed during an incremental cycling protocol to volitional exhaustion, including catecholamines release, oxygen uptake (V̇o2), arteriovenous O2 difference, cardiac output (Q̇), and systolic (SBP) and diastolic blood pressure (DBP). Twelve subjects of the overload group developed signs of F-OR at Mid (decreased performance with concomitant high perceived fatigue), while 12 others did not [acute fatigue group (AF)]. V̇o2max was reduced only in F-OR subjects at Mid. Lower Q̇ and SBP values with greater arteriovenous O2 difference were reported in F-OR subjects at all exercising intensities, while no significant change was observed in the control and AF groups. A concomitant decrease in epinephrine excretion was reported only in the F-OR group. All values returned to baseline at Post. Following an overload endurance training program leading to F-OR, the cardiac response to exhaustive exercise is transiently impaired, possibly due to reduced epinephrine excretion. This finding is likely to explain the complex process of underperformance syndrome experienced by F-OR endurance athletes during heavy load programs.

  18. Influence of increased adrenergic activity and magnesium depletion on cardiac rhythm in alcohol withdrawal.

    PubMed Central

    Denison, H; Jern, S; Jagenburg, R; Wendestam, C; Wallerstedt, S

    1994-01-01

    OBJECTIVE--To investigate the prevalence of arrhythmias in alcoholic men during detoxification and its relation to neuroendocrine activation and electrolyte disturbances. DESIGN--Consecutive case-control study. SETTING--Primary and secondary care, detoxification ward. PATIENTS AND CONTROLS--19 otherwise healthy alcoholic men (DSM-III-R) with withdrawal symptoms necessitating detoxification in hospital. 19 age matched, healthy non-alcoholic men as controls for Holter recordings. INTERVENTIONS--Treatment with chlomethiazole; additional treatment with carbamazepine in patients with previous seizures. MAIN OUTCOME MEASURES--Computer based analyses of mean heart rate and arrhythmias from 24 hour Holter recordings, 24 hour urinary excretion of adrenaline and noradrenaline, magnesium retention measured by means of intravenous loading test, and serum concentrations of electrolytes. RESULTS--The 24 hour mean heart rate was higher in the alcoholic men (97.4 beats/minute, 95% confidence interval (CI) 91.2 to 103.6) than in the controls (69.6 beats/minute, 95% CI 65.4 to 73.8, P < 0.001). However, there was no difference in diurnal heart rate variation. The prevalence of premature supraventricular depolarisations was lower in the alcoholic men (P < 0.05). Neither atrial fibrillation nor malignant ventricular arrhythmias occurred. The sinus tachycardia in the alcoholic men correlated with the concomitant urinary excretion of catecholamines (P < 0.05). The mean serum magnesium concentration was 0.78 mmol/l (95% CI 0.73 to 0.83) in the alcoholic men and 0.83 mmol/l (95% CI 0.81 to 0.85) in a reference population of 55 men aged 40. Magnesium depletion (defined as magnesium retention > 30%) was detected in 10 alcoholic men (53%). Three alcoholic men had serum potassium concentrations < or = 3.3 mmol/l on admission. CONCLUSION--Increased adrenergic activity, magnesium depletion, and hypokalaemia are often seen after heavy drinking, but in alcoholic men without clinical heart disease

  19. Reversal of Myocyte Hypertrophy by Ventricular Unloading: Cardiac Improvement Without Adrenergic Receptor Upregulation and Relocalization

    PubMed Central

    Schnee, Pippa M.; Shah, Naeema; Bergheim, Marianne; Poindexter, Brian J.; Buja, L. Max; Myers, Timothy J.; Radovancevic, Branislav; Frazier, O. Howard; Bick, Roger J.

    2006-01-01

    In previous studies, we found that the improved contractile ability of cardiac myocytes from patients who have had left ventricular assist device (LVAD) support was due to a number of beneficial changes, most notably in calcium handling (increased sarcoplasmic reticulum calcium binding and uptake), improved integrity of cell membranes due to phospholipid reconstruction (reduced lysophospholipid content), and an upregulation of adrenoreceptors (increased adrenoreceptor numbers). However, in the case presented here, there was no increase in adrenoreceptor number, which is something that we usually find in core tissue at the time of LVAD removal or organ transplantation; also, there was no homogeneous postassist device receptor distribution. However, the patient was well maintained for 10 months following LVAD implantation, until a donor organ was available, regardless of the lack of adrenoreceptor improvement. We conclude from these studies that cardiac recovery is the result of the initiation of multiple repair mechanisms, and that the lack of expected changes, in this case increased adrenoreceptors, is not always an accurate indicator of anticipated outcome. We suggest that interventions and strategies have to consider multiple, beneficial changes due to unloading and target a number of biochemical and structural areas to produce improvement, even if not all of these improvements occur. PMID:16926784

  20. Cardioprotective Effect of Ulmus wallichiana Planchon in β-Adrenergic Agonist Induced Cardiac Hypertrophy

    PubMed Central

    Syed, Anees A.; Lahiri, Shibani; Mohan, Divya; Valicherla, Guru R.; Gupta, Anand P.; Kumar, Sudhir; Maurya, Rakesh; Bora, Himanshu K.; Hanif, Kashif; Gayen, Jiaur R.

    2016-01-01

    Ulmus wallichiana Planchon (Family: Ulmaceae), a traditional medicinal plant, was used in fracture healing in the folk tradition of Uttarakhand, Himalaya, India. The present study investigated the cardioprotective effect of ethanolic extract (EE) and butanolic fraction (BF) of U. wallichiana in isoprenaline (ISO) induced cardiac hypertrophy in Wistar rats. Cardiac hypertrophy was induced by ISO (5 mg/kg/day, subcutaneously) in rats. Treatment was performed by oral administration of EE and BF of U. wallichiana (500 and 50 mg/kg/day). The blood pressure (BP) and heart rate (HR) were measured by non-invasive blood pressure measurement technique. Plasma renin, Ang II, NO, and cGMP level were estimated using an ELISA kit. Angiotensin converting enzyme activity was estimated. BP and HR were significantly increased in ISO group (130.33 ± 1.67 mmHg vs. 111.78 ± 1.62 mmHg, p < 0.001 and 450.51 ± 4.90 beats/min vs. 347.82 ± 6.91 beats/min, respectively, p < 0.001). The BP and HR were significantly reduced (EE: 117.53 ± 2.27 mmHg vs. 130.33 ± 1.67 mmHg, p < 0.001, BF: 119.74 ± 3.32 mmHg vs. 130.33 ± 1.67 mmHg, p < 0.001); HR: (EE: 390.22 ± 8.24 beats/min vs. 450.51 ± 4.90 beats/min, p < 0.001, BF: 345.38 ± 6.79 beats/min vs. 450.51 ± 4.90 beats/min, p < 0.001) after the treatment of EE and BF of U. wallichiana, respectively. Plasma renin, Ang II, ACE activity was decreased and NO, cGMP level were increased. The EE and BF of U. wallichiana down regulated the expression of ANP, BNP, TNF-α, IL-6, MMP9, β1-AR, TGFβ1 and up regulated NOS3, ACE2 and Mas expression level, respectively. Thus, this study demonstrated that U. wallichiana has cardioprotective effect against ISO induced cardiac hypertrophy. PMID:28066255

  1. Adenylyl cyclase type 6 overexpression selectively enhances beta-adrenergic and prostacyclin receptor-mediated inhibition of cardiac fibroblast function because of colocalization in lipid rafts.

    PubMed

    Liu, Xiaoqiu; Thangavel, Muthusamy; Sun, Shu Qiang; Kaminsky, Joseph; Mahautmr, Penden; Stitham, Jeremiah; Hwa, John; Ostrom, Rennolds S

    2008-06-01

    Cardiac fibroblasts produce and degrade extracellular matrix and are critical in regulating cardiac remodeling and hypertrophy. Fibroblasts are activated by factors such as transforming growth factor beta and inhibited by agents that elevate 3',5'-cyclic adenosine monophosphate (cAMP) levels. cAMP signal generation and response is known to be compartmentalized in many cell types in part through the colocalization of receptors and specific adenylyl cyclase isoforms in lipid rafts and caveolae. The present study sought to define the localization of key G protein-coupled receptors with adenylyl cyclase type 6 (AC6) in lipid rafts of rat cardiac fibroblasts and to determine if this colocalization was functionally relevant. We found that cardiac fibroblasts produce cAMP in response to agonists for beta-adrenergic (isoproterenol), prostaglandin EP2 (butaprost), adenosine (adenosine-5'-N-ethylcarboxamide, NECA), and prostacyclin (beraprost) receptors. Overexpression of AC6 increased cAMP production stimulated by isoproterenol and beraprost but not by butaprost or NECA. A key function of fibroblasts is the production of collagen. Isoproterenol- and beraprostmediated inhibition of collagen synthesis was also enhanced by AC6 overexpression, while inhibition by butaprost and NECA were unaltered. Lipid raft fractions from cardiac fibroblasts contain the preponderance of beta-adrenergic receptors and AC6 but exclude EP2 receptors. While we could not determine the localization of native prostacyclin receptors, we were able to determine that epitope-tagged prostanoid IP receptors (IPR) expressed in COS7 cells did localize, in part, in lipid raft fractions. These findings indicate that IP receptors are expressed in lipid rafts and can activate raft-localized AC isoforms. AC6 is completely compartmentized in lipid raft domains where it is activated solely by coresident G protein-coupled receptors to regulate cardiac fibroblast function.

  2. Effect of postnatal lead exposure on the development of sympathetic innervation of the heart. [Rats

    SciTech Connect

    Abreu, M.E.

    1983-01-01

    To determine possible mechanisms for this Pb-induced cardiotoxicity, several neutrochemical parameters indicative of cardiac sympathetic innervation were measured in developing rats. Presynaptic indices of nerve terminal development which were studied included steady-state levels of norepinephrine, neuronal uptake and vesicular storage of /sup 3/H-norepinephrine. Analysis of postsynaptic development was accomplished by quantitating the density of ..beta..-adrenergic receptors and by measuring the activity of adenylate cyclase. Rat pups were exposed to Pb from birth to weaning (21 days) via the milk of dams whose drinking water contained 0.2% Pb acetate. This method and level of Pb treatment had no effect on body or heart weight development, however, it did result in a seven-fold increase in the blood Pb content (70-75 ..mu..g/dl) of the treated pups during the period of exposure. Pb exposure accelerated the development of sympathetic innervation of the heart as detected by significant increases in the vesicular uptake of /sup 3/H-norepinephrine and the steady-state concentration of norepinephrine measured at postnatal day 4. On the other hand, ontogeny of the neutronal uptake of /sup 3/H-norepinephrine in the heart and in the forebrain was not affected by Pb treatment. The apparent premature development of sympathetic innervation induced by Pb treatment was not reflected in significant alterations in either the density or the affinity of ..beta..-adrenergic receptor sites determined by the binding kinetics of /sup 3/H-dihydroalprenolol.

  3. Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Cyclic ADP-Ribose (cADPR) Mediate Ca2+ Signaling in Cardiac Hypertrophy Induced by β-Adrenergic Stimulation

    PubMed Central

    Shawl, Asif Iqbal; Im, Soo-Yeul; Nam, Tae-Sik; Lee, Sun-Hwa; Ko, Jae-Ki; Jang, Kyu Yoon; Kim, Donghee; Kim, Uh-Hyun

    2016-01-01

    Ca2+ signaling plays a fundamental role in cardiac hypertrophic remodeling, but the underlying mechanisms remain poorly understood. We investigated the role of Ca2+-mobilizing second messengers, NAADP and cADPR, in the cardiac hypertrophy induced by β-adrenergic stimulation by isoproterenol. Isoproterenol induced an initial Ca2+ transients followed by sustained Ca2+ rises. Inhibition of the cADPR pathway with 8-Br-cADPR abolished only the sustained Ca2+ increase, whereas inhibition of the NAADP pathway with bafilomycin-A1 abolished both rapid and sustained phases of the isoproterenol-mediated signal, indicating that the Ca2+ signal is mediated by a sequential action of NAADP and cADPR. The sequential production of NAADP and cADPR was confirmed biochemically. The isoproterenol-mediated Ca2+ increase and cADPR production, but not NAADP production, were markedly reduced in cardiomyocytes obtained from CD38 knockout mice. CD38 knockout mice were rescued from chronic isoproterenol infusion-induced myocardial hypertrophy, interstitial fibrosis, and decrease in fractional shortening and ejection fraction. Thus, our findings indicate that β-adrenergic stimulation contributes to the development of maladaptive cardiac hypertrophy via Ca2+ signaling mediated by NAADP-synthesizing enzyme and CD38 that produce NAADP and cADPR, respectively. PMID:26959359

  4. Cardiac sympathetic innervation assessed with (123)I-MIBG retains prognostic utility in diabetic patients with severe left ventricular dysfunction evaluated for primary prevention implantable cardioverter-defibrillator.

    PubMed

    García-González, P; Fabregat-Andrés, Ó; Cozar-Santiago, P; Sánchez-Jurado, R; Estornell-Erill, J; Valle-Muñoz, A; Quesada-Dorador, A; Payá-Serrano, R; Ferrer-Rebolleda, J; Ridocci-Soriano, F

    2016-01-01

    Scintigraphy with iodine-123-metaiodobenzylguanidine ((123)I-MIBG) is a non-invasive tool for the assessment of cardiac sympathetic innervation (CSI) that has proven to be an independent predictor of survival. Recent studies have shown that diabetic patients with heart failure (HF) have a higher deterioration in CSI. It is unknown if (123)I-MIBG has the same predictive value for diabetic and non-diabetic patients with advanced HF. An analysis is performed to determine whether CSI with (123)I-MIBG retains prognostic utility in diabetic patients with HF, evaluated for a primary prevention implantable cardioverter-defibrillator (ICD). Seventy-eight consecutive HF patients (48 diabetic) evaluated for primary prevention ICD implantation were prospectively enrolled and underwent (123)I-MIBG to assess CSI (heart-to-mediastinum ratio - HMR). A Cox proportional hazards multivariate analysis was used to determine the influence of (123)I-MIBG images for prediction of cardiac events in both diabetic and non-diabetic patients. The primary end-point was a composite of arrhythmic event, cardiac death, or admission due to HF. During a mean follow-up of 19.5 [9.3-29.3] months, the primary end-point occurred in 24 (31%) patients. Late HMR was significantly lower in diabetic patients (1.30 vs. 1.41, p=0.014). Late HMR≤1.30 was an independent predictor of cardiac events in diabetic (hazard ratio 4.53; p=0.012) and non-diabetic patients (hazard ratio 12.31; p=0.023). Diabetic patients with HF evaluated for primary prevention ICD show a higher deterioration in CSI than non-diabetics; nevertheless (123)I-MIBG imaging retained prognostic utility for both diabetic and non-diabetic patients. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

  5. Innervating sympathetic neurons regulate heart size and the timing of cardiomyocyte cell cycle withdrawal.

    PubMed

    Kreipke, R E; Birren, S J

    2015-12-01

    Sympathetic drive to the heart is a key modulator of cardiac function and interactions between heart tissue and innervating sympathetic fibres are established early in development. Significant innervation takes place during postnatal heart development, a period when cardiomyocytes undergo a rapid transition from proliferative to hypertrophic growth. The question of whether these innervating sympathetic fibres play a role in regulating the modes of cardiomyocyte growth was investigated using 6-hydroxydopamine (6-OHDA) to abolish early sympathetic innervation of the heart. Postnatal chemical sympathectomy resulted in rats with smaller hearts, indicating that heart growth is regulated by innervating sympathetic fibres during the postnatal period. In vitro experiments showed that sympathetic interactions resulted in delays in markers of cardiomyocyte maturation, suggesting that changes in the timing of the transition from hyperplastic to hypertrophic growth of cardiomyocytes could underlie changes in heart size in the sympathectomized animals. There was also an increase in the expression of Meis1, which has been linked to cardiomyocyte cell cycle withdrawal, suggesting that sympathetic signalling suppresses cell cycle withdrawal. This signalling involves β-adrenergic activation, which was necessary for sympathetic regulation of cardiomyocyte proliferation and hypertrophy. The effect of β-adrenergic signalling on cardiomyocyte hypertrophy underwent a developmental transition. While young postnatal cardiomyocytes responded to isoproterenol (isoprenaline) with a decrease in cell size, mature cardiomyocytes showed an increase in cell size in response to the drug. Together, these results suggest that early sympathetic effects on proliferation modulate a key transition between proliferative and hypertrophic growth of the heart and contribute to the sympathetic regulation of adult heart size.

  6. β-Adrenergic receptor desensitization in man: insight into post-exercise attenuation of cardiac function

    PubMed Central

    Hart, Emma; Dawson, Ellen; Rasmussen, Peter; George, Keith; Secher, Niels H; Whyte, Greg; Shave, Rob

    2006-01-01

    Desensitization of the β-adrenoreceptors (β-AR) may contribute to a post-exercise reduction in left ventricular (LV) function. However, attenuation of the chronotropic and inotropic responses to a β-AR agonist may depend upon alterations in parasympathetic tone. Furthermore, changes in cardiac output Q˙ and LV diastolic function in response to a β-AR agonist, pre- to post-prolonged exercise, remain unclear. Seven trained males (mean ± s.d., age 27 ± 6 years) performed 4 h of ergometer rowing. Peak heart rate (HR) and LV systolic and diastolic functional responses to incremental isoproterenol (isoprenaline) infusion (2, 4 and 6 μg kg min−1) were assessed after vagal blockade (glycopyrrolate, 1.2 mg). LV systolic function was assessed by the pressure/volume ratio (systolic blood pressure/end systolic volume) and Q˙, whilst diastolic function was evaluated as peak early and late transmitral filling velocities. Following exercise, the pressure/volume ratio decreased by 25% (P < 0.05), whereas Q˙ was unchanged (P > 0.05). The early/late filling ratio was reduced by 36% after exercise, due to an elevation in late LV filling (P < 0.01). The increase in HR response to isoproterenol infusion was blunted post-exercise at both 4 and 6 μg kg min−1 (127 ± 7 and 132 ± 6 beats min−1) compared with pre-exercise (138 ± 8 and 141 ± 12 beats min−1, P < 0.05). Additionally, the pressure/volume ratio and Q˙ were blunted post-exercise in response to isoproterenol (P < 0.05). In contrast, diastolic function was similar before and after exercise during isoproterenol infusion (P > 0.05). Desensitization of the β-AR contributes to an attenuated left ventricular systolic but not diastolic function following prolonged exercise. PMID:16973702

  7. Beta-adrenergic receptor desensitization in man: insight into post-exercise attenuation of cardiac function.

    PubMed

    Hart, Emma; Dawson, Ellen; Rasmussen, Peter; George, Keith; Secher, Niels H; Whyte, Greg; Shave, Rob

    2006-12-01

    Desensitization of the beta-adrenoreceptors (beta-AR) may contribute to a post-exercise reduction in left ventricular (LV) function. However, attenuation of the chronotropic and inotropic responses to a beta-AR agonist may depend upon alterations in parasympathetic tone. Furthermore, changes in cardiac output and LV diastolic function in response to a beta-AR agonist, pre- to post-prolonged exercise, remain unclear. Seven trained males (mean+/-s.d., age 27+/-6 years) performed 4 h of ergometer rowing. Peak heart rate (HR) and LV systolic and diastolic functional responses to incremental isoproterenol (isoprenaline) infusion (2, 4 and 6 microg kg min-1) were assessed after vagal blockade (glycopyrrolate, 1.2 mg). LV systolic function was assessed by the pressure/volume ratio (systolic blood pressure/end systolic volume) and , whilst diastolic function was evaluated as peak early and late transmitral filling velocities. Following exercise, the pressure/volume ratio decreased by 25% (P<0.05), whereas was unchanged (P>0.05). The early/late filling ratio was reduced by 36% after exercise, due to an elevation in late LV filling (P<0.01). The increase in HR response to isoproterenol infusion was blunted post-exercise at both 4 and 6 microg kg min-1 (127+/-7 and 132+/-6 beats min-1) compared with pre-exercise (138+/-8 and 141+/-12 beats min-1, P<0.05). Additionally, the pressure/volume ratio and were blunted post-exercise in response to isoproterenol (P<0.05). In contrast, diastolic function was similar before and after exercise during isoproterenol infusion (P>0.05). Desensitization of the beta-AR contributes to an attenuated left ventricular systolic but not diastolic function following prolonged exercise.

  8. 2-Year Natural Decline of Cardiac Sympathetic Innervation in Idiopathic Parkinson Disease Studied with 11C-Hydroxyephedrine PET.

    PubMed

    Wong, Ka Kit; Raffel, David M; Bohnen, Nicolaas I; Altinok, Gulcin; Gilman, Sid; Frey, Kirk A

    2017-02-01

    The objective of this study was to detect regional patterns of cardiac sympathetic denervation in idiopathic Parkinson disease (IPD) using (11)C-hydroxyephedrine ((11)C-HED) PET and determine the denervation rate over 2 y.

  9. Saturated high-fat diet-induced obesity increases adenylate cyclase of myocardial β-adrenergic system and does not compromise cardiac function.

    PubMed

    Vileigas, Danielle F; de Deus, Adriana F; da Silva, Danielle C T; de Tomasi, Loreta C; de Campos, Dijon H S; Adorni, Caroline S; de Oliveira, Scarlet M; Sant'Ana, Paula G; Okoshi, Katashi; Padovani, Carlos R; Cicogna, Antonio C

    2016-09-01

    Obesity is a worldwide pandemic associated with high incidence of cardiovascular disease. The mechanisms by which the obesity leads cardiac dysfunction are not fully elucidated and few studies have evaluated the relationship between obesity and proteins involved in myocardial β-adrenergic (βA) system. The purpose of this study was to evaluate the cardiac function and βA pathway components in myocardium of obese rats. Male Wistar rats were distributed into two groups: control (n = 17; standard diet) and obese (n = 17; saturated high-fat diet) fed for 33 weeks. Nutritional profile and comorbidities were assessed. Cardiac structure and function was evaluated by macroscopic postmortem, echocardiographic and isolated papillary muscle analyzes. Myocardial protein expression of β1- and β2-adrenergic receptors, Gαs protein, adenylate cyclase (AC) and protein kinase A (PKA) was performed by Western blot. Cardiac cyclic adenosine monophosphate (cAMP) levels and PKA activity were assessed by ELISA Obese rats showed increased adiposity index (P < 0.001) and several comorbidities as hypertension, glucose intolerance, insulin resistance, and dyslipidemia compared with control rats. Echocardiographic assessment revealed increased left atrium diameter (C: 4.98 ± 0.38 vs. Ob: 5.47 ± 0.53, P = 0.024) and posterior wall shortening velocity (C: 37.1 ± 3.6 vs. Ob: 41.8 ± 3.8, P = 0.007) in obese group. Papillary muscle evaluation indicated that baseline data and myocardial responsiveness to isoproterenol stimulation were similar between the groups. Protein expression of myocardial AC was higher in obese group than in the control (C: 1.00 ± 0.21 vs. Ob: 1.25 ± 0.10, P = 0.025), whereas the other components were unchanged. These results suggest that saturated high-fat diet-induced obesity was not effective in triggering cardiac dysfunction and impair the beta-adrenergic signaling.

  10. DNA immunizations with M2 muscarinic and beta1 adrenergic receptor coding plasmids impair cardiac function in mice.

    PubMed

    Giménez, Luis E D; Hernández, Ciria C Q; Mattos, Elisabete C; Brandão, Izaira Tincani; Olivieri, Bianca; Campelo, Roberto P; Araújo-Jorge, Tânia; Silva, Célio Lopes; Campos de Carvalho, Antônio C; Kurtenbach, Eleonora

    2005-05-01

    Autoimmune mediated myocardial damage is likely to be a pathogenic mechanism for acquired dilated cardiomyopathies. Evidence confirms that autoantibodies that bind to M(2) muscarinic (M(2)AChR) and beta(1) adrenergic receptors (beta(1)AR) are present in idiopathic dilated cardiomyopathy and Chagasic patients' sera. To elucidate the role of these antibodies in cardiac functional impairment, we used a murine model immunized with plasmids encoding the M(2)AChR or beta(1)AR via gene-gun bombardment. Anti-M(2)AChR and beta(1)AR antibodies were detected over the course of 37 weeks. These antibodies were directed to the second extracellular loop (el2) of both receptors and the third intracellular loop (il3) of the M(2)AChR. Peak antibody titers from weeks 2 to 5 against M(2)AChR-el2 and beta(1)AR-el2 as well as elevated titers against M(2)AChR-il3 were detected. Anti-M(2)AChR-il3 and anti-beta(1)AR-el2 antibodies were predominant in IgG1 subclass immunoglobulins, suggesting a T-helper-2 biased lymphocyte response. Heart morphology and function was assessed by echocardiography over the course of 42 weeks. Data showed progressive decrease in left ventricular (LV) wall thickness and LV mass that was mostly evident for beta(1)AR-immunized mice albeit a small change in LV dimensions. Fractional shortening was altered and values of 41%, 37% and 48% were observed at week 42 for the M(2)AChR, beta(1)AR and control groups respectively. In support of autonomic deregulation, a twofold increase in M(2)AChR and a similar decrease in beta(1)AR density were observed in radioligand saturation assays for both experimental groups. Histological analysis revealed myofibril disarray and fibrosis, pointing towards remodeling as a consequence of the long-term presence of anti-receptor antibodies.

  11. The effects of a new ultra-short-acting beta-adrenergic blocker, ONO-1101, on cardiac function during and after cardiopulmonary bypass.

    PubMed

    Ahmet, I; Fukushima, N; Sawa, Y; Masai, T; Kadoba, K; Kagisaki, K; Chang, J C; Yamaguchi, T; Matsuda, H

    1999-01-01

    The administration of an ultra-short-acting beta-adrenergic antagonist, esmolol, has been introduced as a novel method for beating-heart surgery. In the present study, a new ultra-short-acting beta-blocker, ONO-1101, was administered during cardiopulmonary bypass (CPB) to investigate its effects on cardiac function and hemodynamics. Nine adult mongrel dogs underwent 60 min of CPB during which they were given either ONO-1101 (ONO group; n = 4) or saline (control group; n = 5). In the ONO group, the hearts became flaccid enough for surgery to be performed without cardiac standstill within 10 min after the commencement of ONO-1101 with significant decreases in the heart rate, the preload recruitable stroke work (PRSW), and the slope of the end-systolic left ventricular pressure-volume relationship (Emax). The mean arterial pressure and systemic vascular resistance also decreased, but were maintained above 50 mmHg during CPB without catecholamine. These indices increased to the control group level 20 min after the discontinuation of ONO-1101. The serum concentration of ONO-1101 decreased from the maximum level of 121 +/- 15 microg/ml soon after infusion to 11 +/- 5 microg/ml within 30 min after discontinuation. These data suggest that ONO-1101 may be useful to enable beating-heart surgery to be performed without aortic cross-clamp as an ultra-short-acting beta-adrenergic blocker.

  12. Effects of α-lipoic acid therapy on sympathetic heart innervation in patients with previous experience of transient takotsubo cardiomyopathy.

    PubMed

    Marfella, Raffaele; Barbieri, Michelangela; Sardu, Celestino; Rizzo, Maria Rosaria; Siniscalchi, Mario; Paolisso, Pasquale; Ambrosino, Maria; Fava, Ilaria; Materazzi, Crescenzo; Cinquegrana, Giorgio; Gottilla, Rossella; Elia, Luigi Raffaele; D'andrea, Davide; Coppola, Antonino; Rambaldi, Pier Francesco; Mauro, Ciro; Mansi, Luigi; Paolisso, Giuseppe

    2016-02-01

    Takotsubo syndrome is a stress cardiomyopathy, characterized by reversible left ventricle (LV) apical ballooning in the absence of significant angiographic coronary artery stenosis. The frequent association with emotional stress suggests in this disease an autonomic nervous system involvement. We could think that a therapeutic treatment targeting heart sympathetic dysfunction could be of crucial importance. From January 2010 to June 2012, 886 patients were consecutively evaluated at Cardarelli Hospital, Naples, Italy. Among these, 48 patients met takotsubo cardiomyopathy (TCM) criteria. Each patient was assessed with history and physical examination, 12-lead electrocardiogram, serum troponin, coronary arteriography, and left ventricular angiogram, perfusion myocardial scintigraphy with technetium 99m, with echocardiography and 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. At discharge, the surviving patients were randomly assigned to α-lipoic acid (ALA) treatment (600mg once daily) or placebo. Following discharge, after the initial TCM event, patients returned to our outpatient clinic at Internal Medicine of the Second University Naples for the follow-up evaluation quarterly until 12 months. Routine analysis, myocardial damage serum markers, oxidative stress serum markers, pro-inflammatory cytokines, and sympathetic tone activity were evaluated in all patients. ALA administration improved MIBG defect size at 12 months compared to placebo. Adrenergic cardiac innervation dysfunction in TCM patients persists after previous experience of transient stress-induced cardiac dysfunction. ALA treatment improves the adrenergic cardiac innervation. This study evaluates whether sympatho-vagal alterations are TCM event-related. Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

  13. β-Adrenergic Receptor Activation Induces Internalization of Cardiac Cav1.2 Channel Complexes through a β-Arrestin 1-mediated Pathway*S⃞

    PubMed Central

    Lipsky, Rachele; Potts, Essie M.; Tarzami, Sima T.; Puckerin, Akil A.; Stocks, Joanne; Schecter, Alison D.; Sobie, Eric A.; Akar, Fadi G.; Diversé-Pierluissi, María A.

    2008-01-01

    Voltage-dependent calcium channels (VDCCs) play a pivotal role in normal excitation-contraction coupling in cardiac myocytes. These channels can be modulated through activation of β-adrenergic receptors (β-ARs), which leads to an increase in calcium current (ICa-L) density through cardiac Cav1 channels as a result of phosphorylation by cAMP-dependent protein kinase A. Changes in ICa-L density and kinetics in heart failure often occur in the absence of changes in Cav1 channel expression, arguing for the importance of post-translational modification of these channels in heart disease. The precise molecular mechanisms that govern the regulation of VDCCs and their cell surface localization remain unknown. Our data show that sustained β-AR activation induces internalization of a cardiac macromolecular complex involving VDCC and β-arrestin 1 (β-Arr1) into clathrin-coated vesicles. Pretreatment of myocytes with pertussis toxin prevents the internalization of VDCCs, suggesting that Gi/o mediates this response. A peptide that selectively disrupts the interaction between CaV1.2 and β-Arr1 and tyrosine kinase inhibitors readily prevent agonist-induced VDCC internalization. These observations suggest that VDCC trafficking is mediated by G protein switching to Gi of the β-AR, which plays a prominent role in various cardiac pathologies associated with a hyperadrenergic state, such as hypertrophy and heart failure. PMID:18458091

  14. {beta}1-Adrenergic receptor activation induces mouse cardiac myocyte death through both L-type calcium channel-dependent and -independent pathways.

    PubMed

    Wang, Wei; Zhang, Hongyu; Gao, Hui; Kubo, Hajime; Berretta, Remus M; Chen, Xiongwen; Houser, Steven R

    2010-08-01

    Cardiac diseases persistently increase the contractility demands of cardiac myocytes, which require activation of the sympathetic nervous system and subsequent increases in myocyte Ca(2+) transients. Persistent exposure to sympathetic and/or Ca(2+) stress is associated with myocyte death. This study examined the respective roles of persistent beta-adrenergic receptor (beta-AR) agonist exposure and high Ca(2+) concentration in myocyte death. Ventricular myocytes (VMs) were isolated from transgenic (TG) mice with cardiac-specific and inducible expression of the beta(2a)-subunit of the L-type Ca(2+) channel (LTCC). VMs were cultured, and the rate of myocyte death was measured in the presence of isoproterenol (ISO), other modulators of Ca(2+) handling and the beta-adrenergic system, and inhibitors of caspases and reactive oxygen species generation. The rate of myocyte death was greater in TG vs. wild-type myocytes and accelerated by ISO in both groups, although ISO did not increase LTCC current (I(Ca-L)) in TG-VMs. Nifedipine, an LTCC antagonist, only partially prevented myocyte death. These results suggest both LTCC-dependent and -independent mechanisms in ISO induced myocyte death. ISO increased the contractility of wild type and TG-VMs by enhancing sarcoplasmic reticulum function and inhibiting sarco(endo)plasmic reticulum Ca(2+)-ATPase, Na(+)/Ca(2+) exchanger, and CaMKII partially protected myocyte from death induced by both Ca(2+) and ISO. Caspase and reactive oxygen species inhibitors did not, but beta(2)-AR activation did, reduce myocyte death induced by enhanced I(Ca-L) and ISO stimulation. Our results suggest that catecholamines induce myocyte necrosis primarily through beta(1)-AR-mediated increases in I(Ca-L), but other mechanisms are also involved in rodents.

  15. Caveolae-specific activation loop between CaMKII and L-type Ca(2+) channel aggravates cardiac hypertrophy in α1-adrenergic stimulation.

    PubMed

    Tonegawa, Kota; Otsuka, Wataru; Kumagai, Shohei; Matsunami, Sachi; Hayamizu, Nao; Tanaka, Shota; Moriwaki, Kazumasa; Obana, Masanori; Maeda, Makiko; Asahi, Michio; Kiyonari, Hiroshi; Fujio, Yasushi; Nakayama, Hiroyuki

    2017-03-01

    Activation of CaMKII induces a myriad of biological processes and plays dominant roles in cardiac hypertrophy. Caveolar microdomain contains many calcium/calmodulin-dependent kinase II (CaMKII) targets, including L-type Ca(2+) channel (LTCC) complex, and serves as a signaling platform. The location of CaMKII activation is thought to be critical; however, the roles of CaMKII in caveolae are still elusive due to lack of methodology for the assessment of caveolae-specific activation. Our aim was to develop a novel tool for the specific analysis of CaMKII activation in caveolae and to determine the functional role of caveolar CaMKII in cardiac hypertrophy. To assess the caveolae-specific activation of CaMKII, we generated a fusion protein composed of phospholamban and caveolin-3 (cPLN-Cav3) and GFP fusion protein with caveolin-binding domain fused to CaMKII inhibitory peptide (CBD-GFP-AIP), which inhibits CaMKII activation specifically in caveolae. Caveolae-specific activation of CaMKII was detected using phosphospecific antibody for PLN (Thr(17)). Furthermore, adenoviral overexpression of LTCC β2a-subunit (β2a) in NRCMs showed its constitutive phosphorylation by CaMKII, which induces hypertrophy, and that both phosphorylation and hypertrophy are abolished by CBD-GFP-AIP expression, indicating that β2a phosphorylation occurs specifically in caveolae. Finally, β2a phosphorylation was observed after phenylephrine stimulation in β2a-overexpressing mice, and attenuation of cardiac hypertrophy after chronic phenylephrine stimulation was observed in nonphosphorylated mutant of β2a-overexpressing mice. We developed novel tools for the evaluation and inhibition of caveolae-specific activation of CaMKII. We demonstrated that phosphorylated β2a dominantly localizes to caveolae and induces cardiac hypertrophy after α1-adrenergic stimulation in mice.NEW & NOTEWORTHY While signaling in caveolae is thought to be important in cardiac hypertrophy, direct evidence is missing

  16. The innervation of the hepatic portal vein in the rabbit: ultrastructural evidence against "purinergic" neurotransmission.

    PubMed

    Gibbins, I L

    1981-01-01

    The relative density of adrenergic and non-adrenergic nerves in the hepatic portal vein of the rabbit has been determined ultrastructurally. Adrenergic nerves were visualised with the modified chromaffin procedure of Tranzer and Richards (1976). Nearly equal numbers of adrenergic and non-adrenergic nerve profiles were found, indicating a much greater density of innervation by non-adrenergic nerves than that described by Burnstock et al. (1979) using light microscopic histochemical methods. These results imply that part of the argument used by Burnstock et al. (1979) to support "purinergic" transmission in rabbit portal vein is probably invalid.

  17. Paradoxical SR Ca2+ release in guinea-pig cardiac myocytes after β-adrenergic stimulation revealed by two-photon photolysis of caged Ca2+

    PubMed Central

    Lindegger, Nicolas; Niggli, Ernst

    2005-01-01

    In heart muscle the amplification and shaping of Ca2+ signals governing contraction are orchestrated by recruiting a variable number of Ca2+ sparks. Sparks reflect Ca2+ release from the sarcoplasmic reticulum (SR) via Ca2+ release channels (ryanodine receptors, RyRs). RyRs are activated by Ca2+ influx via L-type Ca2+ channels with a specific probability that may depend on regulatory mechanisms (e.g. β-adrenergic stimulation) or diseased states (e.g. heart failure). Changes of RyR phosphorylation may be critical for both regulation and impaired function in disease. Using UV flash photolysis of caged Ca2+ and short applications of caffeine in guinea-pig ventricular myocytes, we found that Ca2+ release signals on the cellular level were largely governed by global SR content. During β-adrenergic stimulation resting myocytes exhibited smaller SR Ca2+ release signals when activated by photolysis (62.3% of control), resulting from reduced SR Ca2+ content under these conditions (58.6% of control). In contrast, local signals triggered with diffraction limited two-photon photolysis displayed the opposite behaviour, exhibiting a larger Ca2+ release (164% of control) despite reduced global and local SR Ca2+ content. This apparent paradox implies changes of RyR open probabilities after β-adrenergic stimulation, enhancing local regenerativity and reliability of Ca2+ signalling. Thus, our results underscore the importance of phosphorylation of RyRs (or of a related protein), as a regulatory physiological mechanism that may also provide new therapeutic avenues to recover impaired Ca2+ signalling during cardiac disease. PMID:15774509

  18. β-Adrenergic stimulation increases Cav3.1 activity in cardiac myocytes through protein kinase A.

    PubMed

    Li, Yingxin; Wang, Fang; Zhang, Xiaoying; Qi, Zhao; Tang, Mingxin; Szeto, Christopher; Li, Ying; Zhang, Hongyu; Chen, Xiongwen

    2012-01-01

    The T-type Ca(2+) channel (TTCC) plays important roles in cellular excitability and Ca(2+) regulation. In the heart, TTCC is found in the sinoatrial nodal (SAN) and conduction cells. Cav3.1 encodes one of the three types of TTCCs. To date, there is no report regarding the regulation of Cav3.1 by β-adrenergic agonists, which is the topic of this study. Ventricular myocytes (VMs) from Cav3.1 double transgenic (TG) mice and SAN cells from wild type, Cav3.1 knockout, or Cav3.2 knockout mice were used to study β-adrenergic regulation of overexpressed or native Cav3.1-mediated T-type Ca(2+) current (I(Ca-T(3.1))). I(Ca-T(3.1)) was not found in control VMs but was robust in all examined TG-VMs. A β-adrenergic agonist (isoproterenol, ISO) and a cyclic AMP analog (dibutyryl-cAMP) significantly increased I(Ca-T(3.1)) as well as I(Ca-L) in TG-VMs at both physiological and room temperatures. The ISO effect on I(Ca-L) and I(Ca-T) in TG myocytes was blocked by H89, a PKA inhibitor. I(Ca-T) was detected in control wildtype SAN cells but not in Cav3.1 knockout SAN cells, indicating the identity of I(Ca-T) in normal SAN cells is mediated by Cav3.1. Real-time PCR confirmed the presence of Cav3.1 mRNA but not mRNAs of Cav3.2 and Cav3.3 in the SAN. I(Ca-T) in SAN cells from wild type or Cav3.2 knockout mice was significantly increased by ISO, suggesting native Cav3.1 channels can be upregulated by the β-adrenergic (β-AR) system. In conclusion, β-adrenergic stimulation increases I(Ca-T(3.1)) in cardiomyocytes(,) which is mediated by the cAMP/PKA pathway. The upregulation of I(Ca-T(3.1)) by the β-adrenergic system could play important roles in cellular functions involving Cav3.1.

  19. Innervation of eccrine sweat glands.

    PubMed

    Sokolov, V E; Shabadash, S A; Zelikina, T I

    1980-01-01

    In recent years it has been shown on the example of primate skin that in addition to abundant cholinergic innervation, the eccrine glands are also supplied by adrenergic fibers, containing catecholamines. The presence of an adrenergic component of the innervation is demonstrated on the plantar eccrine sweat glands of a number of rodents and the cat by the detection of monoamine oxidase in it. The myelin nerve trunks, the short unmyelinated varicose terminals in direct contact with the secretory cells, as well as the mitochondria of cells of the eccrine sweat glands are rich in monoamine oxidase. Specific and nonspecific cholinesterases are localized in the dense network of nerves in lacing the secretory portions of the glands; individual fibers accompany the excretory ducts. The acetylcholinesterase concentration is lower than the concentration of nonspecific cholinesterase. In rats with chemical sympathectomy, induced by four-week administration of 25 mg/kg guanethidine from the first day of birth, in which 99% of the neurons in the stellate ganglia die, the monoamine oxidase concentration in the myelin nerves and in the mitochondria of the secretory cells drops very sharply, and acetylcholinesterase disappears from the nerves surrounding the glands.

  20. The alpha-1A adrenergic receptor agonist A61603 reduces cardiac polyunsaturated fatty acid and endocannabinoid metabolites associated with inflammation in vivo

    PubMed Central

    Willis, Monte S.; Ilaiwy, Amro; Montgomery, Megan D.; Simpson, Paul C.; Jensen, Brian C.

    2017-01-01

    Introduction Alpha-1-adrenergic receptors (α1-ARs) are G-protein coupled receptors (GPCRs) with three highly homologous subtypes (α1A, α1B, and α1D). Of these three subtypes, only the α1A and α1B are expressed in the heart. Multiple pre-clinical models of heart injury demonstrate cardioprotective roles for the α1A. Non-selective α1-AR activation promotes glycolysis in the heart, but the functional α1-AR subtype and broader metabolic effects have not been studied. Objectives Given the high metabolic demands of the heart and previous evidence indicating benefit from α1A activation, we chose to investigate the effects of α1A activation on the cardiac metabolome in vivo. Methods Mice were treated for one week with a low, subpressor dose of A61603, a highly selective and potent α1A agonist. Cardiac tissue and serum were analyzed using a non-targeted metabolomics approach. Results We identified previously unrecognized metabolic responses to α1A activation, most notably broad reduction in the abundance of polyunsaturated fatty acids (PUFAs) and endocannabinoids (ECs). Conclusion Given the well characterized roles of PUFAs and ECs in inflammatory pathways, these findings suggest a possible role for cardiac α1A-ARs in the regulation of inflammation and may offer novel insight into the mechanisms underlying the cardioprotective benefit of selective pharmacologic α1A activation. PMID:28533737

  1. The role of beta-adrenergic activity in the production of cardiac and aortic arch anomalies in chick embryos.

    PubMed

    Hodach, R J; Hodach, A E; Fallon, J F; Folts, J D; Bruyere, H J; Gilbert, E F

    1975-08-01

    The sympathomimetic amines isoproterenol, epinephrine, norepinephrine, and phenylephrine are structural derivatives of beta-phenylethylamine and have proportionately different effects on alpha- and beta-adrenergic receptors. Chick embryos in ovo were each administered a single dose of one of these compounds at concentrations ranging from 0.4 times 10(-9) to 20 times 10(-9) mol/5 mul saline during Hamburger and Hamilton stages 20-27. In other experiments embryos were pretreated with the beta-antagonist propranolol and subsequently administered isoproterenol. 743 cardiovascular anomalies were produced. The production of cardiovascular anomalies was proportional to the degree of beta-adrenergic activity of each drug. The frequency of anomalies was significantly reduced by pretreatment with propranolol. At all concentrations tested the anomaly rate was greater in chick embryos receiving an experimental compound than in controls. The general types of anomalies included aortic arch defects, ventricular septal defect, double outlet right ventricle, aortic hypoplasia, and truncus arteriosus. These results demonstrate that activation of the beta-adrenergic receptor mechanism is directly related to the cardiovascular anomalies produced in the chick embryos.

  2. Detailed comparative anatomy of the extrinsic cardiac nerve plexus and postnatal reorganization of the cardiac position and innervation in the great apes: orangutans, gorillas, and chimpanzees.

    PubMed

    Kawashima, Tomokazu; Sato, Fumi

    2012-03-01

    To speculate how the extrinsic cardiac nerve plexus (ECNP) evolves phyletically and ontogenetically within the primate lineage, we conducted a comparative anatomical study of the ECNP, including an imaging examination in the great apes using 20 sides from 11 bodies from three species and a range of postnatal stages from newborns to mature adults. Although the position of the middle cervical ganglion (MG) in the great apes tended to be relatively lower than that in humans, the morphology of the ECNP in adult great apes was almost consistent with that in adult humans but essentially different from that in the lesser apes or gibbons. Therefore, the well-argued anatomical question of when did the MG acquire communicating branches with the spinal cervical nerves and appear constantly in all sympathetic cardiac nerves during primate evolution is clearly considered to be after the great apes and gibbons split. Moreover, a horizontal four-chambered heart and a lifted cardiac apex with a relatively large volume in newborn great apes rapidly changed its position downward, as seen in humans during postnatal growth and was associated with a reduction in the hepatic volume by imaging diagnosis and gross anatomy. In addition, our observation using a range of postnatal stages exhibits that two sympathetic ganglia, the middle cervical and cervicothoracic ganglia, differed between the early and later postnatal stages. Copyright © 2011 Wiley Periodicals, Inc.

  3. Regional heterogeneity in cardiac sympathetic innervation in acute myocardial infarction: relationship with myocardial oedema on magnetic resonance.

    PubMed

    Gimelli, Alessia; Masci, Pier Giorgio; Liga, Riccardo; Grigoratos, Chrysanthos; Pasanisi, Emilio Maria; Lombardi, Massimo; Marzullo, Paolo

    2014-09-01

    To assess the relationships between myocardial structure and function on cardiac magnetic resonance (CMR) imaging and sympathetic tone on (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy early after myocardial infarction (MI). Ten patients underwent (123)I-MIBG and (99m)Tc-tetrofosmin rest cadmium zinc telluride scintigraphy 4 ± 1 days after MI. The segmental left ventricular (LV) relative radiotracer uptake of both (99m)Tc-tetrofosmin and early (123)I-MIBG was calculated. The day after scintigraphy, on CMR imaging, the extent of ischaemia-related oedema and of myocardial fibrosis (late gadolinium enhancement, LGE) was assessed. Accordingly, the extent of oedema and LGE was evaluated for each segment and segmental wall thickening determined. Based on LGE distribution, LV segments were categorized as "infarcted" (56 segments), "adjacent" (66 segments) or "remote" (48 segments). Infarcted segments showed a more depressed systolic wall thickening and greater extent of oedema than adjacent segments (p < 0.001) and remote segments (p < 0.001). Interestingly, while uptake of (99m)Tc-tetrofosmin was significantly depressed only in infarcted segments (p < 0.001 vs. both adjacent and remote segments), uptake of (123)I-MIBG was impaired not only in infarcted segments (p < 0.001 vs. remote) but also in adjacent segments (p = 0.024 vs. remote segments). At the regional level, after correction for (99m)Tc-tetrofosmin and LGE distribution, segmental (123)I-MIBG uptake (p < 0.001) remained an independent predictor of ischaemia-related oedema. After acute MI the regional impairment of sympathetic tone extends beyond the area of altered myocardial perfusion and is associated with myocardial oedema.

  4. Slowing of shortening velocity of rat cardiac myocytes by adenosine receptor stimulation regardless of beta-adrenergic stimulation.

    PubMed Central

    Strang, K T; Mentzer, R M; Moss, R L

    1995-01-01

    1. Single ventricular myocytes were enzymatically isolated, incubated with the A1-purinergic and beta-adrenergic receptor-specific agonists N6-cyclopentyladenosine (CPA) and isoprenaline (Iso), and then rapidly skinned. Ca2+ sensitivity of isometric tension and unloaded shortening velocity (Vo) were measured, and protein kinase A (PKA)-specific phosphorylations of troponin I (TnI) and C-protein were assessed by back-phosphorylation of cell suspensions with [gamma-32P]-ATP. 2. Isoprenaline treatment decreased the Ca2+ sensitivity of isometric tension relative to propranolol-treated controls, as did simultaneous stimulation with Iso and CPA (Iso + CPA). CPA alone had no effect on Ca2+ sensitivity. Vo was greater in Iso-treated cells than in paired controls, while Vo was significantly less than control in both Iso + CPA-treated and CPA-treated cells. 3. Phosphorylation of TnI and C-protein was increased by Iso treatment and also when Iso and CPA were simultaneously applied. CPA alone caused a significant decrease in the phosphorylation state of these two proteins. 4. From these results we conclude that A1-purinergic receptor stimulation does not inhibit beta-adrenergic receptor-mediated phosphorylation of myofilament proteins, nor does it alter the Ca2+ sensitivity of isometric tension at the level of the myofilaments. However, A1-receptor stimulation does decrease Vo at the level of the myofilaments by a mechanism that is independent of beta-adrenergically mediated phosphorylation of TnI and C-protein. Images Figure 1 Figure 4 PMID:7473228

  5. Sympathetic innervation during development is necessary for pancreatic islet architecture and functional maturation

    PubMed Central

    Borden, Philip; Houtz, Jessica; Leach, Steven D.; Kuruvilla, Rejji

    2013-01-01

    Summary Sympathetic neurons depend on target-derived neurotrophic cues to control their survival and growth. However, whether sympathetic innervation contributes reciprocally to the development of target tissues is less clear. Here, we report that sympathetic innervation is necessary for the formation of the pancreatic islets of Langerhans and for their functional maturation. Genetic or pharmacological ablation of sympathetic innervation during development resulted in altered islet architecture, reduced insulin secretion and impaired glucose tolerance in mice. Similar defects were observed with pharmacological blockade of β-adrenergic signaling. Conversely, the administration of a β-adrenergic agonist restored islet morphology and glucose tolerance in de-innervated animals. Furthermore, in neuron-islet co-cultures, sympathetic neurons promoted islet cell migration in a β-adrenergic dependent manner. This study reveals that islet architecture requires extrinsic inductive cues from neighboring tissues such as sympathetic nerves, and suggests that early perturbations in sympathetic innervation might underlie metabolic disorders. PMID:23850289

  6. Alpha2-adrenergic receptor agonists as analgesics.

    PubMed

    Boyd, R E

    2001-08-01

    Alpha2-adrenergic receptor agonists are analgesic agents, and the alpha2-adrenergic agonist clonidine has been used in clinical studies for regional analgesia after intrathecal administration. We review here recent developments concerning the structure activity relationships of a new class of potent alpha2-adrenergic agonists and their use as analgesic agents. The effect of structure upon cardiovascular side-effects is also monitored, such as the prolongation of the QT portion of the cardiac action potential.

  7. Cross-talk between cardiac kappa-opioid and beta-adrenergic receptors in developing hypertensive rats.

    PubMed

    Yu, X C; Wang, H X; Zhang, W M; Wong, T M

    1999-03-01

    effects of NE and forskolin on the electrically induced [Ca2+]i transient was attenuated in SHR aged from 8 weeks when the blood pressure was rapidly increasing. The different time courses of altered responses to U50,488H, and NE and forskolin suggest that the attenuated negative modulation of kappa-receptor stimulation on the beta-adrenergic receptor is not due to the signal transduction pathway activated by beta-adrenergic stimulation. In 13-week-old SHR with the arterial blood pressure restored to normal by pharmacological manipulations, the blunted responses to NE, U50,488H and forskolin still occurred, indicating that the altered responses to activation of beta-adrenergic and kappa-opioid receptors and adenylate cyclase are not secondary to hypertension.

  8. Adrenergic regulation of a key cardiac potassium channel can contribute to atrial fibrillation: evidence from an IKs transgenic mouse

    PubMed Central

    Sampson, Kevin J; Terrenoire, Cecile; Cervantes, Daniel O; Kaba, Riyaz A; Peters, Nicholas S; Kass, Robert S

    2008-01-01

    Inherited gain-of-function mutations of genes coding for subunits of the heart slow potassium (IKs) channel can cause familial atrial fibrillation (AF). Here we consider a potentially more prevalent mechanism and hypothesize that β-adrenergic receptor (β-AR)-mediated regulation of the IKs channel, a natural gain-of-function pathway, can also lead to AF. Using a transgenic IKs channel mouse model, we studied the role of the channel and its regulation by β-AR stimulation on atrial arrhythmias. In vivo administration of isoprenaline (isoproterenol) predisposes IKs channel transgenic mice but not wild-type (WT) littermates that lack IKs to prolonged atrial arrhythmias. Patch-clamp analysis demonstrated expression and isoprenaline-mediated regulation of IKs in atrial myocytes from transgenic but not WT littermates. Furthermore, computational modelling revealed that β-AR stimulation-dependent accumulation of open IKs channels accounts for the pro-arrhythmic substrate. Our results provide evidence that β-AR-regulated IKs channels can play a role in AF and imply that specific IKs deregulation, perhaps through disruption of the IKs macromolecular complex necessary for β-AR-mediated IKs channel regulation, may be a novel therapeutic strategy for treating this most common arrhythmia. PMID:18006587

  9. [Beta-adrenergic receptor blocker poisoning].

    PubMed

    Reingardiene, Dagmara

    2007-01-01

    Beta-adrenergic receptor blocking drugs are used in the treatment of hypertension, angina, myocardial infarction, cardiac dysrhythmia, cardiomyopathy, migraine headache, thyrotoxicosis, and glaucoma. beta-adrenergic receptor blocking agents are competitive antagonist at beta(1), beta(2), or both types of adrenergic receptors. Overdoses of beta-adrenergic receptor blockers are uncommon, but are associated with significant morbidity and mortality. This review article discusses the properties of beta-adrenergic receptor blockers, presents the doses of these drugs causing toxicity and doses, after ingestion of which, referral to an emergency department is recommended. Clinical presentation of overdose (the cardiovascular, neurologic manifestations, pulmonary and other complications), diagnosis, and treatment (gastrointestinal decontamination; the usage of atropine, phosphodiesterase inhibitors, glucagon, insulin; indications for cardiac pacing, extracorporeal procedures of drug removal, etc.) are analyzed. In addition, this article focuses on clinical course and prognosis of beta-blocker overdose.

  10. Localization of cardiac L-type Ca2+ channels to a caveolar macromolecular signaling complex is required for β2-adrenergic regulation

    PubMed Central

    Balijepalli, Ravi C.; Foell, Jason D.; Hall, Duane D.; Hell, Johannes W.; Kamp, Timothy J.

    2006-01-01

    L-type Ca2+ channels play a critical role in regulating Ca2+-dependent signaling in cardiac myocytes, including excitation-contraction coupling; however, the subcellular localization of cardiac L-type Ca2+ channels and their regulation are incompletely understood. Caveolae are specialized microdomains of the plasmalemma rich in signaling molecules and supported by the structural protein caveolin-3 in muscle. Here we demonstrate that a subpopulation of L-type Ca2+ channels is localized to caveolae in ventricular myocytes as part of a macromolecular signaling complex necessary for β2-adrenergic receptor (AR) regulation of ICa,L. Immunofluorescence studies of isolated ventricular myocytes using confocal microscopy detected extensive colocalization of caveolin-3 and the major pore-forming subunit of the L-type Ca channel (Cav1.2). Immunogold electron microscopy revealed that these proteins colocalize in caveolae. Immunoprecipitation from ventricular myocytes using anti-Cav1.2 or anti-caveolin-3 followed by Western blot analysis showed that caveolin-3, Cav1.2, β2-AR (not β1-AR), G protein αs, adenylyl cyclase, protein kinase A, and protein phosphatase 2a are closely associated. To determine the functional impact of the caveolar-localized β2-AR/Cav1.2 signaling complex, β2-AR stimulation (salbutamol plus atenolol) of ICa,L was examined in pertussis toxin-treated neonatal mouse ventricular myocytes. The stimulation of ICa,L in response to β2-AR activation was eliminated by disruption of caveolae with 10 mM methyl β-cyclodextrin or by small interfering RNA directed against caveolin-3, whereas β1-AR stimulation (norepinephrine plus prazosin) of ICa,L was not altered. These findings demonstrate that subcellular localization of L-type Ca2+ channels to caveolar macromolecular signaling complexes is essential for regulation of the channels by specific signaling pathways. PMID:16648270

  11. Levels of circulating anti-muscarinic and anti-adrenergic antibodies and their effect on cardiac arrhythmias and dysautonomia in murine models of Chagas disease.

    PubMed

    Daliry, Anissa; Pereira, Isabela Resende; Pereira-Junior, Pedro Paulo; Ramos, Isalira Peroba; Vilar-Pereira, Glaucia; Silvares, Raquel Rangel; Lannes-Vieira, Joseli; Campos De Carvalho, Antônio Carlos

    2014-11-01

    SUMMARY Antibodies (Ab) recognizing G-protein coupled receptors, such as β 1 and β 2 adrenergic (anti-β 1-AR and anti-β 2-AR, respectively) and muscarinic cholinergic receptors (anti-M2-CR) may contribute to cardiac damage, however their role in chronic chagasic cardiomyopathy is still controversial. We describe that Trypanosoma cruzi-infected C3H/He mice show increased P and QRS wave duration, and PR and QTc intervals, while the most significant ECG alterations in C57BL/6 are prolonged P wave and PR interval. Echocardiogram analyses show right ventricle dilation in infected animals of both mouse lineages. Analyses of heart rate variability (HRV) in chronically infected C3H/He mice show no alteration of the evaluated parameters, while C57BL/6 infected mice display significantly lower values of HRV components, suggesting autonomic dysfunction. The time-course analysis of anti-β 1-AR, anti-β 2-AR and anti-M2-CR Ab titres in C3H/He infected mice indicate that anti-β 1-AR Ab are detected only in the chronic phase, while anti-β 2-AR and anti-M2-CR are observed in the acute phase, diminish at 60 dpi and increase again in the chronic phase. Chronically infected C57BL/6 mice presented a significant increase in only anti-M2-CR Ab titres. Furthermore, anti-β 1-AR, anti-β 2-AR and anti-M2-CR, exhibit significantly higher prevalence in chronically T. cruzi-infected C3H/He mice when compared with C57BL/6. These observations suggest that T. cruzi infection leads to host-specific cardiac electric alterations.

  12. Beta-adrenergic or parasympathetic inhibition, heart rate and cardiac output during normoxic and acute hypoxic exercise in humans.

    PubMed

    Hopkins, Susan R; Bogaard, Harm J; Niizeki, Kyuichi; Yamaya, Yoshiki; Ziegler, Michael G; Wagner, Peter D

    2003-07-15

    Acute hypoxia increases heart rate (HR) and cardiac output (Qt) at a given oxygen consumption (VO2) during submaximal exercise. It is widely believed that the underlying mechanism involves increased sympathetic activation and circulating catecholamines acting on cardiac beta receptors. Recent evidence indicating a continued role for parasympathetic modulation of HR during moderate exercise suggests that increased parasympathetic withdrawal plays a part in the increase in HR and Qt during hypoxic exercise. To test this, we separately blocked the beta-sympathetic and parasympathetic arms of the autonomic nervous system (ANS) in six healthy subjects (five male, one female; mean +/- S.E.M. age = 31.7+/-1.6 years, normoxic maximal VO2 (VO2,max)=3.1+/-0.3 l min(-1)) during exercise in conditions of normoxia and acute hypoxia (inspired oxygen fraction=0.125) to VO2,max. Data were collected on different days under the following conditions: (1)control, (2) after 8.0 mg propranolol i.v. and (3) after 0.8 mg glycopyrrolate i.v. Qt was measured using open-circuit acetylene uptake. Hypoxia increased venous [adrenaline] and [noradrenaline] but not [dopamine] at a given VO2 (P<0.05, P<0.01 and P=0.2, respectively). HR/VO2 and Qt/VO2 increased during hypoxia in all three conditions (P<0.05). Unexpectedly, the effects of hypoxia on HR and Qt were not significantly different from control with either beta-sympathetic or parasympathetic inhibition. These data suggest that although acute exposure to hypoxia increases circulating [catecholamines], the effects of hypoxia on HR and Qt do not necessarily require intact cardiac muscarinic and beta receptors. It may be that cardiac alpha receptors play a primary role in elevating HR and Qt during hypoxic exercise, or perhaps offer an alternative mechanism when other ANS pathways are blocked.

  13. Cardiac β2-Adrenergic Receptor Phosphorylation at Ser355/356 Regulates Receptor Internalization and Functional Resensitization.

    PubMed

    Fan, Xiaofang; Gu, Xuejiang; Zhao, Ru; Zheng, Qingqing; Li, Lan; Yang, Wenbing; Ding, Lu; Xue, Feng; Fan, Junming; Gong, Yongsheng; Wang, Yongyu

    2016-01-01

    Previous studies have demonstrated that β2-adrenergic receptors (β2ARs) can be phosphorylated by G protein-coupled receptor kinases (GRKs) and protein kinase A (PKA), affecting β2AR internalization and desensitization. However, the exact physiological function of β2ARs in cardiomyocytes is unknown. In this study, we showed that neonatal mouse cardiomyocytes had different contraction and internalization responses to sustained or repeated, transient agonist stimulation. Specifically, short-time stimulation (10 min) with epinephrine or norepinephrine increased the cardiomyocyte contraction rate, reaching a maximum at 5 min, followed by a slow decline. When the agonist was re-added after a 60-min wash-out period, the increase in the cardiomyocyte contraction rate was similar to the initial response. In contrast, when cardiomyocytes were exposed continuously to epinephrine or norepinephrine for 60 min, the second agonist stimulation did not increase the contraction response. These results indicated that continuous β2AR stimulation caused functional desensitization. Phosphorylation of β2ARs at serine (Ser)355/356 GRK phosphorylation sites, but not at Ser345/346 PKA phosphorylation sites increased with continuous epinephrine stimulation for 60 min. Accordingly, β2AR internalization increased. Interestingly, β2AR internalization was blocked by mutations at the GRK phosphorylation sites, but not by mutations at the PKA phosphorylation sites. Furthermore, inhibition of β2AR dephosphorylation by okadaic acid, a phosphatase 2A inhibitor, impaired the recovery of internalized β2ARs and reduced the cardiomyocyte contraction rate in response to epinephrine. Finally, epinephrine treatment induced the physical interaction of β-arrestin with internalized β2ARs in cardiomyocytes. Together, these data revealed the essential role of the Ser355/356 phosphorylation status of β2ARs in regulating receptor internalization and physiological resensitization in neonatal

  14. Immobilization Stress With α2-Adrenergic Stimulation Induces Regional and Transient Reduction of Cardiac Contraction Through Gi Coupling in Rats.

    PubMed

    Kuroda, Ryohei; Shintani-Ishida, Kaori; Unuma, Kana; Yoshida, Ken-ichi

    2015-01-01

    Stress cardiomyopathy is characterized by transient apical hypokinesia related to catecholamine overflow. Recently, excessive epinephrine administration was shown to recapitulate stress cardiomyopathy through β2-adrenoceptor (AR)-inhibitory G protein (Gi) coupling in rats. We aimed to study whether α2-AR and Gi affect cardiac contraction in rats in which emotional stress was evoked using immobilization (IMO). Echocardiography results showed that when male rats were exposed to IMO for 30 minutes and then injected with the α2-AR agonist xylazine (Xy), ejection fraction and the movement of the anterior wall (AW) were suppressed, maximally at 5 minutes post-injection, whereas posterior wall (PW) movement was preserved. At the same time points, the phosphorylation of Ser282 in myosin-binding protein-C (MyBP-C-Ser282) was higher in the PW than in the AW. Pretreatment with the Gi inhibitor pertussis toxin (PTX) reversed the low contractility and MyBP-C-Ser282 phosphorylation in the AW, but induced lethal heart failure in 3 out of 11 rats. Moreover, at 5 minutes after Xy injection following 30 minutes of IMO, serum epinephrine levels were increased. Thus, in rats exposed to psychological stress, α2-AR stimulation triggered transient hypo-contractility and MyBP-C-Ser282 hypo-phosphorylation in the AW, in association with an epinephrine surge. PTX treatment reversed the AW hypo-contractility and MyBP-C hypo-phosphorylation, but induced acute heart failure. These findings suggest α2AR/Gi-dependent signaling attenuates MyBP-C phosphorylation and contractility in the AW through an epinephrine surge in rats subjected to IMO and α2-AR stimulation. This model can recapitulate stress cardiomyopathy and thereby deepen our understanding of regional cardiac hypo-contractility and prosurvival mechanisms.

  15. Adrenergic Regulation of HCN4 Channel Requires Protein Association with β2-Adrenergic Receptor*

    PubMed Central

    Greene, Derek; Kang, Seungwoo; Kosenko, Anastasia; Hoshi, Naoto

    2012-01-01

    β1- and β2-adrenergic receptors utilize different signaling mechanisms to control cardiac function. Recent studies demonstrated that β2-adrenergic receptors (β2ARs) colocalize with some ion channels that are critical for proper cardiac function. Here, we demonstrate that β2ARs form protein complexes with the pacemaker HCN4 channel, as well as with other subtypes of HCN channels. The adrenergic receptor-binding site was identified at a proximal region of the N-terminal tail of the HCN4 channel. A synthetic peptide derived from the β2AR-binding domain of the HCN4 channel disrupted interaction between HCN4 and β2AR. In addition, treatment with this peptide prevented adrenergic augmentation of pacemaker currents and spontaneous contraction rates but did not affect adrenergic regulation of voltage-gated calcium currents. These results suggest that the ion channel-receptor complex is a critical mechanism in ion channel regulation. PMID:22613709

  16. Adrenergic regulation of HCN4 channel requires protein association with β2-adrenergic receptor.

    PubMed

    Greene, Derek; Kang, Seungwoo; Kosenko, Anastasia; Hoshi, Naoto

    2012-07-06

    β(1)- and β(2)-adrenergic receptors utilize different signaling mechanisms to control cardiac function. Recent studies demonstrated that β(2)-adrenergic receptors (β(2)ARs) colocalize with some ion channels that are critical for proper cardiac function. Here, we demonstrate that β(2)ARs form protein complexes with the pacemaker HCN4 channel, as well as with other subtypes of HCN channels. The adrenergic receptor-binding site was identified at a proximal region of the N-terminal tail of the HCN4 channel. A synthetic peptide derived from the β(2)AR-binding domain of the HCN4 channel disrupted interaction between HCN4 and β(2)AR. In addition, treatment with this peptide prevented adrenergic augmentation of pacemaker currents and spontaneous contraction rates but did not affect adrenergic regulation of voltage-gated calcium currents. These results suggest that the ion channel-receptor complex is a critical mechanism in ion channel regulation.

  17. Cholinergic innervation of human mesenteric lymphatic vessels.

    PubMed

    D'Andrea, V; Bianchi, E; Taurone, S; Mignini, F; Cavallotti, C; Artico, M

    2013-11-01

    The cholinergic neurotransmission within the human mesenteric lymphatic vessels has been poorly studied. Therefore, our aim is to analyse the cholinergic nerve fibres of lymphatic vessels using the traditional enzymatic techniques of staining, plus the biochemical modifications of acetylcholinesterase (AChE) activity. Specimens obtained from human mesenteric lymphatic vessels were subjected to the following experimental procedures: 1) drawing, cutting and staining of tissues; 2) staining of total nerve fibres; 3) enzymatic staining of cholinergic nerve fibres; 4) homogenisation of tissues; 5) biochemical amount of proteins; 6) biochemical amount of AChE activity; 6) quantitative analysis of images; 7) statistical analysis of data. The mesenteric lymphatic vessels show many AChE positive nerve fibres around their wall with an almost plexiform distribution. The incubation time was performed at 1 h (partial activity) and 6 h (total activity). Moreover, biochemical dosage of the same enzymatic activity confirms the results obtained with morphological methods. The homogenates of the studied tissues contain strong AChE activity. In our study, the lymphatic vessels appeared to contain few cholinergic nerve fibres. Therefore, it is expected that perivascular nerve stimulation stimulates cholinergic nerves innervating the mesenteric arteries to release the neurotransmitter AChE, which activates muscarinic or nicotinic receptors to modulate adrenergic neurotransmission. These results strongly suggest, that perivascular cholinergic nerves have little or no effect on the adrenergic nerve function in mesenteric arteries. The cholinergic nerves innervating mesenteric arteries do not mediate direct vascular responses.

  18. A histochemical study of vegetative innervation of blood-vessels of serosa.

    PubMed

    Khaisman, E B

    1975-01-01

    Research was carried out into the morphological substrate of the dual (sympathetic and parasympathetic) innervation of blood-vessels of the serosa, including the vessels of microcirculatory system. Tests were carried out on total preparations of the pericardium, pleura and peritoneum of dogs and cats. Using histochemical methods to show up adrenergic (Falck-Hillarp's method) and cholinergic (Koelle-Gomori's method) nerve structures the architectonics of both components of vasomotor innervation in various parts of the arterial and venous sytem of the serosa was described a gradient of their saturation with adrenergic and cholinergic innervation structures gradually decrease, the vessels branching out shown and entering the region of the terminal blood supply. Vegetative innervation of the precapillary arterioles and capillaries appears inconsistent and is mainly restricted to single synaptic contacts arising along the route of adrenergic and cholinergic terminals. In vessels of the venus system, including postcapillary venules and small collecting veins, vegetative innervation (adrenergic and cholinergic) invariably appears scanty and frequently can not be detected at all.

  19. Additive competitive interaction of verapamil and quinidine at alpha-adrenergic receptors of isolated cardiac guinea pig myocytes and human platelets

    SciTech Connect

    Mueller, A.; Noack, E.

    1988-01-01

    Recent clinical work has questioned the safety of a combined therapy of oral quinidine and intravenenous verapamil, because some patients were reported to react with severe hypotension probably due to drug interactions with vascular alpha-adrenergic receptors. In order to obtain further quantitative information on the underlying mechanism, the authors used the radioligands (/sup 3/H)-prazosin and (/sup 3/H)-yohimbine to perform binding studies on intact cells, with predominantly alpha-1 (isolated myocytes) or alpha-2 subtypes (human platelets) of adrenergic receptors. Their studies confirm that both verapamil and quinidine possess a distinct alpha-adrenergic receptor blocking activity and do not discriminate between the alpha-1 and alpha-2 subtype. Their interaction was competitive and in the presence of both drugs inhibition of radioligand binding was additive. The alpha-adrenergic blockade by verapamil was stereospecific as D-verapamil increased the dissociation constant of the radioligand to a much lesser degree than L-verapamil. The calcium channel blocker nitrendipine, a 1,4-dihydropyridine derivative, did not show any competition up to concentrations of 10 ..mu..mol/l. 26 references, 5 figures, 1 table.

  20. [18F]Fluoro-hydroxyphenethylguanidines: Efficient Synthesis and Comparison of Two Structural Isomers as Radiotracers of Cardiac Sympathetic Innervation.

    PubMed

    Jung, Yong-Woon; Jang, Keun Sam; Gu, Guie; Koeppe, Robert A; Sherman, Phillip S; Quesada, Carole A; Raffel, David M

    2017-03-21

    Fluorine-18 labeled phenethylguanidines are currently under development in our laboratory as radiotracers for quantifying regional cardiac sympathetic nerve density using PET imaging techniques. In this study, we report an efficient synthesis of 18F-hydroxyphenethylguanidines consisting of nucleophilic aromatic [18F]fluorination of a protected diaryliodonium salt precursor followed by a single deprotection step to afford the desired radiolabeled compound. This approach has been shown to reliably produce 4-[18F]fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG, [18F]1) and its structural isomer 3-[18F]fluoro-p-hydroxyphenethylguanidine ([18F]3F-PHPG, [18F]2) with good radiochemical yields. Preclinical evaluations of [18F]2 in non-human primates were performed to compare its imaging properties, metabolism, and myocardial kinetics with those obtained previously with [18F]1. The results of these studies have demonstrated that [18F]2 exhibits imaging properties comparable to those of [18F]1. Myocardial tracer kinetic analysis of each tracer provides quantitative metrics of cardiac sympathetic nerve density. Based on these findings, first-in-human PET studies with [18F]1 and [18F]2 are currently in progress to assess their ability to accurately measure regional cardiac sympathetic denervation in patients with heart disease, with the ultimate goal of selecting a lead compound for further clinical development.

  1. Synthesis and bioevaluation of [18F]4-fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG): a novel radiotracer for quantitative PET studies of cardiac sympathetic innervation

    PubMed Central

    Jang, Keun Sam; Jung, Yong-Woon; Sherman, Phillip S.; Quesada, Carole A.; Gu, Guie; Raffel, David M.

    2013-01-01

    A new cardiac sympathetic nerve imaging agent, [18F]4-fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG), was synthesized and evaluated. The radiosynthetic intermediate [18F]4-fluoro-m-tyramine ([18F]4F-MTA) was prepared and then sequentially reacted with cyanogen bromide and NH4Br/NH4OH to afford [18F]4F-MHPG. Initial bioevaluations of [18F]4F-MHPG (biodistribution studies in rats and kinetic studies in the isolated rat heart) were similar to results previously reported for the carbon-11 labeled analog [11C]4F-MHPG. The neuronal uptake rate of [18F]4F-MHPG into the isolated rat heart was 0.68 ml/min/g wet and its retention time in sympathetic neurons was very long (T1/2 > 13 h). A PET imaging study in a nonhuman primate with [18F]4F-MHPG provided high quality images of the heart, with heart-to-blood ratios at 80–90 min after injection of 5-to-1. These initial kinetic and imaging studies of [18F]4F-MHPG suggest that this radiotracer may allow for more accurate quantification of regional cardiac sympathetic nerve density than is currently possible with existing neuronal imaging agents. PMID:23416009

  2. The Innervation of Teeth

    PubMed Central

    Bradlaw, Robert

    1936-01-01

    The author, using the staining methods of Bielschowski, Gross, Beckwith, Weigert-Pal and Cajal in frozen and serial paraffin and celloidin sections, has investigated the dental innervations of man, monkey, dog, cat, and guinea-pig in health and disease. He discusses the anatomy and physiology of the dental innervation and the effect of section of the inferior dental nerve on the trophic, vasomotor, protective, and sensory functions, with special reference to the relation between dental disease and neuropathies. He describes the innervation of the tooth germ and the nature of the growing fibrils seen before calcification in the dentinal papilla and draws attention to the innervation of the periodontal membrane. He has found that these nerves anastomose across the crest of the interdental septa with their fellows and demonstrates coiled sub-cemental nerve-endings. He has been unable to find any difference in the eruption and casting of teeth after section of the inferior dental nerve, and does not find degeneration of the nerves of deciduous teeth prior to casting to be inevitable. He discusses the effect of local anæsthesia on the dental pulp, some of the causes of odontalgia and neuralgia and the effect of old age and general disease on the dental innervation. He has failed with lethal or continued sublethal doses of ethyl and methyl alcohol, lead or tetanus and diphtheria toxins, using the oral, gastric, subcutaneous and intravenous route, to produce dental neuronic change. The effects of fracture of teeth and jaws, the introduction of arsenic into the pulp chamber and amputation and extirpation of the pulp are examined. The vital resistance of the pulp and the significance of granulomata as a protective mechanism are discussed. The author has found that after extraction although there is at first degeneration of the nerve-fibres concerned, there may subsequently be regeneration, sometimes in the form of plexiform neuroma. He has produced degenerative changes in

  3. A histochemical study on the innervation of the pancreas of the one-humped camel (Camelus dromedarius).

    PubMed Central

    Qayyum, M A; Fatani, J A; Shaad, F U; Mohajir, A M

    1987-01-01

    Autonomic innervation of the pancreas of the camel has been studied using histochemical techniques for the demonstration of adrenergic and cholinergic (acetylcholinesterase-positive) nerves. Both extrinsic and intrinsic innervation of the pancreas were found. Distinct peri-acinar, perivascular, peri-insular and periductal plexuses were found as well as both adrenergic and cholinergic ganglia. The role of the autonomic nerves in the synthesis and release of insulin, glucagon and somatostatin is discussed. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:3654346

  4. Specificity and impact of adrenergic projections to the midbrain dopamine system.

    PubMed

    Mejias-Aponte, Carlos A

    2016-06-15

    Dopamine (DA) is a neuromodulator that regulates different brain circuits involved in cognitive functions, motor coordination, and emotions. Dysregulation of DA is associated with many neurological and psychiatric disorders such as Parkinson's disease and substance abuse. Several lines of research have shown that the midbrain DA system is regulated by the central adrenergic system. This review focuses on adrenergic interactions with midbrain DA neurons. It discusses the current neuroanatomy including source of adrenergic innervation, type of synapses, and adrenoceptors expression. It also discusses adrenergic regulation of DA cell activity and neurotransmitter release. Finally, it reviews several neurological and psychiatric disorders where changes in adrenergic system are associated with dysregulation of the midbrain DA system. This article is part of a Special Issue entitled SI: Noradrenergic System. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Innervation of the human gastric wall.

    PubMed Central

    Kyösola, K; Rechardt, L; Veijola, L; Waris, T; Penttilä, O

    1980-01-01

    The intrinsic innervation of the human gastric wall was studied by means of (1) demonstration of the acetylcholinesterase activity, (2) fluorescence microscopy, and (3) electron microscopy. The cholinergic innervation was rich: in the mucosa, a dense three dimensional network consisting of single delicate varicose acetylcholinesterase-positive axons and small nerve fascicles was observed in close relation to the gastric glands. In the submucosa, large nerve trunks and densely woven plexuses mainly consisting of single varicose axons (obviously perivascular plexuses)) were seen. In the muscularis external, a small-meshed net consisting of single varicose axons and nerve fascicles was observed. The ganglia of the myenteric plexus were small and scattered irregularly between and within the muscle layers. Most of the nerve cells exhibited moderate to intense acetylcholinesterase activity. In the serosa, only a few nerves were observed. By fluorescence microscopy, an abundance of brightly yellow fluorescing irregularly fusiform enterochromaffin cells was observed in the epithelial lining of the antral glands. The parietal cells of the fundic glands exhibited a granular, yellow to orange autofluorescence. Fluorescing axons were seen in intimate relation to some enterochromaffin cells, whereas most enterochromaffin cells and parietal cells did not receive any direct functional adrenergic innervation. In the other tissue layers, only a few fluorescing nerves were seen. The main ultrastructural characteristics of the intrinsic innervation of the mucosa were: (1) 'Innervation fasciculée'; (2) the axons were unmyelinated; (3) two main types of nerve terminals were identified according to their vesicle population(s): (a) nerve terminals containing only clear vesicles, (b) nerve terminals containing clear vesicles and large dense-cored vesicles. Most of the axons and nerve terminals within the nerve fascicles were acetylcholinesterase-positive. The nerve terminals were

  6. Present state of alpha- and beta-adrenergic drugs I. The adrenergic receptor.

    PubMed

    Ahlquist, R P

    1976-11-01

    The cardiovascular alpha adrenergic receptors evoke vasoconstriction, the cardiovascular beta receptors evoke vasodilation and cardiac stimulation. All blood vessels have both alpha and beta receptors. In some areas, for example skin and kidney, the alpha receptors predominate. In some vascular beds, for example the nutrient vessels in skeletal muscle, beta receptors predominate. In other beds, such as coronary, visceral, and connective tissue both receptors are active. The cardiovascular effects of adrenergic agonists depend on which receptor they act on. Phenylephrine is specific for alpha receptors. Isoproterenol is specific for beta receptors. Epinephrine and norepinephrine act on both. The real value of knowing the receptor specificity of each agonist is that side effects can more easily be predicted. For example, adrenergic cardiac stimulants are antiasthmatics. Therefore, adrenergic antiasthmatics can produce excessive cardiac stimulation. For the future, agonists that are not only receptor-specific but also tissue-specific will be developed. The first of these in the United States is terbutaline. The rest of the world has in addition a similar drug, salbutamol. No one knows if this drug will be approved for use by American physicians.

  7. Hostility, social support, and adrenergic receptor responsiveness among African-American and white men and women.

    PubMed

    Hughes, Joel W; Sherwood, Andrew; Blumenthal, James A; Suarez, Edward C; Hinderliter, Alan L

    2003-01-01

    We examined the relationship between beta-adrenergic receptor responsiveness and hostility and social support in African American and white men and women. The participants were 149 men and women, aged 25 to 45 years with SBP < 160 and DBP < 105. Hostility and social support were assessed with standardized self-report measures. An isoproterenol challenge was used to evaluate beta-adrenergic receptor responsiveness, and a phenylephrine challenge was used to evaluate alpha-adrenergic receptor responsiveness. Hostility and social support were unrelated to alpha-adrenergic receptor responsiveness. Hostility and satisfaction with perceived social support predicted beta-adrenergic receptor responsiveness in multiple linear regression analyses controlling for race, gender, age, SBP, and resting heart rate. High hostility was associated with reduced cardiac beta-adrenergic receptor function among both white and African American men. Low levels of satisfaction with social support were associated with reduced cardiac beta-adrenergic receptor responsiveness among men and women. Hostility and satisfaction with social support shared some variance in models predicting beta-adrenergic receptor responsiveness. Reduced beta-adrenergic receptor responsiveness is associated with higher levels of hostility among men, and is associated with lower levels of satisfaction with social support among men and women. Impaired beta-adrenergic receptor function, which is a common characteristic of cardiovascular disease, may be a marker of increased cardiovascular disease risk among individuals high in hostility and low in social support.

  8. Neuronal Na+ Channels Are Integral Components of Pro-arrhythmic Na+/Ca2+ Signaling Nanodomain That Promotes Cardiac Arrhythmias During β-adrenergic Stimulation

    PubMed Central

    Radwański, Przemysław B.; Ho, Hsiang-Ting; Veeraraghavan, Rengasayee; Brunello, Lucia; Liu, Bin; Belevych, Andriy E.; Unudurthi, Sathya D.; Makara, Michael A.; Priori, Silvia G.; Volpe, Pompeo; Armoundas, Antonis A.; Dillmann, Wolfgang H.; Knollmann, Bjorn C.; Mohler, Peter J.; Hund, Thomas J.; Györke, Sándor

    2016-01-01

    Background Cardiac arrhythmias are a leading cause of death in the US. Vast majority of these arrhythmias including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with increased levels of circulating catecholamines and involve abnormal impulse formation secondary to aberrant Ca2+ and Na+ handling. However, the mechanistic link between β-AR stimulation and the subcellular/molecular arrhythmogenic trigger(s) remains elusive. Methods and Results We performed functional and structural studies to assess Ca2+ and Na+ signaling in ventricular myocyte as well as surface electrocardiograms in mouse models of cardiac calsequestrin (CASQ2)-associated CPVT. We demonstrate that a subpopulation of Na+ channels (neuronal Na+ channels; nNav) that colocalize with RyR2 and Na+/Ca2+ exchanger (NCX) are a part of the β-AR-mediated arrhythmogenic process. Specifically, augmented Na+ entry via nNav in the settings of genetic defects within the RyR2 complex and enhanced sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA)-mediated SR Ca2+ refill is both an essential and a necessary factor for the arrhythmogenesis. Furthermore, we show that augmentation of Na+ entry involves β-AR-mediated activation of CAMKII subsequently leading to nNav augmentation. Importantly, selective pharmacological inhibition as well as silencing of Nav1.6 inhibit myocyte arrhythmic potential and prevent arrhythmias in vivo. Conclusion These data suggest that the arrhythmogenic alteration in Na+/Ca2+ handling evidenced ruing β-AR stimulation results, at least in part, from enhanced Na+ influx through nNav. Therefore, selective inhibition of these channels and Nav1.6 in particular can serve as a potential antiarrhythmic therapy. PMID:27747307

  9. Neuronal Na(+) Channels Are Integral Components of Pro-arrhythmic Na(+)/Ca(2+) Signaling Nanodomain That Promotes Cardiac Arrhythmias During β-adrenergic Stimulation.

    PubMed

    Radwański, Przemysław B; Ho, Hsiang-Ting; Veeraraghavan, Rengasayee; Brunello, Lucia; Liu, Bin; Belevych, Andriy E; Unudurthi, Sathya D; Makara, Michael A; Priori, Silvia G; Volpe, Pompeo; Armoundas, Antonis A; Dillmann, Wolfgang H; Knollmann, Bjorn C; Mohler, Peter J; Hund, Thomas J; Györke, Sándor

    2016-06-01

    Cardiac arrhythmias are a leading cause of death in the US. Vast majority of these arrhythmias including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with increased levels of circulating catecholamines and involve abnormal impulse formation secondary to aberrant Ca(2+) and Na(+) handling. However, the mechanistic link between β-AR stimulation and the subcellular/molecular arrhythmogenic trigger(s) remains elusive. We performed functional and structural studies to assess Ca(2+) and Na(+) signaling in ventricular myocyte as well as surface electrocardiograms in mouse models of cardiac calsequestrin (CASQ2)-associated CPVT. We demonstrate that a subpopulation of Na(+) channels (neuronal Na(+) channels; nNav) that colocalize with RyR2 and Na(+)/Ca(2+) exchanger (NCX) are a part of the β-AR-mediated arrhythmogenic process. Specifically, augmented Na(+) entry via nNav in the settings of genetic defects within the RyR2 complex and enhanced sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA)-mediated SR Ca(2+) refill is both an essential and a necessary factor for the arrhythmogenesis. Furthermore, we show that augmentation of Na(+) entry involves β-AR-mediated activation of CAMKII subsequently leading to nNav augmentation. Importantly, selective pharmacological inhibition as well as silencing of Nav1.6 inhibit myocyte arrhythmic potential and prevent arrhythmias in vivo. These data suggest that the arrhythmogenic alteration in Na(+)/Ca(2+) handling evidenced ruing β-AR stimulation results, at least in part, from enhanced Na(+) influx through nNav. Therefore, selective inhibition of these channels and Nav1.6 in particular can serve as a potential antiarrhythmic therapy.

  10. Blocking the beta-adrenergic system does not affect sweat gland function during heat acclimation.

    PubMed

    Martinez, Ricardo; Jones, Douglas; Hodge, Daniel; Buono, Michael J

    2012-08-16

    The purpose of the current study was to test the hypothesis that the beta-adrenergic innervation of the human eccrine sweat gland facilitates greater sweat production following heat acclimation. Eight healthy subjects (mean ± SD age: 25.1 ± 4.1 years, weight: 79.0 ± 16.1 kg, and VO(2)max: 48.5 ± 8.0 ml/kg/min) underwent active heat acclimation by walking at 40% of their VO(2)max for 8 days (90 min a day) in an environmental chamber (35.3 ± 0.8°C and 40.2 ± 2.1% rH). To test the hypothesis, the adrenergic component of sweat gland innervation was inhibited by continuously administering a 0.5% solution of the beta-adrenergic antagonist propranolol via iontophoresis to a 5 cm(2) area of one forearm during each 90-min exercise bout. The opposing control forearm underwent iontophoresis with a saline solution. Following heat acclimation, mean sweat rate in the inhibited and control forearm was 0.47 ± 0.30 mg/cm(2)/min and 0.44 ± 0.25mg/cm(2)/min, respectively. Findings of the current study fail to support the hypothesis that adrenergic innervation facilitates human eccrine sweat gland function during heat acclimation, as no significant differences in sweating were observed. In light of the above, the physiological significance of the dual cholinergic and adrenergic innervation of the eccrine sweat gland has yet to be determined.

  11. Impaired alpha1-adrenergic responses in aged rat hearts.

    PubMed

    Montagne, Olivier; Le Corvoisier, Philippe; Guenoun, Thierry; Laplace, Monique; Crozatier, Bertrand

    2005-06-01

    To determine age-related changes in the cardiac effect of alpha1-adrenergic stimulation, both cardiomyocyte Ca2+-transient and cardiac protein kinase C (PKC) activity were measured in 3-month- (3MO) and 24-month- (24MO) old Wistar rats. Ca2+ transients obtained under 1 Hz pacing by microfluorimetry of cardiomyocyte loaded with indo-1 (405/480 nm fluorescence ratio) were compared in control conditions (Kreb's solution alone) and after alpha1-adrenergic stimulation (phenylephrine or cirazoline, an alpha1-specific agonist). PKC activity and PKC translocation index (particulate/total activity) were also assayed before and after alpha1-adrenergic stimulation. In 3MO, cirazoline induced a significant increase in Ca2+ transient for a 10(-9) M concentration which returned to control values for larger concentrations. In contrast, in 24MO, we observed a constant negative effect of cirazoline on the Ca2+ transient with a significant decrease at 10(-6) M compared with both baseline and Kreb's solution. Preliminary experiments showed that, in a dose-response curve to phenylephrine, the response of Ca2+ transient was maximal at 10(-7) M. This concentration induced a significant increase in Ca2+ transient in 3MO and a significant decrease in 24MO. The same concentration was chosen to perform PKC activity measurements under alpha1-adrenergic stimulation. In the basal state, PKC particulate activity was higher in 24MO than that in 3MO but was not different in cytosolic fractions; so that the translocation index was higher in 24MO (P < 0.01). After phenylephrine, a translocation of PKC toward the particulate fraction was observed in 3MO but not in 24MO. In conclusion, cardiac alpha1-adrenoceptor response was found to be impaired in aged hearts. The negative effect of alpha1-adrenergic stimulation on Ca2+ transient in cardiomyocytes obtained from old rats can be related to an absence of alpha1-adrenergic-induced PKC translocation.

  12. Innervation of the Heart: An Invisible Grid within a Black Box

    PubMed Central

    Kapa, Suraj; DeSimone, Christopher; Asirvatham, Samuel J.

    2015-01-01

    Autonomic control of cardiovascular function is mediated by a complex interplay between central, peripheral, and innate cardiac components. This interplay is what mediates the normal cardiovascular response to physiologic and pathologic stressors, including blood pressure, cardiac contractile function, and arrhythmias. However, in order to understand how modern therapies directly affecting autonomic function may be harnessed to treat various cardiovascular disease states requires an intimate understanding of anatomic and physiologic features of the innervation of the heart. Thus, in this review, we focus on defining features of the central, peripheral, and cardiac components of cardiac innervation, how each component may contribute to dysregulation of normal cardiac function in various disease states and how modulation of these components may offer therapeutic options for these diseases. PMID:26254961

  13. Innervation of the heart: An invisible grid within a black box.

    PubMed

    Kapa, Suraj; DeSimone, Christopher V; Asirvatham, Samuel J

    2016-04-01

    Autonomic control of cardiovascular function is mediated by a complex interplay between central, peripheral, and innate cardiac components. This interplay is what mediates the normal cardiovascular response to physiologic and pathologic stressors, including blood pressure, cardiac contractile function, and arrhythmias. However, in order to understand how modern therapies directly affecting autonomic function may be harnessed to treat various cardiovascular disease states requires an intimate understanding of anatomic and physiologic features of the innervation of the heart. Thus, in this review, we focus on defining features of the central, peripheral, and cardiac components of cardiac innervation, how each component may contribute to dysregulation of normal cardiac function in various disease states, and how modulation of these components may offer therapeutic options for these diseases.

  14. Adrenergic deficiency leads to impaired electrical conduction and increased arrhythmic potential in the embryonic mouse heart.

    PubMed

    Baker, Candice; Taylor, David G; Osuala, Kingsley; Natarajan, Anupama; Molnar, Peter J; Hickman, James; Alam, Sabikha; Moscato, Brittany; Weinshenker, David; Ebert, Steven N

    2012-07-06

    To determine if adrenergic hormones play a critical role in the functional development of the cardiac pacemaking and conduction system, we employed a mouse model where adrenergic hormone production was blocked due to targeted disruption of the dopamine β-hydroxylase (Dbh) gene. Immunofluorescent histochemical evaluation of the major gap junction protein, connexin 43, revealed that its expression was substantially decreased in adrenergic-deficient (Dbh-/-) relative to adrenergic-competent (Dbh+/+ and Dbh+/-) mouse hearts at embryonic day 10.5 (E10.5), whereas pacemaker and structural protein staining appeared similar. To evaluate cardiac electrical conduction in these hearts, we cultured them on microelectrode arrays (8×8, 200 μm apart). Our results show a significant slowing of atrioventricular conduction in adrenergic-deficient hearts compared to controls (31.4±6.4 vs. 15.4±1.7 ms, respectively, p<0.05). To determine if the absence of adrenergic hormones affected heart rate and rhythm, mouse hearts from adrenergic-competent and deficient embryos were cultured ex vivo at E10.5, and heart rates were measured before and after challenge with the β-adrenergic receptor agonist, isoproterenol (0.5 μM). On average, all hearts showed increased heart rate responses following isoproterenol challenge, but a significant (p<0.05) 225% increase in the arrhythmic index (AI) was observed only in adrenergic-deficient hearts. These results show that adrenergic hormones may influence heart development by stimulating connexin 43 expression, facilitating atrioventricular conduction, and helping to maintain cardiac rhythm during a critical phase of embryonic development.

  15. Cardiovascular regulation by central adrenergic mechanisms and its alteration by hypotensive drugs.

    PubMed

    Haeusler, G

    1975-06-01

    Electrical stimulation of the posterior hypothalamus is followed by an immediate increase in sympathetic nerve activity and rise in blood pressure. Destruction of hypothalamic adrenergic structures by local unilateral injection of 6-hydroxydopamine into the posterior hypothalamus reduced the blood pressure rise in response to stimulation of the lesioned side. This and numerous other findings indicate an involvement of central adrenergic neurons in the mediation of an increase of sympathetic nerve activity caused by hypothalamic stimulation. However, central adrenergic neurons do not seem to be an integral part of the sympathoexcitatory pathways originating in the posterior hypothalamus but rather facilitate their activation: after almost complete norepinephrine depletion produced by combined treatment with reserpine and alpha-methl-p-tyrosine, hypothalamic stimulation was still followed by an increase in spontaneous sympathetic nerve activity. Stimulation of an alpha-adrenoceptive site, probably located in the lower brain stem, mimics an activation of the baroreceptor reflex. The hypotensive drug, clonidine, stimulates this alpha-adrenoceptive site. In low doses clonidine facilitates the activation of the reflex, and in high doses this drug induces a state which closely resembles a pronounced activation of the reflex. Experiments following depletion of norepinephrine suggest that the central part of the baroreceptor reflex arc does not contain adrenergic neurons. However, these findings are compatible with the view that some neurons within the reflex arc are supplied with alpha-adrenoceptors. For the present it cannot be stated with certainty whether these alpha-adrenoceptors possess an innervation by adrenergic neurons projecting onto the reflex arc. In favor of such an innervation are the obsevations that alpha-methyldopa has its site of action in the lower brain stem and that the integrity of central adrenergic neurons is essential for its hypotensive effect. It

  16. Beta-Adrenergic Agonists

    PubMed Central

    Barisione, Giovanni; Baroffio, Michele; Crimi, Emanuele; Brusasco, Vito

    2010-01-01

    Inhaled β2-adrenoceptor (β2-AR) agonists are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptoms-relievers and, in combination with inhaled corticosteroids, as disease-controllers. In this article, we first review the basic mechanisms by which the β2-adrenergic system contributes to the control of airway smooth muscle tone. Then, we go on describing the structural characteristics of β2-AR and the molecular basis of G-protein-coupled receptor signaling and mechanisms of its desensitization/ dysfunction. In particular, phosphorylation mediated by protein kinase A and β-adrenergic receptor kinase are examined in detail. Finally, we discuss the pivotal role of inhaled β2-AR agonists in the treatment of asthma and the concerns about their safety that have been recently raised. PMID:27713285

  17. Beta-adrenergic receptor function is acutely altered in surgical patients.

    PubMed

    Marty, J; Nimier, M; Rocchiccioli, C; Mantz, J; Luscombe, F; Henzel, D; Loiseau, A; Desmonts, J M

    1990-07-01

    Catecholamine-induced desensitization of beta-adrenergic receptors resulting in hyporesponsiveness to further stimulation has been frequently reported after an increase in endogenous catecholamines. To examine the possibility of beta-adrenoceptor desensitization due to intraoperative adrenergic activation (surgical stress), the alterations of human lymphocyte beta-adrenergic receptor density and affinity observed after anesthesia and surgery were studied using (-)125I-iodocyanopindolol binding in 19 patients undergoing noncardiac surgical procedures with general anesthesia (thiopental, fentanyl, and halothane or isoflurane). In 13 patients, repeated determinations of plasma levels of norepinephrine and epinephrine showed an increase during the surgical procedure (norepinephrine +60%; epinephrine +60%); this change was not observed in the remaining patients. A significant postoperative increase in receptor density (Bmax +25%) and a significant decrease of receptor affinity for isoproterenol (IC50 +22%) were found in the patients who experienced intraoperative adrenergic activation. By contrast, no significant change in beta-receptor density or affinity was found in the patients who had normal intraoperative adrenergic activation. In addition, heart rate responses to the postoperative changes in plasma catecholamines (an index of cardiac sensitivity to agonist) were significantly attenuated in patients who experienced both intraoperative adrenergic activation and a decrease in affinity of beta-receptor for agonist, suggesting hyporesponsiveness to beta stimulation. We conclude that beta-adrenergic receptors and, consequently, beta-adrenergic responsiveness might be altered by perioperative adrenergic activation in surgical patients.

  18. Netrin-1 controls sympathetic arterial innervation

    PubMed Central

    Brunet, Isabelle; Gordon, Emma; Han, Jinah; Cristofaro, Brunella; Broqueres-You, Dong; Liu, Chun; Bouvrée, Karine; Zhang, Jiasheng; del Toro, Raquel; Mathivet, Thomas; Larrivée, Bruno; Jagu, Julia; Pibouin-Fragner, Laurence; Pardanaud, Luc; Machado, Maria J.C.; Kennedy, Timothy E.; Zhuang, Zhen; Simons, Michael; Levy, Bernard I.; Tessier-Lavigne, Marc; Grenz, Almut; Eltzschig, Holger; Eichmann, Anne

    2014-01-01

    Autonomic sympathetic nerves innervate peripheral resistance arteries, thereby regulating vascular tone and controlling blood supply to organs. Despite the fundamental importance of blood flow control, how sympathetic arterial innervation develops remains largely unknown. Here, we identified the axon guidance cue netrin-1 as an essential factor required for development of arterial innervation in mice. Netrin-1 was produced by arterial smooth muscle cells (SMCs) at the onset of innervation, and arterial innervation required the interaction of netrin-1 with its receptor, deleted in colorectal cancer (DCC), on sympathetic growth cones. Function-blocking approaches, including cell type–specific deletion of the genes encoding Ntn1 in SMCs and Dcc in sympathetic neurons, led to severe and selective reduction of sympathetic innervation and to defective vasoconstriction in resistance arteries. These findings indicate that netrin-1 and DCC are critical for the control of arterial innervation and blood flow regulation in peripheral organs. PMID:24937433

  19. Adrenergic modulation of olfactory bulb circuitry affects odor discrimination.

    PubMed

    Doucette, Wilder; Milder, Julie; Restrepo, Diego

    2007-08-01

    A rodent's survival depends upon its ability to perceive odor cues necessary to guide mate selection, sexual behavior, foraging, territorial formation, and predator avoidance. Arguably, the need to discriminate odor cues in a complex olfactory environment requires a highly adaptable olfactory system. Indeed, it has been proposed that context-dependent modulation of the initial sensory relay could alter olfactory perception. Interestingly, 40% of the adrenergic innervation from the locus coeruleus, fibers that are activated by contextual cues, innervates the first relay station in the olfactory system (the main olfactory bulb). Here we utilize restricted pharmacological inhibition of olfactory bulb noradrenergic receptors in awake-behaving animals. We show that combined blockade of alpha and beta adrenergic receptors does not impair two-odor discrimination behavior per se but does impair the ability to discriminate perceptually similar odors. Thus, contextual cues conveyed by noradrenergic fibers alter processing before the second synapse in the olfactory cortex, resulting in tuning of the ability to discriminate between similar odors.

  20. Pulmonary noradrenergic innervation of rat and monkey: a comparative study

    PubMed Central

    El-Bermani, Al-Walid I.

    1978-01-01

    El-Bermani, Al-Walid I. (1978).Thorax, 33, 167-174. Pulmonary noradrenergic innervation of rat and monkey: a comparative study. The noradrenergic innervation of rat and monkey lungs was studied using the fluorescence histochemical method for norepinephrine of Falck (1962). In both species the noradrenergic nerves enter the lung at the hilum in association with the bronchial arteries. Major differences were noted in the distribution and pattern of these nerves, the most important of which are as follows: (1) Noradrenergic nerves have terminal varicosities in all divisions of the rat bronchial artery but are varicose in only the medium and small bronchial arteries of the monkey. (2) Noradrenergic terminals (varicosities) are in direct association with the bronchial smooth muscle in the monkey, but in the rat most of the noradrenergic nerves pass through the smooth muscle layer without forming terminal varicosities. Smooth muscle noradrenergic innervation is seen only at bifurcation points. (3) In the monkey pulmonary artery, noradrenergic terminals are restricted to the adventitio-medial junction while they appear in the media of the rat pulmonary artery. (4) Noradrenergic terminals are present in all pulmonary vein divisions of the monkey whereas in the rat the large pulmonary veins lack noradrenergic nerves. Both rat and monkey bronchial arteries and pulmonary veins were found to have adrenergic terminal varicosities deep in the medial layer. The rat pulmonary artery also has such medial terminations. In both species there is a preponderance of noradrenergic terminals in the vasa vasorum, and we think that this may be important in regulating the delivery of humoral substances to vascular walls. Images PMID:96545

  1. Morphology and innervation of the teleost physostome swim bladders and their functional evolution in non-teleostean lineages.

    PubMed

    Zaccone, Daniele; Sengar, Manvendra; Lauriano, Eugenia R; Pergolizzi, Simona; Macri', Francesco; Salpietro, Lorenza; Favaloro, Angelo; Satora, Leszek; Dabrowski, Konrad; Zaccone, Giacomo

    2012-12-01

    Swim bladders and lungs are homologous structures. Phylogenetically ancient actinopterygian fish such as Cladistians (Polypteriformes), Ginglymods (Lepisosteids) and lungfish have primitive lungs that have evolved in the Paleozoic freshwater earliest gnathostomes as an adaptation to hypoxic stress. Here we investigated the structure and the role of autonomic nerves in the physostome swim bladder of the cyprinid goldfish (Carassius auratus) and the respiratory bladder of lepisosteids: the longnose gar and the spotted gar (Lepisosteus osseus and L. oculatus) to demonstrate that these organs have different innervation patterns that are responsible for controlling different functional aspects. The goldfish swim bladder is a richly innervated organ mainly controlled by cholinergic and adrenergic innervation also involving the presence of non-adrenergic non-cholinergic (NANC) neurotransmitters (nNOS, VIP, 5-HT and SP), suggesting a simple model for the regulation of the swim bladder system. The pattern of the autonomic innervation of the trabecular muscle of the Lepisosteus respiratory bladder is basically similar to that of the tetrapod lung with overlapping of both muscle architecture and control nerve patterns. These autonomic control elements do not exist in the bladders of the two species studied since they have very different physiological roles. The ontogenetic origin of the pulmonoid swim bladder (PSB) of garfishes may help understand how the expression of these autonomic control substances in the trabecular muscle is regulated including their interaction with the corpuscular cells in the respiratory epithelium of this bimodal air-breathing fish.

  2. Adrenergic and non-adrenergic control of active skeletal muscle blood flow: implications for blood pressure regulation during exercise.

    PubMed

    Holwerda, Seth W; Restaino, Robert M; Fadel, Paul J

    2015-03-01

    Blood flow to active skeletal muscle increases markedly during dynamic exercise. However, despite the massive capacity of skeletal muscle vasculature to dilate, arterial blood pressure is well maintained. Sympathetic nerve activity is elevated with increased intensity of dynamic exercise, and is essential for redistribution of cardiac output to active skeletal muscle and maintenance of arterial blood pressure. In addition, aside from the sympathetic nervous system, evidence from human studies is now emerging that supports roles for non-adrenergic vasoconstrictor pathways that become active during exercise and contribute to vasoconstriction in active skeletal muscle. Neuropeptide Y and adenosine triphosphate are neurotransmitters that are co-released with norepinephrine from sympathetic nerve terminals capable of producing vasoconstriction. Likewise, plasma concentrations of arginine vasopressin, angiotensin II (Ang II) and endothelin-1 (ET-1) increase during dynamic exercise, particularly at higher intensities. Ang II and ET-1 have both been shown to be important vasoconstrictor pathways for restraint of blood flow in active skeletal muscle and the maintenance of arterial blood pressure during exercise. Indeed, although both adrenergic and non-adrenergic vasoconstriction can be attenuated in exercising muscle with greater intensity of exercise, with the higher volume of blood flow, the active skeletal muscle vasculature remains capable of contributing importantly to the maintenance of blood pressure. In this brief review we provide an update on skeletal muscle blood flow regulation during exercise with an emphasis on adrenergic and non-adrenergic vasoconstrictor pathways and their potential capacity to offset vasodilation and aid in the regulation of blood pressure.

  3. Sympathetic innervation of human muscle spindles

    PubMed Central

    Radovanovic, Dina; Peikert, Kevin; Lindström, Mona; Domellöf, Fatima Pedrosa

    2015-01-01

    The aim of the present study was to investigate the presence of sympathetic innervation in human muscle spindles, using antibodies against neuropeptide Y (NPY), NPY receptors and tyrosine hydroxylase (TH). A total of 232 muscle spindles were immunohistochemically examined. NPY and NPY receptors were found on the intrafusal fibers, on the blood vessels supplying muscle spindles and on free nerve endings in the periaxial space. TH-immunoreactivity was present mainly in the spindle nerve and vessel. This is, to our knowledge, the first morphological study concerning the sympathetic innervation of the human muscle spindles. The results provide anatomical evidence for direct sympathetic innervation of the intrafusal fibers and show that sympathetic innervation is not restricted to the blood vessels supplying spindles. Knowledge about direct sympathetic innervation of the muscle spindle might expand our understanding of motor and proprioceptive dysfunction under stress conditions, for example, chronic muscle pain syndromes. PMID:25994126

  4. Noradrenergic innervation of juvenile nasopharyngeal angiofibroma.

    PubMed

    Wang, H W; Su, W Y; Wang, J Y

    1994-01-01

    The glyoxylic catecholaminergic histofluorescence method was employed on tissues from five cases of juvenile nasopharyngeal angiofibroma in order to study the sympathetic innervation present. There was no sympathetic innervation identified in tumor parenchyma while some scant noradrenergic fibers were found in the tumor border. These findings indicate that keeping a dissection surface out of tumor during planned excisions may be very important, as vessels there have more sympathetic innervation which will then result in good vessel contraction in controlling bleeding. Non-diseased nasal mucosa from each patient was used as control tissue, with its submucosa seen to be filled with noradrenergic innervation. Some noradrenergic fibers were also found to innervate the muscle layers of arterioles or venules adjacent to the sphenopalatine foramen.

  5. Sympathetic innervation of human muscle spindles.

    PubMed

    Radovanovic, Dina; Peikert, Kevin; Lindström, Mona; Domellöf, Fatima Pedrosa

    2015-06-01

    The aim of the present study was to investigate the presence of sympathetic innervation in human muscle spindles, using antibodies against neuropeptide Y (NPY), NPY receptors and tyrosine hydroxylase (TH). A total of 232 muscle spindles were immunohistochemically examined. NPY and NPY receptors were found on the intrafusal fibers, on the blood vessels supplying muscle spindles and on free nerve endings in the periaxial space. TH-immunoreactivity was present mainly in the spindle nerve and vessel. This is, to our knowledge, the first morphological study concerning the sympathetic innervation of the human muscle spindles. The results provide anatomical evidence for direct sympathetic innervation of the intrafusal fibers and show that sympathetic innervation is not restricted to the blood vessels supplying spindles. Knowledge about direct sympathetic innervation of the muscle spindle might expand our understanding of motor and proprioceptive dysfunction under stress conditions, for example, chronic muscle pain syndromes.

  6. Neuronal adrenergic and muscular cholinergic contractile hypersensitivity in canine jejunum after extrinsic denervation.

    PubMed

    Balsiger, Bruno M; He, Chong-Liang; Zyromski, Nicholas J; Sarr, Michael G

    2003-01-01

    Extrinsic denervation may be responsible for motor dysfunction after small bowel transplantation. The aim of this study was to examine the role of extrinsic innervation of canine jejunum on contractile activity. An in vitro dose response of cholinergic and adrenergic agonists was evaluated in canine jejunal strips of circular muscle at 0, 2, and 8 weeks in a control group and after jejunoileal extrinsic denervation (EX DEN). Neurons in circular muscle were quantitated by means of immunohistochemical techniques. Adrenergic and cholinergic responses did not differ at any time in the control group. However, at 2 and 8 weeks, extrinsic denervation caused an increased sensitivity to the procontractile effects of the cholinergic agonist bethanechol at the level of the smooth muscle cells, and increased sensitivity to the inhibitory effects of the adrenergic agent norepinephrine mediated at the level of the enteric nervous system. Immunohistochemical analysis showed a reduction in all neurons and a complete lack of adrenergic fibers in the EX DEN group after 2 and 8 weeks. Extrinsic denervation induces enteric neuronal cholinergic and adrenergic smooth muscle hypersensitivity in canine jejunal circular muscle.

  7. Ganglionic adrenergic action modulates ovarian steroids and nitric oxide in prepubertal rat.

    PubMed

    Delgado, Silvia Marcela; Casais, Marilina; Sosa, Zulema; Rastrilla, Ana María

    2006-08-01

    Both peripheral innervation and nitric oxide (NO) participate in ovarian steroidogenesis. The purpose of this work was to analyse the ganglionic adrenergic influence on the ovarian release of steroids and NO and the possible steroids/NO relationship. The experiments were carried out in the ex vivo coeliac ganglion-superior ovarian nerve (SON)-ovary system of prepubertal rats. The coeliac ganglion-SON-ovary system was incubated in Krebs Ringer-bicarbonate buffer in presence of adrenergic agents in the ganglionic compartment. The accumulation of progesterone, androstenedione, oestradiol and NO in the ovarian incubation liquid was measured. Norepinephrine in coeliac ganglion inhibited the liberation of progesterone and increased androstenedione, oestradiol and NO in ovary. The addition of alpha and beta adrenergic antagonists also showed different responses in the liberation of the substances mentioned before, which, from a physiological point of view, reveals the presence of adrenergic receptors in coeliac ganglion. In relation to propranolol, it does not revert the effect of noradrenaline on the liberation of progesterone, which leads us to think that it might also have a "per se" effect on the ganglion, responsible for the ovarian response observed for progesterone. Finally, we can conclude that the ganglionic adrenergic action via SON participates on the regulation of the prepubertal ovary in one of two ways: either increasing the NO, a gaseous neurotransmitter with cytostatic characteristics, to favour the immature follicles to remain dormant or increasing the liberation of androstenedione and oestradiol, the steroids necessary for the beginning of the near first estral cycle.

  8. Heart Development, Diseases, and Regeneration - New Approaches From Innervation, Fibroblasts, and Reprogramming.

    PubMed

    Ieda, Masaki

    2016-09-23

    It is well known that cardiac function is tightly controlled by neural activity; however, the molecular mechanism of cardiac innervation during development and the relationship with heart disease remain undetermined. My work has revealed the molecular networks that govern cardiac innervation and its critical roles in heart diseases such as silent myocardial ischemia and arrhythmias. Cardiomyocytes proliferate during embryonic development, but lose their proliferative capacity after birth. Cardiac fibroblasts are a major source of cells during fibrosis and induce cardiac hypertrophy after myocardial injury in the adult heart. Despite the importance of fibroblasts in the adult heart, the role of fibroblasts in embryonic heart development was previously not determined. I demonstrated that cardiac fibroblasts play important roles in myocardial growth and cardiomyocyte proliferation during embryonic development, and I identified key paracrine factors and signaling pathways. In contrast to embryonic cardiomyocytes, adult cardiomyocytes have little regenerative capacity, leading to heart failure and high mortality rates after myocardial infarction. Leveraging the knowledge of developmental biology, I identified cardiac reprogramming factors that can directly convert resident cardiac fibroblasts into cardiomyocytes for heart regeneration. These findings greatly improved our understanding of heart development and diseases, and provide a new strategy for heart regenerative therapy. (Circ J 2016; 80: 2081-2088).

  9. Species differences in the localization and number of CNS beta adrenergic receptors: Rat versus guinea pig

    SciTech Connect

    Booze, R.M.; Crisostomo, E.A.; Davis, J.N.

    1989-06-01

    The localization and number of beta adrenergic receptors were directly compared in the brains of rats and guinea pigs. The time course of association and saturability of (125I)cyanopindolol (CYP) binding to slide-mounted tissue sections was similar in rats (Kd = 17 pM) and guinea pigs (Kd = 20 pM). The beta-1 and beta-2 receptor subtypes were examined through the use of highly selective unlabeled receptor antagonists, ICI 118,551 (50 nM) and ICI 89,406 (70 nM). Dramatic species differences between rats and guinea pigs were observed in the neuroanatomical regional localization of the beta adrenergic receptor subtypes. For example, in the thalamus prominent beta-1 and beta-2 receptor populations were identified in the rat; however, the entire thalamus of the guinea pig had few, if any, beta adrenergic receptors of either subtype. Hippocampal area CA1 had high levels of beta-2 adrenergic receptors in both rats and guinea pigs but was accompanied by a widespread distribution of beta-2 adrenergic receptors only in rats. Quantitative autoradiographic analyses of 25 selected neuroanatomical regions (1) confirmed the qualitative differences in CNS beta adrenergic receptor localization, (2) determined that guinea pigs had significantly lower levels of beta adrenergic receptors than rats and (3) indicated a differential pattern of receptor subtypes between the two species. Knowledge of species differences in receptor patterns may be useful in designing effective experiments as well as in exploring the relationships between receptor and innervation patterns. Collectively, these data suggest caution be used in extrapolation of the relationships of neurotransmitters and receptors from studies of a single species.

  10. The heart's ‘little brain’ controlling cardiac function in the rabbit

    PubMed Central

    Brack, Kieran E

    2015-01-01

    New Findings •What is the topic of this review? The topic of the review is the intrinsic cardiac nervous system in the rabbit. •What advances does it highlight? The anatomy of rabbit intrinsic ganglia is similar to that of other species, including humans. Immunohistochemistry confirms the presence of cholinergic and adrenergic neurones, with a striking arrangement of neuronal nitric oxide synthase-positive cell bodies. Activation of atrial ganglia produces effects on local and remote regions. Heart disease is a primary cause of mortality in the developed world, and it is well recognized that neural mechanisms play an important role in many cardiac pathologies. The role of extrinsic autonomic nerves has traditionally attracted the most attention. However, there is a rich intrinsic innervation of the heart, including numerous cardiac ganglia (ganglionic plexuses), that has the potential to affect cardiac function independently as well as to influence the actions of the extrinsic nerves. To investigate this, an isolated, perfused, innervated rabbit Langendorff heart preparation was considered the best option. Although ganglionic plexuses have been well described for several species, there was no full description of the anatomy and histochemistry of rabbit hearts. To this end, rabbit intrinsic ganglia were located using acetylcholinesterase histology (n = 33 hearts). This revealed six generalized ganglionic regions, defined as a left neuronal complex above the left pulmonary vein, a right neuronal complex around the base of right cranial vein, three scattered in the dorsal right atrium and a region containing numerous ventricular ganglia located on the conus arteriosus. Using immunohistochemistry, neurons were found to contain choline acetyltransferase or tyrosine hydroxylase and/or neuronal nitric oxide synthase in differing amounts (choline acetyltransferase > tyrosine hydroxylase > neuronal nitric oxide synthase). The function of rabbit intrinsic ganglia

  11. β-Adrenergic blockers.

    PubMed

    Frishman, William H; Saunders, Elijah

    2011-09-01

    KEY POINTS AND PRACTICAL RECOMMENDATIONS: •  β-Blockers are appropriate treatment for patients with hypertension and those who have concomitant ischemic heart disease, heart failure, obstructive cardiomyopathy, or certain arrhythmias. •  β-Blockers can be used in combination with other antihypertensive drugs to achieve maximal blood pressure control. Labetalol can be used in hypertensive emergencies and urgencies. •  β-Blockers may be useful in patients having hyperkinetic circulation (palpitations, tachycardia, hypertension, and anxiety), migraine headache, and essential tremor. •  β-Blockers are highly heterogeneous with respect to various pharmacologic effects: degree of intrinsic sympathomimetic activity, membrane-stabilizing activity, β(1) selectivity, α(1) -adrenergic-blocking effect, tissue solubility, routes of systemic elimination, potencies and duration of action, and specific effects may be important in the selection of a drug for clinical use. •  β-Blocker usage to reduce perioperative ischemia and cardiovascular complications may not benefit as many patients as was once hoped and may actually cause harm in some individuals. Currently the best evidence supports β-blocker use in two patient groups: patients undergoing vascular surgery with known ischemic heart disease or multiple risk factors for it and for patients already receiving β-blockers for known cardiovascular conditions.

  12. Phospholemman is a Negative Feed-Forward Regulator of Ca2+ in β-Adrenergic Signaling, Accelerating β-Adrenergic Inotropy

    PubMed Central

    Yang, Jason H.; Saucerman, Jeffrey J.

    2012-01-01

    Sympathetic stimulation enhances cardiac contractility by stimulating β-adrenergic signaling and protein kinase A (PKA). Recently, phospholemman (PLM) has emerged as an important PKA substrate capable of regulating cytosolic Ca2+ transients. However, it remains unclear how PLM contributes to β-adrenergic inotropy. Here we developed a computational model to clarify PLM's role in the β-adrenergic signaling response. Simulating Na+ and sarcoplasmic reticulum (SR) Ca2+ clamps, we identify an effect of PLM phosphorylation on SR unloading as the key mechanism by which PLM confers cytosolic Ca2+ adaptation to long-term β-adrenergic receptor (β-AR) stimulation. Moreover, we show phospholamban (PLB) opposes and overtakes these actions on SR load, forming a negative feed-forward loop in the β-adrenergic signaling cascade. This network motif dominates the negative feedback conferred by β-AR desensitization and accelerates β-AR-induced inotropy. Model analysis therefore unmasks key actions of PLM phosphorylation during β-adrenergic signaling, indicating that PLM is a critical component of the fight-or-flight response. PMID:22289214

  13. Physiological correlates of vagal nerve innervation in lower vertebrates.

    PubMed

    Preston, E; Courtice, G P

    1995-05-01

    In lower vertebrates, cardiac vagal innervation shows less anatomic complexity and specialization than in mammals. To assess the physiological development of vagal specialization in the vertebrates, we investigated cardiac chronotropic effects of electrical stimulation of left and right vagus nerves separately and the interactions between both nerves in anesthetized animals from three vertebrate groups, toad (Bufo marinus), shark (Heterodontus portusjacksoni), and lizard (Physignathus lesueurii). Atropine-sensitive slowing was effected equally by left or right vagi in all species, and chronotropic effects of simultaneous stimulation were the same as the sum of left and right responses. In sharks and lizards, no slowing after atropine was detected (10 Hz stimulation). In toads, after atropine, cardiac slowing was elicited equally by left or right vagal stimulation > 2 Hz. Simultaneous stimulation of both vagi after atropine caused significantly greater slowing than the sum of left and right responses. The results suggest even distribution of left and right vagal nerve endings to pacemaker cells, and limited competition for cardiac receptor sites in lower vertebrates.

  14. Physiology and pharmacology of the cardiovascular adrenergic system.

    PubMed

    Lymperopoulos, Anastasios

    2013-09-04

    Heart failure (HF), the leading cause of death in the western world, ensues in response to cardiac injury or insult and represents the inability of the heart to adequately pump blood and maintain tissue perfusion. It is characterized by complex interactions of several neurohormonal mechanisms that get activated in the syndrome in order to try and sustain cardiac output in the face of decompensating function. The most prominent among these neurohormonal mechanisms is the adrenergic (or sympathetic) nervous system (ANS), whose activity and outflow are greatly elevated in HF. Acutely, provided that the heart still works properly, this activation of the ANS will promptly restore cardiac function according to the fundamental Frank-Starling law of cardiac function. However, if the cardiac insult persists over time, this law no longer applies and ANS will not be able to sustain cardiac function. This is called decompensated HF, and the hyperactive ANS will continue to "push" the heart to work at a level much higher than the cardiac muscle can handle. From that point on, ANS hyperactivity becomes a major problem in HF, conferring significant toxicity to the failing heart and markedly increasing its morbidity and mortality. The present review discusses the role of the ANS in cardiac physiology and in HF pathophysiology, the mechanisms of regulation of ANS activity and how they go awry in chronic HF, and, finally, the molecular alterations in heart physiology that occur in HF along with their pharmacological and therapeutic implications for the failing heart.

  15. Physiology and pharmacology of the cardiovascular adrenergic system

    PubMed Central

    Lymperopoulos, Anastasios

    2013-01-01

    Heart failure (HF), the leading cause of death in the western world, ensues in response to cardiac injury or insult and represents the inability of the heart to adequately pump blood and maintain tissue perfusion. It is characterized by complex interactions of several neurohormonal mechanisms that get activated in the syndrome in order to try and sustain cardiac output in the face of decompensating function. The most prominent among these neurohormonal mechanisms is the adrenergic (or sympathetic) nervous system (ANS), whose activity and outflow are greatly elevated in HF. Acutely, provided that the heart still works properly, this activation of the ANS will promptly restore cardiac function according to the fundamental Frank-Starling law of cardiac function. However, if the cardiac insult persists over time, this law no longer applies and ANS will not be able to sustain cardiac function. This is called decompensated HF, and the hyperactive ANS will continue to “push” the heart to work at a level much higher than the cardiac muscle can handle. From that point on, ANS hyperactivity becomes a major problem in HF, conferring significant toxicity to the failing heart and markedly increasing its morbidity and mortality. The present review discusses the role of the ANS in cardiac physiology and in HF pathophysiology, the mechanisms of regulation of ANS activity and how they go awry in chronic HF, and, finally, the molecular alterations in heart physiology that occur in HF along with their pharmacological and therapeutic implications for the failing heart. PMID:24027534

  16. Purinergic modulation of adult guinea pig cardiomyocytes in long term cultures and co-cultures with extracardiac or intrinsic cardiac neurones.

    PubMed

    Horackova, M; Huang, M H; Armour, J A

    1994-05-01

    To determine the capacity of ATP to modify cardiomyocytes directly or indirectly via peripheral autonomic neurones, the effects of various purinergic agents were studied on long term cultures of adult guinea pig ventricular myocytes and their co-cultures with extracardiac (stellate ganglion) or intrinsic cardiac neurones. Ventricular myocytes and cardiac neurones were enzymatically dissociated and plated together or alone (myocytes only). Myocyte cultures were used for experiments after three to six weeks. The electrical and contractile properties of cultured myocytes and myocyte-neuronal networks were investigated. The spontaneous beating frequency of ventricular myocytes co-cultured with stellate ganglion neurones increased by approximately 140% (p < 0.001) following superfusion with 10(-5) M ATP. This effect was not modified significantly by tetrodotoxin or by beta adrenoceptor blockade (10(-5) M timolol), but was eliminated following application of the P2 antagonist suramin (10(-5) M). Basal spontaneous contractile rate was reduced by approximately 86% (p < 0.001) in the presence of suramin, indicating the existence of tonically active purinergic synaptic mechanisms in stellate ganglion neurone-myocyte cocultures. Suramin did not significantly affect non-innervated myocyte cultures. ATP increased myocyte contractile rate in intrinsic cardiac neurone-myocyte co-cultures by approximately 40% (p < 0.01) under control conditions, but when beta adrenergic receptors of tetrodotoxin sensitive neural responses were blocked, ATP induced greater augmentation (> 100%). In contrast, ATP induced much smaller effects in non-innervated myocyte cultures (approximately 26%, p < 0.01). Analogues of AT) showed the following order of potency: ATP > UTP > MSATP > beta gamma ATP > alpha beta ATP. Adenosine (10(-4) M) attenuated the beating frequency of myocytes in both types of co-culture, while not significantly affecting non-innervated myocyte cultures. The experimental model used

  17. Inhibitory action of gamma-aminobutyric acid on the excitatory but not inhibitory innervation of the rat anococcygeus muscle.

    PubMed

    Hughes, P R; Morgan, P F; Stone, T W

    1982-12-01

    1 The effects of gamma-aminobutyric acid (GABA), ethylenediamine, 3-aminopropane sulphonic acid and (+/-)-baclofen have been examined on the responses to stimulation of the adrenergic excitatory and non-adrenergic non-cholinergic inhibitory innervation of the rat anococcygeus muscle in vitro. 2 GABA produced a dose-related depression of the contractile responses to field stimulation. Ethylenediamine and baclofen also depressed the contractile responses, though they were less potent than GABA. 3-Aminopropane sulphonic acid was almost inactive. The inhibitory action of GABA was not modified by phentolamine, propranolol or bicuculline methylbromide. 3 GABA did not affect the contractile responses of the anococcygeus muscle to noradrenaline, phenylephrine or carbachol in untreated muscles or those treated with 6-hydroxydopamine in vitro. 4 In preparations in which tone was raised by continuous perfusion with carbachol in the presence of phentolamine, field stimulation relaxed the muscle. GABA had no effect on this inhibitory response, and did not itself produce any relaxation. 5 It is concluded that GABA exerts a presynaptic inhibitory action on the excitatory adrenergic but not on the inhibitory innervation of the anococcygeus muscle, and that the GABA receptor involved exhibits properties of the previously described GABAB site.

  18. Evidence for dopaminergic vasodilator innervation of the canine paw pad.

    PubMed Central

    Bell, C.; Lang, W. J.

    1979-01-01

    1 In chloralose-anaesthetized dogs pretreated with guanethidine and pancuronium, electrical stimulation (0.2 to 5 Hz) of the peripheral end of the cut tibial nerve caused a frequency-dependent increase in femoral blood flow which was restricted to the paw pads. 2 This neurogenic vasodilatation was not attenuated by atropine, mepyramine plus burimamide, indomethacin or propranolol. It was, however, attenuated in a dose-dependent manner by intra-arterial administration of the dopamine receptor antagonist, ergometrine (0.05 to 0.5 mg). 3 The effect of ergometrine could not be explained by non-specific effects on axonal conduction or transmission or by vasospasm of the blood vessels of the paw-pads. 4 In dogs with intact tibial nerves, a pharmacologically similar dilator response localized to the paw-pads could be elicited by electrical stimulation of loci in the ipsilateral diencephalon and midbrain. This response was not due to inhibition of adrenergic vasomotor tone and was abolished by systemic ganglion blockade or by tibial nerve section as well as by femoral arterial administration of ergometrine. 5 It is suggested that the vasculature of the canine paw pads is innervated by a population of autonomic axons which utilize dopamine or a related substance as a transmitter substance and activation of which causes vasodilation. PMID:40651

  19. Development of Cortical GABAergic Innervation

    PubMed Central

    Jovanovic, Jasmina N.; Thomson, Alex M.

    2011-01-01

    The mature neocortex contains many different classes of GABAergic inhibitory interneurons, distributed, with some degree of selectivity, through six layers, and through many different regions. Some of the events in the early lives of these neurones that may determine their ultimate destination, their maturation and their selective innervation of targets appropriate for each subtype, are discussed. Both time and place of birth influence the class of interneuron that an early post-mitotic interneuronal precursor will become, driven by the selective expression of different combinations of transcription factors in different regions of their birth places in the ganglionic eminence and ventricular zone. The long distance migration of these precursors along tangential routes in marginal, subventricular, and intermediate zones and their final radial movement, into the developing cortex, is regulated by chemical cues, both attractant and repellent. Once they arrive at their final destination, they must integrate into the developing circuitry. As they mature within the cortex, their axons grow and branch in highly specific patterns that may be partially determined by the genetic blueprint for each interneuronal class and partly by the environment in which they find themselves. Finally, as each interneuron class begins to form synapses with only certain postsynaptic targets, cell–cell recognition, most probably via protein–protein interactions across the synaptic cleft, facilitate the formation of appropriate synapses. PMID:21808605

  20. Distribution of adrenergic receptors in the enteric nervous system of the guinea pig, mouse, and rat.

    PubMed

    Nasser, Yasmin; Ho, Winnie; Sharkey, Keith A

    2006-04-10

    Adrenergic receptors in the enteric nervous system (ENS) are important in control of the gastrointestinal tract. Here we describe the distribution of adrenergic receptors in the ENS of the ileum and colon of the guinea pig, rat, and mouse by using single- and double-labelling immunohistochemistry. In the myenteric plexus (MP) of the rat and mouse, alpha2a-adrenergic receptors (alpha2a-AR) were widely distributed on neurons and enteric glial cells. alpha2a-AR mainly colocalized with calretinin in the MP, whereas submucosal alpha2a-AR neurons colocalized with vasoactive intestinal polypeptide (VIP), neuropeptide Y, and calretinin in both species. In the guinea pig ileum, we observed widespread alpha2a-AR immunoreactivity on nerve fibers in the MP and on VIP neurons in the submucosal plexus (SMP). We observed extensive beta1-adrenergic receptor (beta1-AR) expression on neurons and nerve fibers in both the MP and the SMP of all species. Similarly, the beta2-adrenergic receptor (beta2-AR) was expressed on neurons and nerve fibers in the SMP of all species, as well as in the MP of the mouse. In the MP, beta1- and beta2-AR immunoreactivity was localized to several neuronal populations, including calretinin and nitrergic neurons. In the SMP of the guinea pig, beta1- and beta2-AR mainly colocalized with VIP, whereas, in the rat and mouse, beta1- and beta2-AR were distributed among the VIP and calretinin populations. Adrenergic receptors were widely localized on specific neuronal populations in all species studied. The role of glial alpha2a-AR is unknown. These results suggest that sympathetic innervation of the ENS is directed toward both enteric neurons and enteric glia.

  1. Memory Enhancement Induced by Post-Training Intrabasolateral Amygdala Infusions of [beta]-Adrenergic or Muscarinic Agonists Requires Activation of Dopamine Receptors: Involvement of Right, but Not Left, Basolateral Amygdala

    ERIC Educational Resources Information Center

    LaLumiere, Ryan T.; McGaugh, James L.

    2005-01-01

    Previous findings indicate that the noradrenergic, dopaminergic, and cholinergic innervations of the basolateral amygdala (BLA) modulate memory consolidation. The current study investigated whether memory enhancement induced by post-training intra-BLA infusions of a [beta]-adrenergic or muscarinic cholinergic agonist requires concurrent activation…

  2. Memory Enhancement Induced by Post-Training Intrabasolateral Amygdala Infusions of [beta]-Adrenergic or Muscarinic Agonists Requires Activation of Dopamine Receptors: Involvement of Right, but Not Left, Basolateral Amygdala

    ERIC Educational Resources Information Center

    LaLumiere, Ryan T.; McGaugh, James L.

    2005-01-01

    Previous findings indicate that the noradrenergic, dopaminergic, and cholinergic innervations of the basolateral amygdala (BLA) modulate memory consolidation. The current study investigated whether memory enhancement induced by post-training intra-BLA infusions of a [beta]-adrenergic or muscarinic cholinergic agonist requires concurrent activation…

  3. The role of adrenergic activation on murine luteal cell viability and progesterone production.

    PubMed

    Wang, Jing; Tang, Min; Jiang, Huaide; Wu, Bing; Cai, Wei; Hu, Chuan; Bao, Riqiang; Dong, Qiming; Xiao, Li; Li, Gang; Zhang, Chunping

    2016-09-15

    Sympathetic innervations exist in mammalian CL. The action of catecholaminergic system on luteal cells has been the focus of a variety of studies. Norepinephrine (NE) increased progesterone secretion of cattle luteal cells by activating β-adrenoceptors. In this study, murine luteal cells were treated with NE and isoprenaline (ISO). We found that NE increased the viability of murine luteal cells and ISO decreased the viability of luteal cells. Both NE and ISO promoted the progesterone production. Nonselective β-adrenergic antagonist, propranolol reversed the effect of ISO on cell viability but did not reverse the effect of NE on cell viability. Propranolol blocked the influence of NE and ISO on progesterone production. These results reveal that the increase of luteal cell viability induced by NE is not dependent on β-adrenergic activation. α-Adrenergic activation possibly contributes to it. Both NE and ISO increased progesterone production through activating β-adrenergic receptor. Further study showed that CyclinD2 is involved in the increase of luteal cell induced by NE. 3β-Hydroxysteroid dehydrogenase, LHR, steroidogenic acute regulatory protein (StAR), and PGF2α contribute to the progesterone production induced by NE and ISO. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus.

    PubMed

    O'Dell, Thomas J; Connor, Steven A; Guglietta, Ryan; Nguyen, Peter V

    2015-09-01

    Encoding new information in the brain requires changes in synaptic strength. Neuromodulatory transmitters can facilitate synaptic plasticity by modifying the actions and expression of specific signaling cascades, transmitter receptors and their associated signaling complexes, genes, and effector proteins. One critical neuromodulator in the mammalian brain is norepinephrine (NE), which regulates multiple brain functions such as attention, perception, arousal, sleep, learning, and memory. The mammalian hippocampus receives noradrenergic innervation and hippocampal neurons express β-adrenergic receptors, which are known to play important roles in gating the induction of long-lasting forms of synaptic potentiation. These forms of long-term potentiation (LTP) are believed to importantly contribute to long-term storage of spatial and contextual memories in the brain. In this review, we highlight the contributions of noradrenergic signaling in general and β-adrenergic receptors in particular, toward modulating hippocampal LTP. We focus on the roles of NE and β-adrenergic receptors in altering the efficacies of specific signaling molecules such as NMDA and AMPA receptors, protein phosphatases, and translation initiation factors. Also, the roles of β-adrenergic receptors in regulating synaptic "tagging" and "capture" of LTP within synaptic networks of the hippocampus are reviewed. Understanding the molecular and cellular bases of noradrenergic signaling will enrich our grasp of how the brain makes new, enduring memories, and may shed light on credible strategies for improving mental health through treatment of specific disorders linked to perturbed memory processing and dysfunctional noradrenergic synaptic transmission.

  5. Mice Lacking Adrenergic Signaling Have Normal Cochlear Responses and Normal Resistance to Acoustic Injury but Enhanced Susceptibility to Middle-Ear Infection

    PubMed Central

    Le, Mina; Larsen, Erik; Lee, Suh-Kyung; Rosowski, John J.; Thomas, Steven A.; Liberman, M. Charles

    2010-01-01

    The vasculature and neurons of the inner ear receive adrenergic innervation from the cervical sympathetic chain, and adrenergic receptors may be expressed by cells of the organ of Corti and stria vascularis, despite a lack of direct sympathetic innervation. To assess the functional role of adrenergic signaling in the auditory periphery, we studied mice with targeted deletion of the gene for dopamine β-hydroxylase (DBH), which catalyzes the conversion of dopamine to noradrenaline; thus, these mutant mice have no measurable adrenaline or noradrenaline. Dbh−/− mice were more susceptible to spontaneous middle-ear infection than their control littermates, consistent with a role for sympathetics in systemic and/or local immune response. At 6–8 weeks of age, cochlear thresholds and suprathreshold responses assessed by auditory brainstem responses and distortion product otoacoustic emissions, as well as light-microscopic morphology, were indistinguishable from controls, if ears with conductive hearing loss were eliminated. Dbh−/− mice were no more susceptible to acoustic injury than controls, despite prior reports that sympathectomy reduces noise damage. Dbh−/− mice showed enhancement of shock-evoked olivocochlear suppression of cochlear responses, which may arise from the loss of adrenergic inputs to olivocochlear neurons in the brainstem. However, adrenergic modulation of olivocochlear efferents does not mediate the protective effect of contralateral cochlear destruction on ipsilateral response to acoustic overexposure. PMID:20503062

  6. Innervation of the Mouse Cornea during Development

    PubMed Central

    McKenna, Chelsey C.

    2011-01-01

    Purpose. Dense innervation of the cornea is important for maintaining its homeostasis and transparency. Although corneal nerves have been well studied in adults, little is known about mammalian corneal innervation during development. This study provides a detailed profile of nerves at various stages of mouse cornea development. Methods. Mouse heads and corneas were collected at various stages of development including embryonic days (E)12.5 to E16.5, postnatal days (P)0, P10, three weeks after birth, and the adult. Corneas were immunostained with an anti-neuron–specific β-tubulin antibody (TUJ1). Fluorescently labeled nerves in whole-mount tissues and sections were imaged and analyzed for their axonal projections during eye development. Results. The first nerve bundles appear at the periphery of the anterior portion of the eye by E12.5. Initial projection into the stroma occurs at E13.5 without formation of a pericorneal nerve ring. Between E13.5 and E16.5, nerve bundles project directly into the periphery of the presumptive cornea stroma. They branch repeatedly as they extend toward the cornea center and epithelium. Concomitantly, nerve bundles originating from four quadrants of the eye bifurcate into smaller branches that innervate the entire stroma. The first epithelial innervation occurs at E16.5. Epithelial nerves arrange into patterns that project toward the center subsequently forming a swirl at three weeks after birth, which becomes more pronounced in adults. Conclusions. Nerve bundles that arise from four quadrants of the eye innervate the mouse cornea. The nerve bundles directly innervate the stroma without forming a pericorneal nerve ring. Radial arrangement of epithelial nerves gradually becomes centrally oriented, subsequently forming a swirl pattern. PMID:20811061

  7. β-Adrenergic response is counteracted by extremely-low-frequency pulsed electromagnetic fields in beating cardiomyocytes.

    PubMed

    Cornacchione, Marisa; Pellegrini, Manuela; Fassina, Lorenzo; Mognaschi, Maria Evelina; Di Siena, Sara; Gimmelli, Roberto; Ambrosino, Paolo; Soldovieri, Maria Virginia; Taglialatela, Maurizio; Gianfrilli, Daniele; Isidori, Andrea M; Lenzi, Andrea; Naro, Fabio

    2016-09-01

    Proper β-adrenergic signaling is indispensable for modulating heart frequency. Studies on extremely-low-frequency pulsed electromagnetic field (ELF-PEMF) effects in the heart beat function are contradictory and no definitive conclusions were obtained so far. To investigate the interplay between ELF-PEMF exposure and β-adrenergic signaling, cultures of primary murine neonatal cardiomyocytes and of sinoatrial node were exposed to ELF-PEMF and short and long-term effects were evaluated. The ELF-PEMF generated a variable magnetic induction field of 0-6mT at a frequency of 75Hz. Exposure to 3mT ELF-PEMF induced a decrease of contraction rate, Ca(2+) transients, contraction force, and energy consumption both under basal conditions and after β-adrenergic stimulation in neonatal cardiomyocytes. ELF-PEMF exposure inhibited β-adrenergic response in sinoatrial node (SAN) region. ELF-PEMF specifically modulated β2 adrenergic receptor response and the exposure did not modify the increase of contraction rate after adenylate cyclase stimulation by forskolin. In HEK293T cells transfected with β1 or β2 adrenergic receptors, ELF-PEMF exposure induced a rapid and selective internalization of β2 adrenergic receptor. The β-adrenergic signaling, was reduced trough Gi protein by ELF-PEMF exposure since the phosphorylation level of phospholamban and the PI3K pathway were impaired after isoproterenol stimulation in neonatal cardiomyocytes. Long term effects of ELF-PEMF exposure were assessed in cultures of isolated cardiomyocytes. ELF-PEMF counteracts cell size increase, the generation of binucleated of cardiomyocytes and prevents the up-regulation of hypertrophic markers after β-adrenergic stimulation, indicating an inhibition of cell growth and maturation. These data show that short and long term exposure to ELF-PEMF induces a reduction of cardiac β-adrenergic response at molecular, functional and adaptative levels.

  8. Functional differences between junctional and extrajunctional adrenergic receptor activation in mammalian ventricle

    PubMed Central

    Ajijola, Olujimi A.; Vaseghi, Marmar; Zhou, Wei; Yamakawa, Kentaro; Benharash, Peyman; Hadaya, Joseph; Lux, Robert L.; Mahajan, Aman

    2013-01-01

    Increased cardiac sympathetic activation worsens dispersion of repolarization and is proarrhythmic. The functional differences between intrinsic nerve stimulation and adrenergic receptor activation remain incompletely understood. This study was undertaken to determine the functional differences between efferent cardiac sympathetic nerve stimulation and direct adrenergic receptor activation in porcine ventricles. Female Yorkshire pigs (n = 13) underwent surgical exposure of the heart and stellate ganglia. A 56-electrode sock was placed over the ventricles to record epicardial electrograms. Animals underwent bilateral sympathetic stimulation (BSS) (n = 8) or norepinephrine (NE) administration (n = 5). Activation recovery intervals (ARIs) were measured at each electrode before and during BSS or NE. The degree of ARI shortening during BSS or NE administration was used as a measure of functional nerve or adrenergic receptor density. During BSS, ARI shortening was nonuniform across the epicardium (F value 9.62, P = 0.003), with ARI shortening greatest in the mid-basal lateral right ventricle and least in the midposterior left ventricle (LV) (mean normalized values: 0.9 ± 0.08 vs. 0.56 ± 0.08; P = 0.03). NE administration resulted in greater ARI shortening in the LV apex than basal segments [0.91 ± 0.04 vs. 0.63 ± 0.05 (averaged basal segments); P = 0.003]. Dispersion of ARIs increased in 50% and 60% of the subjects undergoing BSS and NE, respectively, but decreased in the others. There is nonuniform response to cardiac sympathetic activation of both porcine ventricles, which is not fully explained by adrenergic receptor density. Different pools of adrenergic receptors may mediate the cardiac electrophysiological effects of efferent sympathetic nerve activity and circulating catecholamines. PMID:23241324

  9. Non-adrenergic, non-cholinergic reflex secretion of parotid saliva in rats elicited by mastication and acid applied on the tongue.

    PubMed

    Ekström, J

    1998-09-01

    Chewing and acid on the tongue evoked a flow of saliva from the duct-cannulated parotid gland of the conscious rat despite pretreatment with atropine and adrenoceptor antagonists. This non-adrenergic, non-cholinergic (NANC) response depended on an intact parasympathetic innervation and was abolished by a tachykinin antagonist. The present findings are consistent with a physiological role for the secretory NANC mechanisms of the salivary glands.

  10. The sympathetic innervation of the human foot.

    PubMed

    Dellon, A Lee; Höke, Ahmet; Williams, Eric H; Williams, Chris G; Zhang, Zijie; Rosson, Gedge D

    2012-04-01

    The sympathetic innervation of the hand was demonstrated using formaldehyde staining techniques in the 1990s and provides a basis for both medical (botulinum toxin type A) and surgical (sympathectomy) therapeutic approaches. This research investigates the sympathetic innervation of the human foot using tyrosine hydroxylase immunohistochemistry. With institutional review board approval, six freshly amputated lower extremities had arterial, venous, and peripheral nerve biopsies obtained at the distal leg, ankle, and forefoot levels. Tibial, peroneal, sural, and saphenous nerves were processed immediately for immunohistochemical staining using an anti-tyrosine hydroxylase antibody, for light and electron microscopy evaluation. Qualitative assessments noted the presence or absence of tyrosine hydroxylase-positive fibers in artery, vein, and peripheral nerve. Within the nerve, location of the tyrosine hydroxylase staining was noted. The presence of tyrosine hydroxylase-positive material was identified in each artery, vein, and nerve examined at each level of the foot and ankle. For the artery, the staining was in the adventitia, and rarely in the media of the vessel wall. There were clear entry points into the artery from the connective tissue. For the vein, the staining was more evenly distributed but to a lesser intensity than in the artery. Within each nerve at the proximal levels, the staining was diffusely throughout the fascicles, with clear sites of fibers leaving the periphery. It is concluded that (1) sympathetic innervation of the foot arrives along each peripheral nerve, (2) the vessels already contain sympathetic innervation at the level of the ankle, and (3) the sympathetic innervation of the foot is extensive.

  11. Nonclassical Innervation Patterns In Mammalian Extraocular Muscles

    PubMed Central

    da Silva Costa, Roberta M.; Kung, Jennifer; Poukens, Vadims; Demer, Joseph L.

    2013-01-01

    Purpose The abducens (CN6) and oculomotor (CN3) nerves (nn) enter target extraocular muscles (EOMs) via their global surfaces; the trochlear (CN4) nerve enters the superior oblique (SO) muscle on its orbital surface. Motor nn are classically described as entering the EOMs in their middle thirds. We investigated EOM innervation that does not follow the classic pattern. Methods Intact, whole orbits of two humans and one each monkey, cow, and rabbit were paraffin embedded, serially sectioned in coronal plane, and prepared with Masson’s trichrome and by choline acetyltransferase (ChAT) immunohistochemistry. Nerves innervating EOMs were traced from the orbital apex toward the scleral insertion, and some were reconstructed in three dimensions. Results Classical motor nn positive for ChAT entered rectus and SO EOMs and coursed anteriorly, without usually exhibiting recurrent branches. In every orbit, nonclassical (NC) nn entered each EOM well posterior to classical motor nn. These NC nn entered and arborized in the posterior EOMs, mainly within the orbital layer (OL), but often traveled into the global layer or entered an adjacent EOM. Other NC nn originated in the orbital apex and entered each EOM through its orbital surface, ultimately anastomosing with classical motor nn. Mixed sensory and motor nn interconnected EOM spindles. Conclusions EOMs exhibit a previously undescribed pattern of NC innervation originating in the proximal orbit that partially joins branches of the classical motor nn. This NC innervation appears preferential for the OL, and may have mixed supplemental motor and/or proprioceptive functions, perhaps depending upon species. The origin of the NC innervation is currently unknown. PMID:22559851

  12. Effects of ovarian hormones on beta-adrenergic and muscarinic receptors in rat heart

    SciTech Connect

    Klangkalya, B.; Chan, A.

    1988-01-01

    The in vitro and in vivo effects of estrogen and progesterone on muscarinic and ..beta..-adrenergic receptors of cardiac tissue were studied in ovariectomized (OVX) rats. The binding assay for muscarinic receptors was performed under a nonequilibrium condition; whereas the binding assay for ..beta..-adrenergic receptors, under an equilibrium condition. Estrogenic compounds and progesterone were found to have no effect on the binding of the radioligand, (/sup 3/H)-dihydroalprenolol, to ..beta..-adrenergic receptors in vitro. However, progestins but not estrogenic compounds inhibited the binding of the radioligand, (/sup 3/H)-quinuclidinyl benzilate, to muscarinic receptors in vitro, with progesterone as the most potent inhibitor. Progesterone was found to decrease the apparent affinity of muscarinic receptors for (/sup 3/H)(-)QNB in vitro. Daily treatment of OVX rats with estradiol benzoate or progesterone for 4 days had no effect on the muscarinic or ..beta..-adrenergic receptors with respect to the binding affinity and receptor density. However, administrations of these hormones together for 4 days caused an increase in the receptor density of muscarinic receptors without a significant effect on their apparent binding affinity; also these hormones induced a decrease in the binding affinity and an increase in the receptor density of ..beta..-adrenergic receptors.

  13. Effects of adrenergic agents on the expression of zebrafish (Danio rerio) vitellogenin Ao1

    SciTech Connect

    Yin Naida; Jin Xia; He Jiangyan; Yin Zhan

    2009-07-01

    Teleost vitellogenins (VTGs) are large multidomain apolipoproteins, traditionally considered to be estrogen-responsive precursors of the major egg yolk proteins, expressed and synthesized mainly in hepatic tissue. The inducibility of VTGs has made them one of the most frequently used in vivo and in vitro biomarkers of exposure to estrogen-active substances. A significant level of zebrafish vtgAo1, a major estrogen responsive form, has been unexpectedly found in heart tissue in our present studies. Our studies on zebrafish cardiomyopathy, caused by adrenergic agonist treatment, suggest a similar protective function of the cardiac expressed vtgAo1. We hypothesize that its function is to unload surplus intracellular lipids in cardiomyocytes for 'reverse triglyceride transportation' similar to that found in lipid transport proteins in mammals. Our results also demonstrated that zebrafish vtgAo1 mRNA expression in heart can be suppressed by both {alpha}-adrenergic agonist, phenylephrine (PE) and {beta}-adrenergic agonist, isoproterenol (ISO). Furthermore, the strong stimulation of zebrafish vtgAo1 expression in plasma induced by the {beta}-adrenergic antagonist, MOXIsylyl, was detected by Enzyme-Linked ImmunoSorbent Assay (ELISA). Such stimulation cannot be suppressed by taMOXIfen, an antagonist to estrogen receptors. Thus, our present data indicate that the production of teleost VTG in vivo can be regulated not only by estrogenic agents, but by adrenergic signals as well.

  14. Cardiac catheterization

    MedlinePlus

    Catheterization - cardiac; Heart catheterization; Angina - cardiac catheterization; CAD - cardiac catheterization; Coronary artery disease - cardiac catheterization; Heart valve - cardiac catheterization; Heart failure - ...

  15. The Adrenergic Nervous System in Heart Failure: Pathophysiology and Therapy

    PubMed Central

    Lymperopoulos, Anastasios; Rengo, Giuseppe; Koch, Walter J.

    2013-01-01

    Heart failure (HF), the leading cause of death in the western world, develops when a cardiac injury or insult impairs the ability of the heart to pump blood and maintain tissue perfusion. It is characterized by a complex interplay of several neurohormonal mechanisms that get activated in the syndrome in order to try and sustain cardiac output in the face of decompensating function. Perhaps the most prominent among these neurohormonal mechanisms is the adrenergic (or sympathetic) nervous system (ANS), whose activity and outflow are enormously elevated in HF. Acutely, and if the heart works properly, this activation of the ANS will promptly restore cardiac function. However, if the cardiac insult persists over time, chances are the ANS will not be able to maintain cardiac function, the heart will progress into a state of chronic decompensated HF, and the hyperactive ANS will continue to “push” the heart to work at a level much higher than the cardiac muscle can handle. From that point on, ANS hyperactivity becomes a major problem in HF, conferring significant toxicity to the failing heart and markedly increasing its morbidity and mortality. The present review discusses the role of the ANS in cardiac physiology and in HF pathophysiology, the mechanisms of regulation of ANS activity and how they go awry in chronic HF, methods of measuring ANS activity in HF, the molecular alterations in heart physiology that occur in HF along with their pharmacological and therapeutic implications, and, finally, drugs and other therapeutic modalities used in HF treatment that target or affect the ANS and its effects on the failing heart. PMID:23989716

  16. Facial vein in the rabbit. Neurogenic vasodilation mediated by beta-adrenergic receptors.

    PubMed

    Pegram, B L; Bevan, R D; Bevan, J A

    1976-12-01

    A segment of the facial vein of the rabbit, that opposite the buccal cavity, responds to norepinephrine (NE) and opposite the buccal cavity, responds to norepinephrine (NE) and transmural nerve stimulation (TNS) by a brisk biphasic dilation. The dilation in response to both procedures is reveresed by prior exposure to propranolol (10(-6)M). Pretreatment with phenoxybenzamine (10(-5)M) increases the size of the neurogenic response and displaces the NE dose-relaxation curve to the left. Histamine causes a constrictor response exclusively. Sympathetic stimulation of a segment of the facial vein proximal to this buccal segment, and also of the external jugular vein, results in constriction. Light microscopy showed no fequtres which can account for the dilation, and fluorescence histochemistry using a modified Flack technique showed a dense adrenergic nerve plexus extending throughout the thickness of the media. We found that frequency-response characteristics and neuronal uptake of 3H-NE were consistent with findings for a blood vessel with a heavy medial innervation. Also, monoamine oxidase and catechol O-methyltransferase activities were similar to those found in other rabbit veins. Furthermore, these results are consistent with an adrenergic neuroeffector organization in which there is a predominance of beta- over alpha-adrenergic receptors. In conclusion, the presence of a dilator response in this buccal segment of the facial vein may be related to its location in the wall of the cheek, where it may be subjected to considerable stretch.

  17. Origins of serotonin innervation of forebrain structures

    NASA Technical Reports Server (NTRS)

    Kellar, K. J.; Brown, P. A.; Madrid, J.; Bernstein, M.; Vernikos-Danellis, J.; Mehler, W. R.

    1977-01-01

    The tryptophan hydroxylase activity and high-affinity uptake of (3H) serotonin ((3H)5-HT) were measured in five discrete brain regions of rats following lesions of the dorsal or median raphe nuclei. Dorsal raphe lesions reduced enzyme and uptake activity in the striatum only. Median raphe lesions reduced activities in the hippocampus, septal area, frontal cortex, and, to a lesser extent, in the hypothalamus. These data are consistent with the suggestion that the dorsal and median raphe nuclei are the origins of two separate ascending serotonergic systems - one innervating striatal structures and the other mesolimbic structures, predominantly. In addition, the data suggest that measurements of high-affinity uptake of (3H)5-HT may be a more reliable index of innervation than either 5-HT content or tryptophan hydroxylase activity.

  18. Origins of serotonin innervation of forebrain structures

    NASA Technical Reports Server (NTRS)

    Kellar, K. J.; Brown, P. A.; Madrid, J.; Bernstein, M.; Vernikos-Danellis, J.; Mehler, W. R.

    1977-01-01

    The tryptophan hydroxylase activity and high-affinity uptake of (3H) serotonin ((3H)5-HT) were measured in five discrete brain regions of rats following lesions of the dorsal or median raphe nuclei. Dorsal raphe lesions reduced enzyme and uptake activity in the striatum only. Median raphe lesions reduced activities in the hippocampus, septal area, frontal cortex, and, to a lesser extent, in the hypothalamus. These data are consistent with the suggestion that the dorsal and median raphe nuclei are the origins of two separate ascending serotonergic systems - one innervating striatal structures and the other mesolimbic structures, predominantly. In addition, the data suggest that measurements of high-affinity uptake of (3H)5-HT may be a more reliable index of innervation than either 5-HT content or tryptophan hydroxylase activity.

  19. Sympathetic innervation promotes vascular smooth muscle differentiation.

    PubMed

    Damon, Deborah H

    2005-06-01

    The sympathetic nervous system (SNS) is an important modulator of vascular smooth muscle (VSM) growth and function. Several lines of evidence suggest that the SNS also promotes VSM differentiation. The present study tests this hypothesis. Expression of smooth muscle myosin (SM2) and alpha-actin were assessed by Western analysis as indexes of VSM differentiation. SM2 expression (normalized to alpha-actin) in adult innervated rat femoral and tail arteries was 479 +/- 115% of that in noninnervated carotid arteries. Expression of alpha-actin (normalized to GAPDH or total protein) in 30-day-innervated rat femoral arteries was greater than in corresponding noninnervated femoral arteries from guanethidine-sympathectomized rats. SM2 expression (normalized to alpha-actin) in neonatal femoral arteries grown in vitro for 7 days in the presence of sympathetic ganglia was greater than SM2 expression in corresponding arteries grown in the absence of sympathetic ganglia. In VSM-endothelial cell cultures grown in the presence of dissociated sympathetic neurons, alpha-actin (normalized to GAPDH) was 300 +/- 66% of that in corresponding cultures grown in the absence of neurons. This effect was inhibited by an antibody that neutralized the activity of transforming growth factor-beta2. All of these data indicate that sympathetic innervation increased VSM contractile protein expression and thereby suggest that the SNS promotes and/or maintains VSM differentiation.

  20. Social temperament and lymph node innervation

    PubMed Central

    Sloan, Erica K.; Capitanio, John P.; Tarara, Ross P.; Cole, Steve W.

    2008-01-01

    Socially inhibited individuals show increased vulnerability to viral infections, and this has been linked to increased activity of the sympathetic nervous system (SNS). To determine whether structural alterations in SNS innervation of lymphoid tissue might contribute to these effects, we assayed the density of catecholaminergic nerve fibers in 13 lymph nodes from 7 healthy adult rhesus macaques that showed stable individual differences in propensity to socially affiliate (Sociability). Tissues from Low Sociable animals showed a 2.8-fold greater density of catecholaminergic innervation relative to tissues from High Sociable animals, and this was associated with a 2.3-fold greater expression of nerve growth factor (NGF) mRNA, suggesting a molecular mechanism for observed differences. Low Sociable animals also showed alterations in lymph node expression of the immunoregulatory cytokine genes IFNG and IL4, and lower secondary IgG responses to tetanus vaccination. These findings are consistent with the hypothesis that structural differences in lymphoid tissue innervation might potentially contribute to relationships between social temperament and immunobiology. PMID:18068331

  1. Two-photon microscopy of dermal innervation in a human re-innervated model of skin.

    PubMed

    Sevrain, David; Le Grand, Yann; Buhé, Virginie; Jeanmaire, Christine; Pauly, Gilles; Carré, Jean-Luc; Misery, Laurent; Lebonvallet, Nicolas

    2013-04-01

    When skin is injured, innervation can be severely disrupted. The subsequent re-innervation processes are poorly understood notably because of the inability to image the full meandering course of nerves with their ramifications and endings from histological slices. In this letter, we report on two-photon excitation fluorescence (TPEF) microscopy of entire human skin explants re-innervated by rodent sensory neurons labelled with the styryl dye FM1-43. TPEF imaging of nerve fibres to a depth up to roughly 300 μm within the dermis was demonstrated, allowing three-dimensional reconstruction of the neural tree structure. Endogenous second-harmonic imaging of type I fibrillar collagen was performed in parallel to TPEF imaging using the same nonlinear microscope, revealing the path of the nerves through the dermis.

  2. Neuroanatomy of the Pig Cardiac Ventricles. A Stereomicroscopic, Confocal and Electron Microscope Study.

    PubMed

    Pauziene, Neringa; Rysevaite-Kyguoliene, Kristina; Alaburda, Paulius; Pauza, Audrys G; Skukauskaite, Monika; Masaityte, Aiste; Laucaityte, Goda; Saburkina, Inga; Inokaitis, Hermanas; Plisiene, Jurgita; Pauza, Dainius H

    2017-10-01

    Although the pig is a model for heart disease, the neuroanatomy of cardiac ventricles (CV) in this species remains undetailed. We aimed to define the innervation pattern of pig CV, combining histochemistry for acetylcholinesterase, immunofluorescent labeling and electron microscopy. Forty nine examined pig hearts show that the major nerves supplying the ventral side of CV descend from the venous part of the heart hilum. Fewer in number and smaller in size, epicardial nerves supply the dorsal half of the CV. Epicardial nerves on the left ventricle are thicker than those on the right. Ventricular ganglia of various sizes distribute at the basal level of both CV. Averagely, we found 3,848 ventricular neuronal somata per heart. The majority of somata were cholinergic, although ganglionic cells of different neurochemical phenotypes (positive for nNOS, ChAT/nNOS, or ChAT/TH) were also observed. Large and most numerous nerves proceeded within the epicardium. Most of endocardium and myocardium contained a network of nerve bundles and nerve fibers (NFs). But, a large number of thin nerves extended along the bundle of His and its branches. The majority of NFs were adrenergic, while cholinergic NFs were scarce yet more abundant than nitrergic ones. Sensory NFs positive for CGRP were the second most abundant phenotype after adrenergic NFs in all layers of the ventricular wall. Electron microscopy elucidated that ultrastructure of nerves varied between different areas of CV. The described structural organization of CV provides an anatomical basis for further functional and pathophysiological studies in the pig heart. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 300:1756-1780, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  3. Phospholemman and beta-adrenergic stimulation in the heart.

    PubMed

    Wang, JuFang; Gao, Erhe; Song, Jianliang; Zhang, Xue-Qian; Li, Jifen; Koch, Walter J; Tucker, Amy L; Philipson, Kenneth D; Chan, Tung O; Feldman, Arthur M; Cheung, Joseph Y

    2010-03-01

    Phosphorylation at serine 68 of phospholemman (PLM) in response to beta-adrenergic stimulation results in simultaneous inhibition of cardiac Na(+)/Ca(2+) exchanger NCX1 and relief of inhibition of Na(+)-K(+)-ATPase. The role of PLM in mediating beta-adrenergic effects on in vivo cardiac function was investigated with congenic PLM-knockout (KO) mice. Echocardiography showed similar ejection fraction between wild-type (WT) and PLM-KO hearts. Cardiac catheterization demonstrated higher baseline contractility (+dP/dt) but similar relaxation (-dP/dt) in PLM-KO mice. In response to isoproterenol (Iso), maximal +dP/dt was similar but maximal -dP/dt was reduced in PLM-KO mice. Dose-response curves to Iso (0.5-25 ng) for WT and PLM-KO hearts were superimposable. Maximal +dP/dt was reached 1-2 min after Iso addition and declined with time in WT but not PLM-KO hearts. In isolated myocytes paced at 2 Hz. contraction and intracellular Ca(2+) concentration ([Ca(2+)](i)) transient amplitudes and [Na(+)](i) reached maximum 2-4 min after Iso addition, followed by decline in WT but not PLM-KO myocytes. Reducing pacing frequency to 0.5 Hz resulted in much smaller increases in [Na(+)](i) and no decline in contraction and [Ca(2+)](i) transient amplitudes with time in Iso-stimulated WT and PLM-KO myocytes. Although baseline Na(+)-K(+)-ATPase current was 41% higher in PLM-KO myocytes because of increased alpha(1)- but not alpha(2)-subunit activity, resting [Na(+)](i) was similar between quiescent WT and PLM-KO myocytes. Iso increased alpha(1)-subunit current (I(alpha1)) by 73% in WT but had no effect in PLM-KO myocytes. Iso did not affect alpha(2)-subunit current (I(alpha2)) in WT and PLM-KO myocytes. In both WT and NCX1-KO hearts, PLM coimmunoprecipitated with Na(+)-K(+)-ATPase alpha(1)- and alpha(2)-subunits, indicating that association of PLM with Na(+)-K(+)-ATPase did not require NCX1. We conclude that under stressful conditions in which [Na(+)](i) was high, beta-adrenergic agonist

  4. Adrenergic signaling elements in the bladder wall of the adult rat.

    PubMed

    Persyn, Sara; Eastham, Jane; De Wachter, Stefan; Gillespie, James

    2016-12-01

    A growing body of work is describing the absence of a significant sympathetic innervation of the detrusor implying little sympathetic regulation of bladder contractility. However, low doses of adrenergic agonists are capable of relaxing the bladder smooth muscle. If these effects underpin a physiological response then the cellular nature and operation of this system are currently unknown. The present immunohistochemistry study was done to explore the existence of alternative adrenergic signaling elements in the rat bladder wall. Using antibodies to tyrosine hydroxylase (TH) and vesicular mono-amine transporter (vmat), few adrenergic nerves were found in the detrusor although TH immunoreactive (IR) nerves were apparent in the bladder neck. TH-IR and vmat-IR nerves were however abundant surrounding blood vessels. A population of vmat-IR cells was found within the network of interstitial cells that surround the detrusor muscle bundles. These vmat-IR cells were not or only weakly TH-IR. This suggests that these interstitial cells have the capacity to store and release catecholamines that may involve noradrenaline. Cells expressing the β1-adrenoceptor (β1AR-IR) were also detected within the interstitial cell network. Double staining with antibodies to β1AR and vmat suggests that the majority of vmat-IR interstitial cells show β1AR-IR indicative of an autocrine signaling system. In conclusion, a population of interstitial cells has the machinery to store, release and respond to catecholamines. Thus, there might exist a non-neuronal β-adrenergic system operating in the bladder wall possibly linked to one component of motor activity, micro-contractions, a system that may be involved in mechanisms underpinning bladder sensation.

  5. Alpha-Adrenergic receptors in cerebral microvessels of normotensive and spontaneously hypertensive rats

    SciTech Connect

    Kobayashi, H.; Wada, A.; Izumi, F.; Magnoni, M.S.; Trabucchi, M.

    1985-03-01

    In rat cerebral microvessels, we characterized alpha 1- and alpha 2-adrenergic receptors, using (/sup 3/H)prazosin and (/sup 3/H)-p-amino-clonidine as radioligands. (/sup 3/H)Prazosin binding to the cerebral microvessels was saturable and of high affinity (dissociation constant of 78 pM), with a maximum binding of 48 fmol/mg protein. (/sup 3/H)Prazosin binding reached equilibrium within 15 minutes and was dissociated by the addition of 10 microM phentolamine. The inhibitory effects of isomers of norepinephrine and epinephrine on the binding showed that l-isomers were over 10 times more potent than d-isomers. (/sup 3/H)-p-Amino-clonidine binding to the cerebral microvessels was saturable and of high affinity (K/sub D/ . 0.61 nM) with a B/sub max/ of 73 fmol/mg protein. The binding reached equilibrium within 30 minutes, and was dissociated by the addition of 100 microM l-norepinephrine. l-Isomers of norepinephrine and epinephrine were over 10 times more potent than d-isomers in displacing the binding. Thus, both (/sup 3/H)prazosin and (/sup 3/H)-p-amino-clonidine bindings to the cerebral microvessels were characterized by saturability, high affinity, reversibility, and stereo-specificity. Furthermore, the specificity of both binding sites was pharmacologically evaluated by the inhibitory effects of various adrenergic agonists and antagonists on the bindings. These data indicate the existence of alpha-adrenergic receptors in the cerebral microvessels and are consistent with the hypothesis that the cerebral microcirculation is regulated by adrenergic innervation. Furthermore, the receptors were measured in cerebral microvessels of spontaneously hypertensive rats and Wistar-Kyoto controls.

  6. The Role of Neuromediators and Innervation in Cutaneous Wound Healing.

    PubMed

    Ashrafi, Mohammed; Baguneid, Mohamed; Bayat, Ardeshir

    2016-06-15

    The skin is densely innervated with an intricate network of cutaneous nerves, neuromediators and specific receptors which influence a variety of physiological and disease processes. There is emerging evidence that cutaneous innervation may play an important role in mediating wound healing. This review aims to comprehensively examine the evidence that signifies the role of innervation during the overlapping stages of cutaneous wound healing. Numerous neuropeptides that are secreted by the sensory and autonomic nerve fibres play an essential part during the distinct phases of wound healing. Delayed wound healing in diabetes and fetal cutaneous regeneration following wounding further highlights the pivotal role skin innervation and its associated neuromediators play in wound healing. Understanding the mechanisms via which cutaneous innervation modulates wound healing in both the adult and fetus will provide opportunities to develop therapeutic devices which could manipulate skin innervation to aid wound healing.

  7. Development of neuropeptide Y-mediated heart innervation in rats.

    PubMed

    Masliukov, Petr M; Moiseev, Konstantin; Emanuilov, Andrey I; Anikina, Tatyana A; Zverev, Alexey A; Nozdrachev, Alexandr D

    2016-02-01

    Neuropeptide Y (NPY) plays a trophic role in the nervous and vascular systems and in cardiac hypertrophy. However, there is no report concerning the expression of NPY and its receptors in the heart during postnatal development. In the current study, immunohistochemistry and Western blot analysis was used to label NPY, and Y1R, Y2R, and Y5R receptors in the heart tissue and intramural cardiac ganglia from rats of different ages (newborn, 10 days old, 20 days old, 30 days old, 60 days old, 1 year old, and 2 years old).The obtained data suggest age-dependent changes of NPY-mediated heart innervation. The density of NPY-immunoreactive (IR) fibers was the least in newborn animals and increased in the first 20 days of life. In the atria of newborn and 10-day-old rats, NPY-IR fibers were more abundant compared with the ventricles. The vast majority of NPY-IR fibers also contained tyrosine hydroxylase, a key enzyme in catecholamine synthesis.The expression of Y1R increased between 10 and 20 days of life. Faint Y2R immunoreactivity was observed in the atria and ventricles of 20-day-old and older rats. In contrast, the highest level of the expression of Y5R was found in newborn pups comparing with more adult rats. All intramural ganglionic neurons were also Y1R-IR and Y5R-IR and Y2R-negative in all studied animals.Thus, the increasing of density of NPY-containing nerve fibers accompanies changes in relation of different subtypes of NPY receptors in the heart during development.

  8. Management of beta-adrenergic blocker and calcium channel antagonist toxicity.

    PubMed

    Kerns, William

    2007-05-01

    State-of-the-art therapy for beta-adrenergic receptor blocker and calcium channel antagonist toxicity is reviewed in the light of new insights into drug-induced shock. A brief discussion of pathophysiology, including cardiac, hemodynamic, and metabolic effects of cardiac drug toxicity, provides a foundation for understanding the basis of therapy. The major focus of this review is a critical evaluation of antidotal use of calcium, glucagon, catecholamines, insulin-euglycemia, and other novel therapies based on investigational studies and cumulative clinical experience.

  9. Beta-Adrenergic Receptor Blockers in Hypertension: Alive and Well.

    PubMed

    Frishman, William H

    2016-10-27

    βeta-Adrenergic receptor blockers (β-blockers) are an appropriate treatment for patients having systemic hypertension (HTN) who have concomitant ischemic heart disease (IHD), heart failure, obstructive cardiomyopathy, aortic dissection or certain cardiac arrhythmias. β-blockers can be used in combination with other antiHTN drugs to achieve maximal blood pressure control. Labetalol can be used in HTN emergencies and urgencies. β-blockers may be useful in HTN patients having a hyperkinetic circulation (palpitations, tachycardia, HTN, and anxiety), migraine headache, and essential tremor. β-blockers are highly heterogeneous with respect to various pharmacologic properties: degree of intrinsic sympathomimetic activity , membrane stabilizing activity , β1 selectivity, α1-adrenergic blocking effects, tissue solubility, routes of systemic elimination, potencies and duration of action, and specific properties may be important in the selection of a drug for clinical use. β-blocker usage to reduce perioperative myocardial ischemia and cardiovascular (CV) complications may not benefit as many patients as was once hoped, and may actually cause harm in some individuals. Currently the best evidence supports perioperative β-blocker use in two patient groups: patients undergoing vascular surgery with known IHD or multiple risk factors for it, and for those patients already receiving β-blockers for known CV conditions.

  10. Direct contact between sympathetic neurons and rat cardiac myocytes in vitro increases expression of functional calcium channels.

    PubMed Central

    Ogawa, S; Barnett, J V; Sen, L; Galper, J B; Smith, T W; Marsh, J D

    1992-01-01

    To test the hypothesis that direct contact between sympathetic neurons and myocytes regulates expression and function of cardiac Ca channels, we prepared cultures of neonatal rat ventricular myocytes with and without sympathetic ganglia. Contractile properties of myocytes were assessed by an optical-video system. Contractility-pCa curves showed a 60% greater increase in contractility for innervated myocytes compared with control cells at 6.3 mM [Ca]0 (n = 8, P less than 0.05). Cells grown in medium conditioned by growth of ganglia and myocytes were indistinguishable physiologically from control cells. [Bay K 8644]-contractility curves revealed a 60 +/- 10% enhancement of the contractility response at 10(-6) M for innervated cells compared with control cells. The increased response to Bay K 8644 was not blocked by alpha- or beta-adrenergic antagonists. Moreover, increased efficacy of Bay K 8644 was maintained for at least 24 h after denervation produced by removal of ganglia from the culture. Dihydropyridine binding sites were assessed with the L channel-specific radioligand 3[H]PN200-110. PN200-110 binding sites were increased by innervation (51 +/- 5 to 108 +/- 20 fmol/mg protein, P less than 0.01), with no change in KD. Peak current-voltage curves were determined by whole-cell voltage clamp techniques for myocytes contacted by a neuron, control myocytes, and myocytes grown in conditioned medium. Current density of L-type Ca channels was significantly higher in innervated myocytes (10.5 +/- 0.4 pA/pF, n = 5) than in control myocytes (5.9 +/- 0.3 pA/pF, n = 8, P less than 0.01) or myocytes grown in conditioned medium (6.2 +/- 0.2 pA/pF, n = 10, P less than 0.01). Thus, physical contact between a sympathetic neuron and previously uninnervated neonatal rat ventricular myocytes increases expression of functional L-type calcium channels as judged by contractile responses to Ca0 and Bay K 8644, as well as by electrophysiological and radioligand binding properties

  11. β-Adrenergic Receptor and Insulin Resistance in the Heart.

    PubMed

    Mangmool, Supachoke; Denkaew, Tananat; Parichatikanond, Warisara; Kurose, Hitoshi

    2017-01-01

    Insulin resistance is characterized by the reduced ability of insulin to stimulate tissue uptake and disposal of glucose including cardiac muscle. These conditions accelerate the progression of heart failure and increase cardiovascular morbidity and mortality in patients with cardiovascular diseases. It is noteworthy that some conditions of insulin resistance are characterized by up-regulation of the sympathetic nervous system, resulting in enhanced stimulation of β-adrenergic receptor (βAR). Overstimulation of βARs leads to the development of heart failure and is associated with the pathogenesis of insulin resistance in the heart. However, pathological consequences of the cross-talk between the βAR and the insulin sensitivity and the mechanism by which βAR overstimulation promotes insulin resistance remain unclear. This review article examines the hypothesis that βARs overstimulation leads to induction of insulin resistance in the heart.

  12. β-Adrenergic Receptor and Insulin Resistance in the Heart

    PubMed Central

    Mangmool, Supachoke; Denkaew, Tananat; Parichatikanond, Warisara; Kurose, Hitoshi

    2017-01-01

    Insulin resistance is characterized by the reduced ability of insulin to stimulate tissue uptake and disposal of glucose including cardiac muscle. These conditions accelerate the progression of heart failure and increase cardiovascular morbidity and mortality in patients with cardiovascular diseases. It is noteworthy that some conditions of insulin resistance are characterized by up-regulation of the sympathetic nervous system, resulting in enhanced stimulation of β-adrenergic receptor (βAR). Over-stimulation of βARs leads to the development of heart failure and is associated with the pathogenesis of insulin resistance in the heart. However, pathological consequences of the cross-talk between the βAR and the insulin sensitivity and the mechanism by which βAR over-stimulation promotes insulin resistance remain unclear. This review article examines the hypothesis that βARs over-stimulation leads to induction of insulin resistance in the heart. PMID:28035081

  13. Cartography of human diaphragmatic innervation: preliminary data.

    PubMed

    Verin, Eric; Marie, Jean-Paul; Similowski, Thomas

    2011-04-30

    In humans, anatomy indicates that the phrenic nerve mainly arises from the C4 cervical root, with variable C3 and C5 contributions. How this translates into functional innervation is unknown. The diaphragm response to electrical stimulation of C3, C4 and C5 was described in three patients undergoing surgical laryngeal reinnervation with an upper phrenic root (surface chest electrodes at anterior, lateral and posterior sites; oesophageal and gastric pressures (Pes and Pga) to derive transdiaphragmatic pressure (Pdi)). Anatomically, the phrenic nerve predominantly originated from C4. Phrenic stimulation elicited motor responses at the three sites in the three patients, as did C4 stimulation. It produced Pdi values of 9, 11, and 14cmH(2)O in the three patients, respectively, vs. 9, 9, and 7cmH(2)O for C4. C3 stimulation produced modest Pdi responses, whereas C5 stimulation could produce Pdi responses close to those observed with C4 stimulation. These singular observations confirm the dominance of C4 in diaphragm innervation but suggest than C5 can be of importance. Copyright © 2010 Elsevier B.V. All rights reserved.

  14. Visceral nerves: vagal and sympathetic innervation.

    PubMed

    Teff, Karen L

    2008-01-01

    The autonomic nervous system is the primary neural mediator of physiological responses to internal and external stimuli. It is composed of 2 branches: the sympathetic nervous system, which mediates catabolic responses, and the parasympathetic nervous system, composed of the vagus nerve, which regulates anabolic responses. As the vagus nerve innervates most tissues involved in nutrient metabolism, including the stomach, pancreas, and liver, activation of vagal efferent activity has the potential to influence how nutrients are absorbed and metabolized. Vagal efferent activity is initially activated at the onset of food intake by receptors in the oropharyngeal cavity and then during food intake postprandially. Vagal efferent innervation of the pancreas contributes to early-phase insulin release as well as to optimizing postprandial insulin release. In the absence of vagal activation, which occurs when glucose is administered intragastrically, postprandial glucose levels are higher and insulin levels blunted compared with when there is activation of oropharyngeal receptors by food. An induction of vagal efferent activity also occurs during chronic pancreatic B-cell challenge with 48-hour glucose infusions. Under these conditions, the compensatory increase in insulin secretion is partially mediated by an increase in vagal efferent activity. In conclusion, the vagus nerve, part of the parasympathetic nervous system, plays a critical role in the regulation of blood glucose levels and is an often overlooked factor contributing to glucose homeostasis.

  15. An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice

    PubMed Central

    Montgomery, Megan D.; Chan, Trevor; Swigart, Philip M.; Myagmar, Bat-erdene; Dash, Rajesh; Simpson, Paul C.

    2017-01-01

    Alpha-1 adrenergic receptors mediate adaptive effects in the heart and cardiac myocytes, and a myocyte survival pathway involving the alpha-1A receptor subtype and ERK activation exists in vitro. However, data in vivo are limited. Here we tested A61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a selective imidazoline agonist for the alpha-1A. A61603 was the most potent alpha-1-agonist in activating ERK in neonatal rat ventricular myocytes. A61603 activated ERK in adult mouse ventricular myocytes and protected the cells from death caused by the anthracycline doxorubicin. A low dose of A61603 (10 ng/kg/d) activated ERK in the mouse heart in vivo, but did not change blood pressure. In male mice, concurrent subcutaneous A61603 infusion at 10 ng/kg/d for 7 days after a single intraperitoneal dose of doxorubicin (25 mg/kg) increased survival, improved cardiac function, heart rate, and cardiac output by echocardiography, and reduced cardiac cell necrosis and apoptosis and myocardial fibrosis. All protective effects were lost in alpha-1A-knockout mice. In female mice, doxorubicin at doses higher than in males (35–40 mg/kg) caused less cardiac toxicity than in males. We conclude that the alpha-1A-selective agonist A61603, via the alpha-1A adrenergic receptor, prevents doxorubicin cardiomyopathy in male mice, supporting the theory that alpha-1A adrenergic receptor agonists have potential as novel heart failure therapies. PMID:28081170

  16. Follistatin: A Potential Anabolic Treatment for Re-Innervated Muscle

    DTIC Science & Technology

    2016-09-01

    of recombinant follistatin DNA packaged in AAV (into gastrocnemius muscle) or implantation of drug delivery reservoir (with either carrier or...muscles re-innervated. The re-innervated muscle will be treated with either recombinant follistatin protein (delivered thru an implantable drug delivery

  17. Adrenergic desensitization in left ventricle from streptozotocin diabetic swine.

    PubMed

    Roth, D A; White, C D; Hamilton, C D; Hall, J L; Stanley, W C

    1995-10-01

    Patients with diabetes mellitus that exhibit cardiac pump failure display compromised stroke volume, ejection fraction, and slower rates of rise and fall of left ventricular (LV) dP/dt in the absence of ischemic injury. We hypothesized that diabetic cardiomyopathy may involve decrements in adrenergic sensitivity, with specific molecular alterations in the beta-adrenergic receptor (beta AR)- G protein- adenylyl cyclase (AC) signal transduction system. We assessed the effects of 3 months of streptozotocin-induced diabetes (125 mg/kg i.v.; DIAB, n = 10) on myocardial signal transduction in mini-pigs. DIAB were hyperglycemic compared to controls (CON, n = 10; 20.92 +/- 2.64 v 5.24 +/- 0.35 mM glucose), and had lower fasting insulin levels (6.46 +/- 0.97 v 13.68 +/- 3.91 microU/ml). Transmural LV free wall homogenates from DIAB exhibited similar beta AR density as CON, but decreased cAMP production (pmol cAMP/mg prot.min) using these pharmacological stimulators: 10 microM Isoproterenol plus 100 microM GTP (74 +/- 5 v 97 +/- 11); 100 microM Gpp(NH)p (116 +/- 7 v 161 +/- 17); 10 mM fluoride ion (266 +/- 16 v 324 +/- 25). No differences between DIAB and CON were observed when stimulated by 100 microM forskolin (440 +/- 20 v 429 +/- 33), suggesting no alterations in the catalytic subunit of AC. In DIAB, quantitative immunoblotting indicated slightly depressed levels of Gs (552 +/- 44 v 630 +/- 59 pmol/g ww; NS), but a significant redistribution of alpha s from the sarcolemma to the cytosol (32.7 +/- 0.82% v 25.9 +/- 1.7%). Significantly elevated levels of cardiac Gi were seen in DIAB homogenates compared to CON ventricles (2326 +/- 145 v 1522 +/- 181 pmol/g ww), with no alpha i subunit redistribution. We conclude that despite maintained beta AR density, receptor-dependent and G protein-dependent stimulation of AC is depressed so that streptozotocin-induced diabetic LV is affected by increased cardiac Gi, redistribution of Gs alpha to the cytosol, and an increase in the Gi

  18. Dual innervation of neonatal Merkel cells in mouse touch domes.

    PubMed

    Niu, Jingwen; Vysochan, Anna; Luo, Wenqin

    2014-01-01

    Merkel cell-neurite complexes are specialized mechanosensory end organs that mediate discriminative touch sensation. It is well established that type I slowly adapting (SAI) mechanoreceptors, which express neural filament heavy chain (NFH), innervate Merkel cells. It was previously shown that neurotrophic factor NT3 and its receptor TrkC play crucial roles in controlling touch dome Merkel cell innervation of NFH+ fibers. In addition, nerve fibers expressing another neurotrophic tyrosine receptor kinase (NTRK), Ret, innervate touch dome Merkel cells as well. However, the relationship between afferents responsive to NT3/TrkC signaling and those expressing Ret is unclear. It is also controversial if these Ret+ fibers belong to the early or late Ret+ DRG neurons, which are defined based on the co-expression and developmental dependence of TrkA. To address these questions, we genetically traced Ret+ and TrkC+ fibers and analyzed their developmental dependence on TrkA. We found that Merkel cells in neonatal mouse touch domes receive innervation of two types of fibers: one group is Ret+, while the other subset expresses TrkC and NFH. In addition, Ret+ fibers depend on TrkA for their survival and normal innervation whereas NFH+ Merkel cell innervating fibers are almost unaltered in TrkA mutant mice, supporting that Ret+ and NFH+/TrkC+ afferents are two distinct groups. Ret signaling, on the other hand, plays a minor role for the innervation of neonatal touch domes. In contrast, Merkel cells in the glabrous skin are mainly contacted by NFH+/TrkC+ afferents. Taken together, our results suggest that neonatal Merkel cells around hair follicles receive dual innervation while Merkel cells in the glabrous skin are mainly innervated by only SAI mechanoreceptors. In addition, our results suggest that neonatal Ret+ Merkel cell innervating fibers most likely belong to the late but not early Ret+ DRG neurons.

  19. Serotonergic innervation of the rat testis.

    PubMed

    Campos, M B; Vitale, M L; Calandra, R S; Chiocchio, S R

    1990-03-01

    The presence of 5-hydroxytryptamine (5-HT) was determined by h.p.l.c. in perchloric extracts of each isolated compartment of the adult rat testis. The testicular capsule, interstitial cells and interstitial fluid contained 5-HT, but 5-HT was not detected in the tubular compartment. In a group of adult rats, one testis was unilaterally denervated, and the contralateral testis used as control. The superior spermatic nerve, arising from the renal plexus, was excised and 1 week after surgery 5-HT content was measured in the capsule and interstitial fluid of both testes. Denervation caused a significant fall (34%) in 5-HT content. These results indicate that at least part of the testicular 5-HT derives from a serotonergic innervation of the gonad.

  20. Innervation of the gall bladder and biliary pathways in the guinea-pig.

    PubMed Central

    Cai, W Q; Gabella, G

    1983-01-01

    The innervation of the gall bladder and the biliary pathways was studied in guinea-pigs by means of histochemical methods for catecholamines and for acetylcholinesterase on whole mount preparations, on cryostat sections and on sections of plastic-embedded tissues. The gall bladder contains on average 367 neurons in a ganglionated plexus which lies at the outer surface of the muscle coat. The overall appearance of this plexus is rather similar to that of the submucosal plexus of the duodenum. From the gall bladder the plexus extends into the cystic duct, the hepatic duct and the common bile duct, but from the middle portion of the common bile duct downwards, it is positioned at or near the inner surface of the muscle coat. Concurrently with the marked increase in muscle thickness in the lower parts of the common bile duct, another ganglionated plexus appears, which is truly intramuscular. The latter plexus is highly developed, lies usually between longitudinal and circular muscle and resembles in appearance the myenteric plexus of the duodenum, with which it is in continuity. Throughout the biliary system, the extent of the ganglionated plexus is roughly related to the extent of the musculature. An exchange of adrenergic fibres between the ganglionated plexus and perivascular nerves is observed in the gall bladder. Another nerve plexus, without ganglia but rich in adrenergic and acetylcholinesterase-positive fibres, lies between the mucosa and the muscle coat. Very few nerve fibres run into the musculature of the gall bladder. On the other hand, in the thick musculature of the lower portion of the common bile duct, several intramuscular nerve fibres are found. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 PMID:6833124

  1. Computer-assisted anatomic dissection (CAAD): evolution, methodology and application in intra-pelvic innervation study.

    PubMed

    Alsaid, Bayan; Bessede, Thomas; Diallo, Djibril; Karam, Ibrahim; Uhl, Jean François; Delmas, Vincent; Droupy, Stéphane; Benoît, Gérard

    2012-10-01

    Classic anatomical methods have limitations in micro determination of nerve fibre location. Furthermore, the precise detection of the nerve fibres nature is not possible by means of dissection. The combination of immunohistochemistry and three-dimensional reconstruction could be used to resolve these limitations of morphological sciences. Our aim is to describe the evolution of computer-assisted anatomic dissection (CAAD), which is an original method applied to study the distribution of intra-pelvic nerves in anatomic research. Serial transverse sectioning of the pelvic region in rabbit, human fetus, infant and adult cadaver was performed. Sections were immuno-histochemically stained and digitized with a high optical resolution scanner. Photoshop 7 software was used in regrouping of the adult cadaver sections then a tri-dimensional reconstruction was achieved using WinSurf software. The 3D reconstruction of the immuno-histochemically stained histologic sections of the pelvis allowed for precise structural identification of the prostate and its innervations (in fetus, infant and adult). In addition, we reconstructed the entire intra-pelvic organs with accurate demonstration of the location of both adrenergic and cholinergic pathways. Moreover, we performed a virtual dissection of each of the pelvic structures with description of the exact location of the inferior hypogastric plexus, as well as the nature and the distribution of its fibres. The CAAD is an original method in anatomic research, which illustrates the fact that descriptive anatomy is still a dynamic science. This method allows for a 3D presentation of the intra-organic innervation, the nature of the nerve fibres, and the distribution of receptors and their neurotransmitters. This technique improves the understanding of the complex anatomic regions such as the pelvis from both surgical and educational point of view.

  2. The Role of Reactive Oxygen Species in β-Adrenergic Signaling in Cardiomyocytes from Mice with the Metabolic Syndrome

    PubMed Central

    Llano-Diez, Monica; Sinclair, Jon; Yamada, Takashi; Zong, Mei; Fauconnier, Jeremy; Zhang, Shi-Jin; Katz, Abram; Jardemark, Kent; Westerblad, Håkan; Andersson, Daniel C.

    2016-01-01

    The metabolic syndrome is associated with prolonged stress and hyperactivity of the sympathetic nervous system and afflicted subjects are prone to develop cardiovascular disease. Under normal conditions, the cardiomyocyte response to acute β-adrenergic stimulation partly depends on increased production of reactive oxygen species (ROS). Here we investigated the interplay between beta-adrenergic signaling, ROS and cardiac contractility using freshly isolated cardiomyocytes and whole hearts from two mouse models with the metabolic syndrome (high-fat diet and ob/ob mice). We hypothesized that cardiomyocytes of mice with the metabolic syndrome would experience excessive ROS levels that trigger cellular dysfunctions. Fluorescent dyes and confocal microscopy were used to assess mitochondrial ROS production, cellular Ca2+ handling and contractile function in freshly isolated adult cardiomyocytes. Immunofluorescence, western blot and enzyme assay were used to study protein biochemistry. Unexpectedly, our results point towards decreased cardiac ROS signaling in a stable, chronic phase of the metabolic syndrome because: β-adrenergic-induced increases in the amplitude of intracellular Ca2+ signals were insensitive to antioxidant treatment; mitochondrial ROS production showed decreased basal rate and smaller response to β-adrenergic stimulation. Moreover, control hearts and hearts with the metabolic syndrome showed similar basal levels of ROS-mediated protein modification, but only control hearts showed increases after β-adrenergic stimulation. In conclusion, in contrast to the situation in control hearts, the cardiomyocyte response to acute β-adrenergic stimulation does not involve increased mitochondrial ROS production in a stable, chronic phase of the metabolic syndrome. This can be seen as a beneficial adaptation to prevent excessive ROS levels. PMID:27907040

  3. Afferent innervation of the utricular macula in pigeons

    NASA Technical Reports Server (NTRS)

    Si, Xiaohong; Zakir, Mridha Md; Dickman, J. David

    2003-01-01

    Biotinylated dextran amine (BDA) was used to retrogradely label afferents innervating the utricular macula in adult pigeons. The pigeon utriclar macula consists of a large rectangular-shaped neuroepithelium with a dorsally curved anterior edge and an extended medioposterior tail. The macula could be demarcated into several regions based on cytoarchitectural differences. The striola occupied 30% of the macula and contained a large density of type I hair cells with fewer type II hair cells. Medial and lateral extrastriola zones were located outside the striola and contained only type II hair cells. A six- to eight-cell-wide band of type II hair cells existed near the center of the striola. The reversal line marked by the morphological polarization of hair cells coursed throughout the epithelium, near the peripheral margin, and through the center of the type II band. Calyx afferents innervated type I hair cells with calyceal terminals that contained between 2 and 15 receptor cells. Calyx afferents were located only in the striola region, exclusive of the type II band, had small total fiber innervation areas and low innervation densities. Dimorph afferents innervated both type I and type II hair cells with calyceal and bouton terminals and were primarily located in the striola region. Dimorph afferents had smaller calyceal terminals with few type I hair cells, extended fiber branches with bouton terminals and larger innervation areas. Bouton afferents innervated only type II hair cells in the extrastriola and type II band regions. Bouton afferents innervating the type II band had smaller terminal fields with fewer bouton terminals and smaller innervation areas than fibers located in the extrastriolar zones. Bouton afferents had the most bouton terminals on the longest fibers, the largest innervation areas with the highest innervation densities of all afferents. Among all afferents, smaller terminal innervation fields were observed in the striola and large fields were

  4. Afferent innervation of the utricular macula in pigeons.

    PubMed

    Si, Xiaohong; Zakir, Mridha Md; Dickman, J David

    2003-03-01

    Biotinylated dextran amine (BDA) was used to retrogradely label afferents innervating the utricular macula in adult pigeons. The pigeon utriclar macula consists of a large rectangular-shaped neuroepithelium with a dorsally curved anterior edge and an extended medioposterior tail. The macula could be demarcated into several regions based on cytoarchitectural differences. The striola occupied 30% of the macula and contained a large density of type I hair cells with fewer type II hair cells. Medial and lateral extrastriola zones were located outside the striola and contained only type II hair cells. A six- to eight-cell-wide band of type II hair cells existed near the center of the striola. The reversal line marked by the morphological polarization of hair cells coursed throughout the epithelium, near the peripheral margin, and through the center of the type II band. Calyx afferents innervated type I hair cells with calyceal terminals that contained between 2 and 15 receptor cells. Calyx afferents were located only in the striola region, exclusive of the type II band, had small total fiber innervation areas and low innervation densities. Dimorph afferents innervated both type I and type II hair cells with calyceal and bouton terminals and were primarily located in the striola region. Dimorph afferents had smaller calyceal terminals with few type I hair cells, extended fiber branches with bouton terminals and larger innervation areas. Bouton afferents innervated only type II hair cells in the extrastriola and type II band regions. Bouton afferents innervating the type II band had smaller terminal fields with fewer bouton terminals and smaller innervation areas than fibers located in the extrastriolar zones. Bouton afferents had the most bouton terminals on the longest fibers, the largest innervation areas with the highest innervation densities of all afferents. Among all afferents, smaller terminal innervation fields were observed in the striola and large fields were

  5. Afferent innervation of the utricular macula in pigeons

    NASA Technical Reports Server (NTRS)

    Si, Xiaohong; Zakir, Mridha Md; Dickman, J. David

    2003-01-01

    Biotinylated dextran amine (BDA) was used to retrogradely label afferents innervating the utricular macula in adult pigeons. The pigeon utriclar macula consists of a large rectangular-shaped neuroepithelium with a dorsally curved anterior edge and an extended medioposterior tail. The macula could be demarcated into several regions based on cytoarchitectural differences. The striola occupied 30% of the macula and contained a large density of type I hair cells with fewer type II hair cells. Medial and lateral extrastriola zones were located outside the striola and contained only type II hair cells. A six- to eight-cell-wide band of type II hair cells existed near the center of the striola. The reversal line marked by the morphological polarization of hair cells coursed throughout the epithelium, near the peripheral margin, and through the center of the type II band. Calyx afferents innervated type I hair cells with calyceal terminals that contained between 2 and 15 receptor cells. Calyx afferents were located only in the striola region, exclusive of the type II band, had small total fiber innervation areas and low innervation densities. Dimorph afferents innervated both type I and type II hair cells with calyceal and bouton terminals and were primarily located in the striola region. Dimorph afferents had smaller calyceal terminals with few type I hair cells, extended fiber branches with bouton terminals and larger innervation areas. Bouton afferents innervated only type II hair cells in the extrastriola and type II band regions. Bouton afferents innervating the type II band had smaller terminal fields with fewer bouton terminals and smaller innervation areas than fibers located in the extrastriolar zones. Bouton afferents had the most bouton terminals on the longest fibers, the largest innervation areas with the highest innervation densities of all afferents. Among all afferents, smaller terminal innervation fields were observed in the striola and large fields were

  6. Adrenergic antagonists restrict replication of Legionella.

    PubMed

    Harrison, Christopher F; Kicka, Sébastien; Kranjc, Agata; Finsel, Ivo; Chiriano, Gianpaolo; Ouertatani-Sakouhi, Hajer; Soldati, Thierry; Scapozza, Leonardo; Hilbi, Hubert

    2015-07-01

    Legionella pneumophila is a facultative intracellular bacterium, which upon inhalation can cause a potentially fatal pneumonia termed Legionnaires' disease. The opportunistic pathogen grows in environmental amoebae and mammalian macrophages within a unique membrane-bound compartment, the 'Legionella-containing vacuole'. Bacteria are exposed to many environmental cues including small signalling molecules from eukaryotic cells. A number of pathogenic bacteria sense and respond to catecholamine hormones, such as adrenalin and noradrenalin, a process mediated via the QseBC two-component system in some bacteria. In this study, we examined the effect of adrenergic compounds on L. pneumophila, and discovered that the adrenergic receptor antagonists benoxathian, naftopidil, propranolol and labetalol, as well as the QseC sensor kinase inhibitor LED209, reduced the growth of L. pneumophila in broth or amoebae, while replication in macrophages was enhanced. Growth restriction was common to members of the genus Legionella and Mycobacterium, and was observed for L. pneumophila in the replicative but not stationary phase of the biphasic life cycle. Deletion of the L. pneumophila qseBC genes indicated that growth inhibition by adrenergics or LED209 is mediated only to a minor extent by this two-component system, implying the presence of other adrenergic sensing systems. This study identifies adrenergic molecules as novel inhibitors of extra- and intracellular growth of Legionella and reveals LED209 as a potential lead compound to combat infections with Legionella or Mycobacterium spp.

  7. [Muscarinic modulation of cardiac activity].

    PubMed

    Sauviat, M P

    1999-01-01

    The goal of the present review is to report information concerning cardiac innervation or more precisely to approach the modulation of cardiac electrical and mechanical activity by parasympathetic innervation. Acetylcholine (ACh) release by nerve endings from the vagus nerve hyperpolarizes the membrane, shortens action potential (AP) duration and has a negative inotropic effect on cardiac muscle. Toxins are usefull tools in the study of membrane signals. The Caribbean ciguatoxin (C-CTX-1) has a muscarinic effect on frog atrial fibres. The toxin evokes the release of ACh from motoneuron nerve terminals innervating this tissue which allows us to propose a model, similar to the one of the neuromuscular junction (nmj), to describe the events occurring during the triggering and release of ACh. Trachynilysin (TLY) is a proteic toxin which causes an influx of Ca2+ into the cells and releases ACh from nmj synaptic vesicles. TLY has a muscarinic effect on atrial fibres which is explicated in the release of neurotransmitter from the nerve endings generated by the TLY-induced Ca2+ influx. It is known that ACh release from nmj is known to be due to exocytosis of synaptic vesicles via the activation of a proteic complex blocked by botulinum toxins. One of these proteins SNAP-25 is the target of type A botulinum toxin (BoNT/A). The study of hearts isolated from BoNT/A poisoned frogs show that atrial AP is lengthened and reveals the presence of SNAP-25 in nerve endings of this tissue. Moreover, the electrical activity of ventricular muscle is markedly altered; in BoNT/A treated frog, an important outward current activated by internal Ca2+ develops. ACh released from nerve terminals binds to a G protein coupled membrane receptor and activates a K+ channel and other effectors. Five subtypes of muscarinic receptors have been cloned from different tissue (M1, M2, M3, M4) subtypes have been identified in cardiac tissues throughout many species. These receptors coupled with different G

  8. Muscarinic type 1 receptors mediate part of nitric oxide's vagal facilitatory effect in the isolated innervated rat right atrium.

    PubMed

    Hogan, K; Markos, F

    2007-02-01

    We investigated whether vagal cardiac cholinergic facilitation by nitric oxide (NO) is mediated by cardiac muscarinic receptor subtypes in the vagally innervated rat right atrium in vitro. Experiments were carried out in the presence of atenolol (4 microM). The right vagus was stimulated at 4, 8, 16, 32 Hz; pulse duration 1 ms at 20 V for 20s; vagal postganglionic activation was achieved using nicotine (0.1, 0.3, 0.5, 1mM) and the effect on cardiac interval (ms) assessed. Pirenzepine (1 microM), a M1 antagonist, attenuated vagally induced increase in cardiac interval. L-Arginine (0.34 mM) superfused with pirenzepine failed to reverse this attenuation, however, L-arginine applied alone reversed the reduction vagal cardiac slowing. Similarly, sodium nitroprusside (10 microM) applied alone, and not together with pirenzepine, was able to reverse the attenuation of vagal effects caused by pirenzepine. Synthetic MT7 (1 nM) toxin, a selective M1 antagonist confirmed these results. M3 antagonism using para-fluorohexahydrosiladifenidol (p-F-HHSiD) (300 nM) and M4 antagonism with PD 102807 (200 nM) did not affect the vagally induced increase in cardiac interval. Nicotine induced increase in cardiac interval was not altered by pirenzepine. These results show that antagonism of M1 receptors on cardiac vagal preganglionic fibres reduces vagal efficacy which can be recovered by either a nitric oxide synthase substrate or a NO donor.

  9. Effect of short- and long-term portal hypertension on adrenergic, nitrergic and sensory functioning in rat mesenteric artery.

    PubMed

    Sastre, Esther; Balfagón, Gloria; Revuelta-López, Elena; Aller, Maria-Ángeles; Nava, Maria-Paz; Arias, Jaime; Blanco-Rivero, Javier

    2012-04-01

    In the present study, we analysed possible alterations in adrenergic, nitrergic and sensory functioning in mesenteric arteries from rats at 1 and 21 months after partial portal vein ligation, and the mechanisms involved in these alterations, if any. For this purpose, we analysed the vasoconstrictor response to EFS (electrical field stimulation) and the effect of the α-antagonist phentolamine, the NOS (nitric oxide synthase) inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester) and the CGRP (calcitonin gene-related peptide) receptor antagonist CGRP-(8-37) in mesenteric segments from ST (short-term; 1 month) and LT (long-term; 21 months) SO (sham-operated) and pre-hepatic PH (portal hypertensive) rats. The vasomotor responses to NA (noradrenaline), the NO donor DEA-NO (diethylamine NONOate) and CGRP were analysed. NA, NO and CGRP releases were measured. Phospho-nNOS (neuronal NOS) expression was studied. The vasoconstrictor response to EFS was decreased in STPH animals. Phentolamine decreased this vasoconstrictor response more strongly in SO animals. Both L-NAME and CGRP-(8-37) increased vasoconstrictor response to EFS more strongly in PH than SO segments. PH did not modify vasomotor responses to NA, DEA-NO or CGRP, but it decreased NA release while increasing those of NO and CGRP. Phospho-nNOS expression was increased by PH. In LTPH, no differences were observed in vasoconstrictor response to EFS, vasomotor responses or neurotransmitter release when compared with age-matched SO animals. In conclusion, the mesenteric innervation may participate in the development of the characteristic hyperdynamic circulation observed in STPH through the joint action of decreased adrenergic influence, and increased nitrergic and sensory innervations influences. The participation of each innervation normalizes under conditions of LTPH.

  10. Afferent innervation patterns of the saccule in pigeons

    NASA Technical Reports Server (NTRS)

    Zakir, M.; Huss, D.; Dickman, J. D.

    2003-01-01

    The innervation patterns of vestibular saccular afferents were quantitatively investigated in pigeons using biotinylated dextran amine as a neural tracer and three-dimensional computer reconstruction. Type I hair cells were found throughout a large portion of the macula, with the highest density observed in the striola. Type II hair cells were located throughout the macula, with the highest density in the extrastriola. Three classes of afferent innervation patterns were observed, including calyx, dimorph, and bouton units, with 137 afferents being anatomically reconstructed and used for quantitative comparisons. Calyx afferents were located primarily in the striola, innervated a number of type I hair cells, and had small innervation areas. Most calyx afferent terminal fields were oriented parallel to the anterior-posterior axis and the morphological polarization reversal line. Dimorph afferents were located throughout the macula, contained fewer type I hair cells in a calyceal terminal than calyx afferents and had medium sized innervation areas. Bouton afferents were restricted to the extrastriola, with multi-branching fibers and large innervation areas. Most of the dimorph and bouton afferents had innervation fields that were oriented dorso-ventrally but were parallel to the neighboring reversal line. The organizational morphology of the saccule was found to be distinctly different from that of the avian utricle or lagena otolith organs and appears to represent a receptor organ undergoing evolutionary adaptation toward sensing linear motion in terrestrial and aerial species.

  11. Vagal Afferent Innervation of the Lower Esophageal Sphincter

    PubMed Central

    Powley, Terry L.; Baronowsky, Elizabeth A.; Gilbert, Jared M.; Hudson, Cherie N.; Martin, Felecia N.; Mason, Jacqueline K.; McAdams, Jennifer L.; Phillips, Robert J.

    2013-01-01

    To supply a fuller morphological characterization of the vagal afferents innervating the lower esophageal sphincter (LES), specifically to label vagal terminals in the tissues forming the LES in the gastroesophageal junction, the present experiment employed injections of dextran biotin into the nodose ganglia of rats. Four types of vagal afferents innervated the LES. Clasp and sling muscle fibers were directly and prominently innervated by intramuscular arrays (IMAs). Individual IMA terminals subtended about 16° of arc of the esophageal circumference, and, collectively, the terminal fields were distributed within the muscle ring to establish a 360° annulus of mechanoreceptors in the sphincter wall. 3D morphometry of the terminals established that, compared to sling muscle IMAs, clasp muscle IMAs had more extensive arbors and larger receptive fields. In addition, at the cardia, local myenteric ganglia between smooth muscle sheets and striated muscle bundles were innervated by intraganglionic laminar endings (IGLEs), in a pattern similar to the innervation of the myenteric plexus throughout the stomach and esophagus. Finally, as previously described, the principle bundle of sling muscle fibers that links LES sphincter tissue to the antropyloric region of the lesser curvature was innervated by exceptionally long IMAs as well as by unique web ending specializations at the distal attachment of the bundle. Overall, the specialized varieties of densely distributed vagal afferents innervating the LES underscore the conclusion that these sensory projections are critically involved in generating LES reflexes and may be promising targets for managing esophageal dysfunctions. PMID:23583280

  12. Lack of interaction between orexinergic and alpha2-adrenergic neuronal systems in rat cerebrocortical slices.

    PubMed

    Hirota, Kazuyoshi; Kudo, Mihoko; Tose, Ryuji; Yoshida, Hitoshi; Kudo, Tsuyoshi; Kushikata, Tetsuya

    2005-10-14

    Orexinergic and norepinephrinergic alpha2-adrenoceptor expressing neurons contribute to the regulation of the sleep-wakefulness cycle. In the present study, we have examined a possible interaction between orexinergic and alpha2-adrenergic systems in orexin-A (100 nM)- and K+ (25 mM)-evoked norepinephrine release from slices of rat cerebrocortex. In this tissue norepinephrinergic neurons are predominantly innervated via the locus coeruleus. Clonidine concentration-dependently inhibited K+-evoked norepinephrine release with pIC50 (Imax) of 6.44+/-0.38 (48.8+/-6.9%). A selective orexin-1 receptor antagonist, SB-334867 was ineffective. SB-334867 concentration-dependently inhibited orexin A-evoked norepinephrine release with pIC50 (Imax) of 6.05+/-0.14 (86.4+/-5.4%); clonidine (alpha2-agonist) was ineffective. In contrast, yohimbine reversed the inhibitory effects of clonidine (1 microM) on K+-evoked norepinephrine release with pIC50 (Imax) of 6.50+/-0.34 (77.6+/-10.9%); orexin A was ineffective. The present data suggest a lack of interaction between orexinergic and alpha2-adrenergic neurons in rat cerebral cortex.

  13. The beta-adrenergic blocking agents and the treatment of glaucoma.

    PubMed

    Zimmerman, T J; Boger, W P

    1979-01-01

    The autonomic nervous system is divided into the parasympathetic and sympathetic systems, with three types of adrenergic receptors: alpha (smooth muscle contraction), beta1 (cardiac acceleration and fatty acid mobilization) and beta2 (smooth muscle relaxation). Substances affecting the function of the adrenergic system are the agonists or stimulators, which mimic the effects of endogenous norepinephrine or epinephrine, and antagonists or blockers, which block the receptors and prevent stimulation by the agonists. Autonomic stimulation in the eye mediates various changes which apparently affect outflow facility and rate of formation of aqueous humor. Alteration of either or both of these factors by autonomic agonists or antagonists may have a direct or an indirect effect on intraocular pressure. Beta-adrenergic blocking substances have been used to treat a variety of diseases. Some of the effects of these drugs are attributable to properties other than beta blockade, such as intrinsic sympathomimetic activity and local anaesthetic activity. Side effects of this class of drugs require caution in cases of congestive heart failure and in asthmatics. Autonomic agents used in the treatment of ocular hypertension and glaucoma include pilocarpine, a chilinergic agonist, epinephrine, an adrenergic agonist, and various beta adrenergic blockers or antagonists including propranolol, atenolol and timolol. The physico-chemical properties and pharmacokinetics of timolol are reviewed. Data showing a significant reduction in intraocular pressure as a result of ocular instillation of timolol are presented. Reduction of the rate of aqueous formation appears to be the mechanism of action. A low incidence of non-serious side effects is reported.

  14. Innervation of the thick ascending limb of Henle

    SciTech Connect

    Barajas, L.; Powers, K.V.

    1988-08-01

    The overlap of accumulations of autoradiographic grains (AAGs) on profiles of the thick ascending limb of Henle (TALH) was measured in autoradiograms of sections from rat kidneys with monoaminergic nerves labeled by means of tritiated norepinephrine. The amount of AAG overlap was used as an indirect means of quantifying innervation along the TALHs of superficial, mid-cortical, and juxtamedullary nephrons. The density of innervation along the TALH showed nephron heterogeneity; the juxtamedullary nephrons with a high pre- and postjuxtaglomerular apparatus (JGA) TALH density of innervation and the upper and midcortical nephrons with high TALH innervation densities at the level of the JGA. The pre-JGA TALH of the juxtamedullary nephrons had a significantly higher (P less than 0.001) density of innervation than the midcortical or superficial nephrons. The TALHs of juxtamedullary nephrons were found to have substantially more innervation than the TALHs of the other nephrons. For all three populations of nephrons, the pre-JGA TALH had the greatest amount of innervation. Neural regulation of TALH function would occur mainly along the pre-JGA and level of the JGA TALH. This regulation would increase TALH NaCl reabsorption (decrease luminal NaCl concentration) and therefore influence 1) the urinary concentrating mechanism, and 2) renin secretion via the macula densa mechanism. The innervation of the TALH was predominantly associated with the vasculature of the TALH's own nephron. However, innervation associated with medullary ray capillary beds from deeper nephrons was observed on pre-JGA TALHs from superficial and midcortical nephrons.

  15. Compartmentalization of beta-adrenergic signals in cardiomyocytes.

    PubMed

    Xiang, Yang K

    2011-07-08

    Activation of adrenergic receptors (AR) represents the primary mechanism to increase cardiac performance under stress. Activated βAR couple to Gs protein, leading to adenylyl cyclase-dependent increases in secondary-messenger cyclic adenosine monophosphate (cAMP) to activate protein kinase A. The increased protein kinase A activities promote phosphorylation of diversified substrates, ranging from the receptor and its associated partners to proteins involved in increases in contractility and heart rate. Recent progress with live-cell imaging has drastically advanced our understanding of the βAR-induced cAMP and protein kinase A activities that are precisely regulated in a spatiotemporal fashion in highly differentiated myocytes. Several features stand out: membrane location of βAR and its associated complexes dictates the cellular compartmentalization of signaling; βAR agonist dose-dependent equilibrium between cAMP production and cAMP degradation shapes persistent increases in cAMP signals for sustained cardiac contraction response; and arrestin acts as an agonist dose-dependent master switch to promote cAMP diffusion and propagation into intracellular compartments by sequestrating phosphodiesterase isoforms associated with the βAR signaling cascades. These features and the underlying molecular mechanisms of dynamic regulation of βAR complexes with adenylyl cyclase and phosphodiesterase enzymes and the implication in heart failure are discussed.

  16. Indenopyrazole oxime ethers: synthesis and β1-adrenergic blocking activity.

    PubMed

    Angelone, Tommaso; Caruso, Anna; Rochais, Christophe; Caputo, Angela Maria; Cerra, Maria Carmela; Dallemagne, Patrick; Filice, Elisabetta; Genest, David; Pasqua, Teresa; Puoci, Francesco; Saturnino, Carmela; Sinicropi, Maria Stefania; El-Kashef, Hussein

    2015-03-06

    This paper reports the synthesis and cardiac activity of new β-blockers derived from (Z/E)-indeno[1,2-c]pyrazol-4(1H)-one oximes (5a,b). The latter compounds were allowed to react with epichlorohydrin, followed by reacting the oxiranyl derivatives formed (6a,b) with some aliphatic amines to give the target compounds (Z/E)-1-phenyl-1H-indeno[1,2-c]pyrazol-4-one O-((2-hydroxy-3-(substituted amino)propyl)oxime (7a-c) and (Z/E)-1-methyl-1H-indeno[1,2-c]pyrazol-4-one O-((2-hydroxy-3-(substituted amino)propyl)oxime (8a-c). These final products 7a-c and 8a-c were evaluated for their ability to modulate the cardiac performance of a prototype mammalian heart. The results showed that, out of these molecules tested, 7b elicits a more potent depressant effect on contractility and relaxation, and competitively antagonizes β1-adrenergic receptors.

  17. A meta-analysis of the effects of β-adrenergic blockers in chronic heart failure.

    PubMed

    Zhang, Xiaojian; Shen, Chengwu; Zhai, Shujun; Liu, Yukun; Yue, Wen-Wei; Han, Li

    2016-10-01

    Adrenergic β-blockers are drugs that bind to, but do not activate β-adrenergic receptors. Instead they block the actions of β-adrenergic agonists and are used for the treatment of various diseases such as cardiac arrhythmias, angina pectoris, myocardial infarction, hypertension, headache, migraines, stress, anxiety, prostate cancer, and heart failure. Several meta-analysis studies have shown that β-blockers improve the heart function and reduce the risks of cardiovascular events, rate of mortality, and sudden death through chronic heart failure (CHF) of patients. The present study identified results from recent meta-analyses of β-adrenergic blockers and their usefulness in CHF. Databases including Medline/Embase/Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed were searched for the periods May, 1985 to March, 2011 and June, 2013 to August, 2015, and a number of studies identified. Results of those studies showed that use of β-blockers was associated with decreased sudden cardiac death in patients with heart failure. However, contradictory results have also been reported. The present meta-analysis aimed to determine the efficacy of β-blockers on mortality and morbidity in patients with heart failure. The results showed that mortality was significantly reduced by β-blocker treatment prior to the surgery of heart failure patients. The results from the meta-analysis studies showed that β-blocker treatment in heart failure patients correlated with a significant decrease in long-term mortality, even in patients that meet one or more exclusion criteria of the MERIT-HF study. In summary, the findings of the current meta-analysis revealed beneficial effects different β-blockers have on patients with heart failure or related heart disease.

  18. Meta-analysis of the effect of heart rate achieved by perioperative beta-adrenergic blockade on cardiovascular outcomes.

    PubMed

    Biccard, B M; Sear, J W; Foëx, P

    2008-01-01

    Acute perioperative beta-adrenergic blockade may be cardioprotective in the high-risk cardiac patient for major non-cardiac surgery. We have investigated the association between the heart rate achieved with perioperative beta-blockade and the incidence of perioperative cardiac complications. We identified eight randomized studies (1931 patients) reporting acute perioperative beta-blockade and major perioperative cardiovascular outcomes after non-cardiac surgery. The mean heart rates within the first 72 h after operation were analysed. A meta-analysis of means was conducted using a random effects model. A bivariate correlation analysis was conducted using Spearman's correlation coefficient to assess for an association between the mean postoperative heart rate and the 30 day cardiac outcomes. Acute perioperative beta-blockade did not significantly reduce 30 day cardiac death [odds ratio (OR) 0.35, 95% confidence interval (CI) 0.08-1.52] or non-fatal myocardial infarction (OR 0.90, 95% CI 0.52-1.56) in the studies with adequate methodology. The mean (95% CI) heart rate was 73 (71-74) beats min(-1) in the beta-blockade group, which was significantly lower than the placebo group (mean heart rate 82, P=0.0001). There was no correlation between heart rate and 30 day cardiac complications (P=0.848). The reduction in heart rate was associated with increased drug-associated adverse events (OR 2.53, 95% CI 2.05-3.13, P<0.0001). A major limitation of this analysis may be that postoperative heart rate was not a primary outcome in any of the studies identified and the mean postoperative heart rate achieved may be too high to realize optimal cardioprotection. This meta-analysis cannot confirm that heart rate control with beta-adrenergic blockade is cardioprotective. A randomized controlled trial examining the effect of tight perioperative heart rate control with beta-adrenergic blockade on clinically important outcomes and adverse events is warranted.

  19. GPCR signaling and cardiac function.

    PubMed

    Capote, Leany A; Mendez Perez, Roberto; Lymperopoulos, Anastasios

    2015-09-15

    G protein-coupled receptors (GPCRs), such as β-adrenergic and angiotensin II receptors, located in the membranes of all three major cardiac cell types, i.e. myocytes, fibroblasts and endothelial cells, play crucial roles in regulating cardiac function and morphology. Their importance in cardiac physiology and disease is reflected by the fact that, collectively, they represent the direct targets of over a third of the currently approved cardiovascular drugs used in clinical practice. Over the past few decades, advances in elucidation of their structure, function and the signaling pathways they elicit, specifically in the heart, have led to identification of an increasing number of new molecular targets for heart disease therapy. Here, we review these signaling modalities employed by GPCRs known to be expressed in the cardiac myocyte membranes and to directly modulate cardiac contractility. We also highlight drugs and drug classes that directly target these GPCRs to modulate cardiac function, as well as molecules involved in cardiac GPCR signaling that have the potential of becoming novel drug targets for modulation of cardiac function in the future.

  20. Morphology and neurochemistry of rabbit iris innervation.

    PubMed

    He, Jiucheng; Bazan, Haydee E P

    2015-06-01

    The aim of this study was to map the entire nerve architecture and sensory neuropeptide content of the rabbit iris. Irises from New Zealand rabbits were stained with antibodies against neuronal-class βIII-tubulin, calcitonin gene-related peptide (CGRP) and substance P (SP), and whole-mount images were acquired to build a two-dimensional view of the iridal nerve architecture. After taking images in time-lapse mode, we observed thick nerves running in the iris stroma close to the anterior epithelia, forming four to five stromal nerve rings from the iris periphery to the pupillary margin and sub-branches that connected with each other, constituting the stromal nerve plexus. In the anterior side, fine divisions derivated from the stromal nerves, forming a nerve network-like structure to innervate the superficial anterior border layer, with the pupillary margin having the densest innervation. In the posterior side, the nerve bundles ran along with the pupil dilator muscle in a radial pattern. The morphology of the iris nerves on both sides changed with pupil size. To obtain the relative content of the neuropeptides in the iris, the specimens were double stained with βIII-tubulin and CGRP or SP antibodies. Relative nerve fiber densities for each fiber population were assessed quantitatively by computer-assisted analysis. On the anterior side, CGRP-positive nerve fibers constituted about 61%, while SP-positive nerves constitute about 30.5%, of the total nerve content, which was expressed as βIII tubulin-positive fibers. In addition, in the anterior stroma of the collarette region, there were non-neuronal cells that were positive for SP. On the posterior side, CGRP-positive nerve fibers were about 69% of total nerve content, while SP constituted only up to 20%. Similarly, in the trigeminal ganglia (TG), the number of CGRP-positive neurons significantly outnumbered those that were positive for SP. Also, all the SP-positive neurons were labeled with CGRP. This is the

  1. Morphology and Neurochemistry of Rabbit Iris Innervation

    PubMed Central

    He, Jiucheng; Bazan, Haydee E.P.

    2016-01-01

    The aim of this study was to map the entire nerve architecture and sensory neuropeptide content of the rabbit iris. Irises from New Zealand rabbits were stained with antibodies against neuronal-class βIII-tubulin, calcitonin gene-related peptide (CGRP) and substance P (SP), and whole-mount images were acquired to build a two-dimensional view of the iridal nerve architecture. After taking images in time-lapse mode, we observed thick nerves running in the iris stroma close to the anterior epithelia, forming four to five stromal nerve rings from the iris periphery to the pupillary margin and sub-branches that connected with each other, constituting the stromal nerve plexus. In the anterior side, fine divisions derivated from the stromal nerves, forming a nerve network-like structure to innervate the superficial anterior border layer, with the pupillary margin having the densest innervation. In the posterior side, the nerve bundles ran along with the pupil dilator muscle in a radial pattern. The morphology of the iris nerves on both sides changed with pupil size. To obtain the relative content of the neuropeptides in the iris, the specimens were double stained with βIII-tubulin and CGRP or SP antibodies. Relative nerve fiber densities for each fiber population were assessed quantitatively by computer-assisted analysis. On the anterior side, CGRP-positive nerve fibers constituted about 61%, while SP-positive nerves constitute about 30.5%, of the total nerve content, which was expressed as βIII tubulin-positive fibers. In addition, in the anterior stroma of the collarette region, there were non-neuronal cells that were positive for SP. On the posterior side, CGRP-positive nerve fibers were about 69% of total nerve content, while SP constituted only up to 20%. Similarly, in the trigeminal ganglia (TG), the number of CGRP-positive neurons significantly outnumbered those that were positive for SP. Also, all the SP-positive neurons were labeled with CGRP. This is the

  2. Studies of the interaction of 5-hydroxytryptamine and the perivascular innervation of the guinea-pig caecum

    PubMed Central

    Drakontides, Anna B.; Gershon, Michael D.

    1972-01-01

    1. The action and interaction of noradrenaline (NA), 5-hydroxytryptamine (5-HT) and the sympathetic innervation was studied in the isolated taenia of the guinea-pig caecum. 2. Addition of 5-HT led to a contraction of the taenia while addition of NA or perivascular nerve stimulation resulted in relaxation. Responses to 5-HT or perivascular nerve stimulation were abolished by tetrodotoxin. Tetrodotoxin did not affect responses to applied NA. Hexamethonium and hyoscine converted the 5-HT response to a relaxation and augmented the relaxation which followed low frequency perivascular nerve stimulation. Hexamethonium and hyoscine did not affect the dose-response relationship for NA. 3. Fatigue of mechanical responses of the taenia to perivascular nerve stimulation was accelerated when nerves were stimulated in the presence of 5-HT or α-methyl-p-tyrosine (α-MPT). These two agents were additive in this action. 4. Reserpine, 6-hydroxydopamine and α-MPT all reduced the NA content of the taenia. However, only after 6-hydroxydopamine could adrenergic activity be related to NA content. 5. Segments of taenia were incubated with either tritiated NA or 5-HT. An increased rate of release of radioactivity followed perivascular nerve stimulation after incubation with either substance. This release did not occur when tissue was taken from animals given reserpine or 6-hydroxydopamine. 6. It is concluded that 5-HT activates neural elements exclusively while NA has a direct effect on smooth muscle. 5-HT can apparently be taken up by adrenergic axons, and appears to enter the releasable neurotransmitter pool. Since none of the actions characteristic of 5-HT are seen when it is released by adrenergic axons as a false neurotransmitter, the released amine probably fails to reach neuronal receptors for 5-HT. PMID:4342028

  3. Development of rat tibia innervation: colocalization of autonomic nerve fiber markers with growth-associated protein 43.

    PubMed

    Gajda, Mariusz; Litwin, Jan A; Tabarowski, Zbigniew; Zagólski, Olaf; Cichocki, Tadeusz; Timmermans, Jean-Pierre; Adriaensen, Dirk

    2010-01-01

    Development of autonomic innervation of the tibia was investigated in rat fetuses on gestational days (GD) 17-21 and in juvenile animals on postnatal days (PD) 1-28. Double immunofluorescence combined with confocal microscopy was applied to study colocalization of neuronal growth- associated protein 43 (GAP-43) and panneuronal marker protein gene product 9.5 (PGP) with markers of the autonomic nervous system: neuropeptide Y (NPY) and dopamine beta-hydroxylase (DbetaH) for adrenergic, as well as vasoactive intestinal polypeptide (VIP) and vesicular acetylcholine transporter (VAChT) for cholinergic fibers. The first GAP-43-immunoreactive (GAP-IR) nerve fibers were seen on GD17 in the perichondrium of the proximal epiphysis. Further GAP- and PGP-IR innervation appeared in the perichondrium/periosteum of the diaphysis and in the distal epiphysis (GD19), then in the bone marrow and in the intercondylar eminence (GD21). On PD1, NPY-IR and DbetaH-IR fibers appeared within the diaphyseal periosteum and on PD4 within the bone marrow. From PD14, GAP-43 immunoreactivity of NPY-positive fibers decreased. From PD7 on, NPY-IR fibers were observed in cartilage canals of both epiphyses and in the intercondylar eminence. In secondary ossification centers, NPY-IR fibers were seen from PD10, and in the bone marrow of the epiphyses from PD14. First VIP-IR and VAChT-IR fibers were observed on PD4 within the periosteum, bone marrow and patellar ligament. From PD10 on, VIP-positive fibers were seen in the intercondylar eminence, and from PD14 in secondary ossification centers. GAP-43 proved to be superior to PGP 9.5 as marker of growing nerve fibers, mostly due to its earlier appearance. The presence of specific nerve fibers may suggest possible involvement of autonomic innervation in regulation of bone development.

  4. Innervation of the atrioventricular and semi-lunar heart valves: a review.

    PubMed

    Borin, Christophe; Vanhercke, Daniel; Weyns, Andre

    2006-08-01

    Heart valves were historically considered passive structures that function through the haemodynamic forces created by the contraction and relaxation of the myocardium. However, research into valvular structures has revealed that heart valves are very complex, specialized structures that contain both smooth muscle cells and nerve fibres. This is particularly true for the atrioventricular valves, which are by far the most well studied to date. The various heart valves have been shown to contract independently during different moments of the heart cycle, suggesting that compensatory adaptation mechanisms exist to mediate the timing and efficacy of heart valve closure. These adaptations occur via different mechanisms, including neural mechanisms that influence the heart valves. Accumulating evidence continues to improve our understanding of the nerve fibres in the heart (adrenergic, cholinergic, etc.). Future studies will no doubt add to this exciting picture. Here, we review the current morphological knowledge of human and animal heart valve innervation, including discussions of the chordae tendineae and the papillary muscles, as well as the differences between the atrioventricular (AV) valves and the semi-lunar (SL) valves.

  5. The innervation of the rat cervix and its pharmacology in vitro and in vivo

    PubMed Central

    Hollingsworth, M.

    1974-01-01

    1 Contractions of the rat cervix and uterine horns were measured both in vitro and in vivo as changes in luminal perfusion pressure during perfusion at constant flow. 2 Spontaneous cervical and uterine horn contractions in vitro were reduced from rats pre-treated with 17β-oestradiol compared to those ovariectomized only or those pre-treated with 17β-oestradiol plus progesterone. 3 The rat cervix exhibited similar in vitro sensitivities to methacholine, oxytocin, isoprenaline and phenylephrine as did the uterine horns. 4 Transmural stimulation produced cervical and uterine horn contractions, which were blocked by hyoscine or tetrodotoxin, suggesting a cholinergic motor innervation. This was supported by histological findings. 5 In vivo, the injections of propranolol (1.9 × 10-7 mol/kg) or pempidine (3.2 or 6.4 × 10-6 mol/kg) were followed by large cervical and smaller uterine horn contractions, suggesting an adrenergic inhibitory tone mediated by β-adrenoceptors. 6 The evidence for a cervical sphincter is discussed. ImagesFig. 1 PMID:4455329

  6. Retinal input regulates the timing of corticogeniculate innervation.

    PubMed

    Seabrook, Tania A; El-Danaf, Rana N; Krahe, Thomas E; Fox, Michael A; Guido, William

    2013-06-12

    Neurons in layer VI of visual cortex represent one of the largest sources of nonretinal input to the dorsal lateral geniculate nucleus (dLGN) and play a major role in modulating the gain of thalamic signal transmission. However, little is known about how and when these descending projections arrive and make functional connections with dLGN cells. Here we used a transgenic mouse to visualize corticogeniculate projections to examine the timing of cortical innervation in dLGN. Corticogeniculate innervation occurred at postnatal ages and was delayed compared with the arrival of retinal afferents. Cortical fibers began to enter dLGN at postnatal day 3 (P3) to P4, a time when retinogeniculate innervation is complete. However, cortical projections did not fully innervate dLGN until eye opening (P12), well after the time when retinal inputs from the two eyes segregate to form nonoverlapping eye-specific domains. In vitro thalamic slice recordings revealed that newly arriving cortical axons form functional connections with dLGN cells. However, adult-like responses that exhibited paired pulse facilitation did not fully emerge until 2 weeks of age. Finally, surgical or genetic elimination of retinal input greatly accelerated the rate of corticogeniculate innervation, with axons invading between P2 and P3 and fully innervating dLGN by P8 to P10. However, recordings in genetically deafferented mice showed that corticogeniculate synapses continued to mature at the same rate as controls. These studies suggest that retinal and cortical innervation of dLGN is highly coordinated and that input from retina plays an important role in regulating the rate of corticogeniculate innervation.

  7. Antibodies to beta-adrenergic receptors disclosing agonist-like properties in idiopathic dilated cardiomyopathy and Chagas' heart disease.

    PubMed

    Rosenbaum, M B; Chiale, P A; Schejtman, D; Levin, M; Elizari, M V

    1994-04-01

    Recent studies confirm the existence of antibodies (Abs) to beta-adrenoceptors in patients with idiopathic dilated cardiomyopathy and Chagas' heart disease. These Abs can be shown to exert both stimulatory and inhibitory effects, which may play a role in the development of the cardiac abnormalities known to occur in these diseases, including advanced heart failure. The hypothesis is advanced that Chagas' heart disease and some forms of idiopathic dilated cardiomyopathy may represent, at least partially, a form of "adrenergic cardiomyopathy."

  8. Depression and topical ophthalmic beta adrenergic blockade.

    PubMed

    Bourgeois, J A

    1991-05-01

    Beta adrenergic blocking agents are in widespread use as both systemic and topical medications. While they are safely used in the great majority of cases, several side effects are well known. Central nervous system side effects, specifically depression, can be among the most clinically important of these and must be investigated by the clinician.

  9. Beta adrenergic receptors in human cavernous tissue

    SciTech Connect

    Dhabuwala, C.B.; Ramakrishna, C.V.; Anderson, G.F.

    1985-04-01

    Beta adrenergic receptor binding was performed with /sup 125/I iodocyanopindolol on human cavernous tissue membrane fractions from normal tissue and transsexual procedures obtained postoperatively, as well as from postmortem sources. Isotherm binding studies on normal fresh tissues indicated that the receptor density was 9.1 fmoles/mg. with a KD of 23 pM. Tissue stored at room temperature for 4 to 6 hours, then at 4C in saline solution for 19 to 20 hours before freezing showed no significant changes in receptor density or affinity, and provided evidence for the stability of postmortem tissue obtained within the same time period. Beta receptor density of 2 cavernous preparations from transsexual procedures was not significantly different from normal control tissues, and showed that high concentrations of estrogen received by these patients had no effect on beta adrenergic receptor density. Displacement of /sup 125/iodocyanopindolol by 5 beta adrenergic agents demonstrated that 1-propranolol had the greatest affinity followed by ICI 118,551, zinterol, metoprolol and practolol. When the results of these displacement studies were subjected to Scatfit, non- linear regression line analysis, a single binding site was described. Based on the relative potency of the selective beta adrenergic agents it appears that these receptors were of the beta 2 subtype.

  10. Excitatory GABAA receptor in autonomic pelvic ganglion neurons innervating bladder.

    PubMed

    Kim, Na-Hyun; Cha, Seung-Kuy; Kong, In Deok

    2014-04-25

    Major pelvic ganglia (MPG) are relay centers for autonomic reflexes such as micturition and penile erection. MPG innervate the urogenital system, including bladder. γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system, and may also play an important role in some peripheral autonomic ganglia, including MPG. However, the electrophysiological properties and function of GABAA receptor in MPG neurons innervating bladder remain unknown. This study examined the electrophysiological properties and functional roles of GABAA receptors in bladder-innervating neurons identified by retrograde Dil tracing. Neurons innervating bladder showed previously established parasympathetic properties, including small membrane capacitance, lack of T-type Ca(2+) channel expression, and tyrosine-hydroxylase immunoreactivity. GABAA receptors were functionally expressed in bladder innervating neurons, but GABAC receptors were not. GABA elicited strong depolarization followed by increase of intracellular Ca(2+) in neurons innervating bladder, supporting the hypothesis GABA may play an important role in bladder function. These results provide useful information about the autonomic function of bladder in physiological and pathological conditions. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Beta-Adrenergic blockers as antiarrhythmic and antifibrillatory compounds: an overview.

    PubMed

    Singh, Bramah N

    2005-06-01

    Beta-Adrenergic blockers have a wide spectrum of action for controlling cardiac arrhythmias that is larger than initially thought. Data from the past several decades indicate that, as an antiarrhythmic class, beta-blockers remain among the very few pharmacologic agents that reduce the incidence of sudden cardiac death, prolong survival, and ameliorate symptoms caused by arrhythmias in patients with cardiac disease. As a class of compounds, beta-blockers have a fundamental pharmacologic property that attenuates the effects of competitive adrenergic receptors. However, the net clinical effects of the different beta-receptor blockers may vary quantitatively because of variations in associated intrinsic sympathomimetic agonism and in their intrinsic potency for binding to beta-receptors. These individual compounds also differ in their selectivity for beta(1)- and beta(2)-receptors. Metoprolol is a beta(1)-selective blocker, whereas carvedilol is a nonselective beta(1)- and beta(2)-blocker, an antioxidant, and has a propensity to inhibit alpha(1)-receptors and endothelin. Evolving data from controlled and uncontrolled clinical trials suggest that there are clinically significant differences among this class of drugs. Recent evidence also suggests that the antiarrhythmic actions of certain beta-receptor blockers such as carvedilol and metoprolol extend beyond the ventricular tissue to encompass atrial cells and help maintain sinus rhythm in patients with atrial fibrillation, especially in combination with potent antifibrillatory agents such as amiodarone. This introduction provides a current perspective on these newer developments in the understanding of the antiarrhythmic and antifibrillatory actions of beta-blockers.

  12. THE ROLE OF β-ADRENERGIC RECEPTORS IN HEART FAILURE: DIFFERENTIAL REGULATION OF CARDIOTOXICITY AND CARDIOPROTECTION

    PubMed Central

    Bernstein, Daniel; Fajardo, Giovanni; Zhao, Mingming

    2011-01-01

    β-adrenergic receptor blockers have demonstrated significant survival benefit and have become standard therapy for adults with dilated cardiomyopathy, although their efficacy in pediatric patients is still unproven. Recent data suggests that the two major cardiac β-adrenergic receptor subtypes (β1 and β2) couple differentially to intracellular signaling pathways regulating contractility and remodeling. This has led some to suggest that the β1 receptor is the “cardiotoxic subtype” whereas the β2 receptor is “cardioprotective.” Given this paradigm, there could be situations where subtype selective β-blockade or even subtype selective β-stimulation might be beneficial. However, since most of these studies have been performed in isolated cardiomyocytes, their application to clinical practice is unclear. To better understand the roles of β1- vs. β2-receptors in the pathogenesis of clinical cardiomyopathy, we and others have taken advantage of several well-characterized murine models of cardiovascular disease. These studies demonstrate that β-receptor regulation of the balance between cardioprotection and cardiotoxicity is even more complex than previously appreciated: the role of each β-receptor subtype may vary depending on the specific cardiac stressor involved (e.g. ischemia, pressure overload, genetic mutation, cardiotoxin). Furthermore, the remodeling effects of β-receptor signaling have a temporal component, depending on whether a cardiac stress is acute vs. chronic. PMID:21765627

  13. Fatty old hearts: role of cardiac lipotoxicity in age-related cardiomyopathy

    PubMed Central

    Drosatos, Konstantinos

    2016-01-01

    Age-related cardiomyopathy accounts for a significant part of heart failure cases. Imbalance of the energetic equilibrium of the heart along with mitochondrial dysfunction and impaired β-adrenergic receptor signaling contributes in the aggravation of cardiac function in the elderly. In this review article, studies that correlate cardiac aging with lipotoxicity are summarized. The involvement of inhibition of peroxisome proliferator-activated receptor-α, β-adrenergic receptor desensitization, and mitochondrial dysfunction as underlying mechanisms for the lipid-driven age-related cardiomyopathy are presented with the aim to indicate potential therapeutic targets for cardiac aging. PMID:27558317

  14. Sensory innervation of rat contracture shoulder model.

    PubMed

    Ochiai, Nobuyasu; Ohtori, Seiji; Kenmoku, Tomonori; Yamazaki, Hironori; Ochiai, Satoko; Saisu, Takashi; Matsuki, Keisuke; Takahashi, Kazuhisa

    2013-02-01

    To date, few studies have investigated the cause of pain experienced by patients with frozen shoulder. The purposes of this study were to establish a rat contracture model and clarify the innervation pattern of the glenohumeral (GH) joint and subacromial bursa (SAB) using immunohistochemistry in the dorsal root ganglion (DRG) neurons. The rat contracture models were made by tying the animal's humerus and scapula with No. 2-0 FiberWire (Arthrex, Naples, FL, USA). Contracture was confirmed on x-ray images taken 8 weeks after the operation. Subsequently, two kinds of neurotracers, Fluoro-Gold (FG) (Fluorochrome, Denver, CO, USA) and 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI) (Molecular Probes, Eugene, OR, USA), were used to detect the GH joints and SAB separately. FG tracers were injected into GH joints, and DiI tracers were injected into the SAB. At 7 days after injection, DRGs were harvested between C1 and T1. Immunohistochemistry by use of calcitonin gene-related peptide (CGRP) was performed. CGRP is thought to be one of the causes of pain sensation in joint disease. We evaluated the percentages of FG-labeled CGRP-immunoreactive (CGRP-ir) neurons in the total number of FG-labeled neurons and of DiI-labeled CGRP-ir neurons in the total number of DiI-labeled neurons. Abduction and total arc of the rotation were statistically significantly decreased in the contracture group. Furthermore, the percentage of CGRP-ir DRG neurons was significantly higher in the contracture group in both the GH joint and SAB. These results show that pain sensation in rat shoulder contracture may be induced by the up-regulation of CGRP expression in DRG neurons. Copyright © 2013 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved.

  15. Baroreflex sensitivity is higher during acute psychological stress in healthy subjects under β-adrenergic blockade

    PubMed Central

    Truijen, Jasper; Davis, Shyrin C.A.T.; Stok, Wim J.; Kim, Yu-Sok; van Westerloo, David J.; Levi, Marcel; van der Poll, Tom; Westerhof, Berend E.; Karemaker, John M.; van Lieshout, Johannes J.

    2010-01-01

    Acute psychological stress challenges the cardiovascular system with an increase in BP (blood pressure), HR (heart rate) and reduced BRS (baroreflex sensitivity). β-adrenergic blockade enhances BRS during rest, but its effect on BRS during acute psychological stress is unknown. This study tested the hypothesis that BRS is higher during acute psychological stress in healthy subjects under β-adrenergic blockade. Twenty healthy novice male bungee jumpers were randomized and studied with (PROP, n=10) or without (CTRL, n=10) propranolol. BP and HR responses and BRS [cross-correlation time-domain (BRSTD) and cross-spectral frequency-domain (BRSFD) analysis] were evaluated from 30 min prior up to 2 h after the jump. HR, cardiac output and pulse pressure were lower in the PROP group throughout the study. Prior to the bungee jump, BRS was higher in the PROP group compared with the CTRL group [BRSTD: 28 (24–42) compared with 17 (16–28) ms·mmHg−1, P<0.05; BRSFD: 27 (20–34) compared with 14 (9–19) ms·mmHg−1, P<0.05; values are medians (interquartile range)]. BP declined after the jump in both groups, and post-jump BRS did not differ between the groups. In conclusion, during acute psychological stress, BRS is higher in healthy subjects treated with non-selective β-adrenergic blockade with significantly lower HR but comparable BP. PMID:20828371

  16. Spatial distribution of neurons innervated by chandelier cells.

    PubMed

    Blazquez-Llorca, Lidia; Woodruff, Alan; Inan, Melis; Anderson, Stewart A; Yuste, Rafael; DeFelipe, Javier; Merchan-Perez, Angel

    2015-09-01

    Chandelier (or axo-axonic) cells are a distinct group of GABAergic interneurons that innervate the axon initial segments of pyramidal cells and are thus thought to have an important role in controlling the activity of cortical circuits. To examine the circuit connectivity of chandelier cells (ChCs), we made use of a genetic targeting strategy to label neocortical ChCs in upper layers of juvenile mouse neocortex. We filled individual ChCs with biocytin in living brain slices and reconstructed their axonal arbors from serial semi-thin sections. We also reconstructed the cell somata of pyramidal neurons that were located inside the ChC axonal trees and determined the percentage of pyramidal neurons whose axon initial segments were innervated by ChC terminals. We found that the total percentage of pyramidal neurons that were innervated by a single labeled ChC was 18-22 %. Sholl analysis showed that this percentage peaked at 22-35 % for distances between 30 and 60 µm from the ChC soma, decreasing to lower percentages with increasing distances. We also studied the three-dimensional spatial distribution of the innervated neurons inside the ChC axonal arbor using spatial statistical analysis tools. We found that innervated pyramidal neurons are not distributed at random, but show a clustered distribution, with pockets where almost all cells are innervated and other regions within the ChC axonal tree that receive little or no innervation. Thus, individual ChCs may exert a strong, widespread influence on their local pyramidal neighbors in a spatially heterogeneous fashion.

  17. Innervation changes induced by inflammation of the rat thoracolumbar fascia.

    PubMed

    Hoheisel, U; Rosner, J; Mense, S

    2015-08-06

    Recently, the fascia innervation has become an important issue, particularly the existence of nociceptive fibers. Fascia can be a source of pain in several disorders such as fasciitis and non-specific low back pain. However, nothing is known about possible changes of the fascia innervation under pathological circumstances. This question is important, because theoretically pain from the fascia cannot only be due to increased nociceptor discharges, but also to a denser innervation of the fascia by nociceptive endings. In this histological study, an inflammation was induced in the thoracolumbar fascia (TLF) of rats and the innervation by various fiber types compared between the inflamed and intact TLF. Although the TLF is generally considered to have proprioceptive functions, no corpuscular proprioceptors (Pacini and Ruffini corpuscles) were found. To obtain quantitative data, the length of fibers and free nerve endings were determined in the three layers of the rat TLF: inner layer (IL, adjacent to the multifidus muscle), middle layer (ML) and outer layer (OL). The main results were that the overall innervation density showed little change; however, there were significant changes in some of the layers. The innervation density was significantly decreased in the OL, but this change was partly compensated for by an increase in the IL. The density of substance P (SP)-positive - presumably nociceptive - fibers was significantly increased. In contrast, the postganglionic sympathetic fibers were significantly decreased. In conclusion, the inflamed TLF showed an increase of presumably nociceptive fibers, which may explain the pain from a pathologically altered fascia. The meaning of the decreased innervation by sympathetic fibers is obscure at present. The lack of proprioceptive corpuscular receptors within the TLF does not preclude its role as a proprioceptive structure, because some of the free nerve endings may function as proprioceptors.

  18. Promoting bioengineered tooth innervation using nanostructured and hybrid scaffolds.

    PubMed

    Kuchler-Bopp, S; Larrea, A; Petry, L; Idoux-Gillet, Y; Sebastian, V; Ferrandon, A; Schwinté, P; Arruebo, M; Benkirane-Jessel, N

    2017-03-01

    The innervation of teeth mediated by axons originating from the trigeminal ganglia is essential for their function and protection. Immunosuppressive therapy using Cyclosporine A (CsA) was found to accelerate the innervation of transplanted tissues and particularly that of bioengineered teeth. To avoid the CsA side effects, we report in this study the preparation of CsA loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles, their embedding on polycaprolactone (PCL)-based scaffolds and their possible use as templates for the innervation of bioengineered teeth. This PCL scaffold, approved by the FDA and capable of mimicking the extracellular matrix, was obtained by electrospinning and decorated with CsA-loaded PLGA nanoparticles to allow a local sustained action of this immunosuppressive drug. Dental re-associations were co-implanted with a trigeminal ganglion on functionalized scaffolds containing PLGA and PLGA/cyclosporine in adult ICR mice during 2weeks. Histological analyses showed that the designed scaffolds did not alter the teeth development after in vivo implantation. The study of the innervation of the dental re-associations by indirect immunofluorescence and transmission electron microscopy (TEM), showed that 88.4% of the regenerated teeth were innervated when using the CsA-loaded PLGA scaffold. The development of active implants thus allows their potential use in the context of dental engineering. Tooth innervation is essential for their function and protection and this can be promoted in vivo using polymeric scaffolds functionalized with immunosuppressive drug-loaded nanoparticles. Immunosuppressive therapy using biodegradable nanoparticles loaded with Cyclosporine A was found to accelerate the innervation of bioengineered teeth after two weeks of implantation. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  19. Innervation of extraocular pulley smooth muscle in monkeys and humans.

    PubMed

    Demer, J L; Poukens, V; Miller, J M; Micevych, P

    1997-08-01

    Soft pulleys stabilize paths and determine pulling directions of the extraocular muscles (EOMs). This study was conducted to characterize innervation of smooth muscles (SMs) supporting these pulleys. Cadaveric human and monkey orbits were step and serially sectioned for histochemical and immunohistochemical staining. Before perfusion, the superior cervical ganglia of one monkey had been injected with the anterograde tracer Phaseolus vulgaris leukoagglutinin (PHA-L). Immunoperoxidase staining to human SM alpha-actin confirmed pulley SM. Monoclonal and polyclonal antibodies were used to demonstrate PHA-L, tyrosine hydroxylase, dopamine beta-hydroxylase, phenylethanolamine-N-methyltransferase, neuronal nitric oxide synthase (NOS), and synaptophysin. The NADPH-diaphorase reaction was also used as a marker for NOS and the acetylcholinesterase (AChE) reaction for acetylcholine. Pulleys, consisting of collagen and elastin sleeves supported by connective tissue containing SM, were observed around rectus muscles of humans and monkeys. The human and monkey SM was richly innervated. Axons terminating in motor end plates within SM bundles were immunoreactive to PHA-L, tyrosine hydroxylase, and dopamine beta-hydroxylase, but not phenylethanolamine-N-methyltransferase, indicating innervation of pulley SM from the superior cervical ganglion by projections using norepinephrine. Smaller axons and motor end plates were also demonstrated in SM, using NADPH-diaphorase and NOS immunoreactivity, indicating nitroxidergic innervation, and using AchE, indicating cholinergic parasympathetic innervation. The pterygopalatine and, to a lesser extent, the ciliary ganglia, but not the Edinger-Westphal nucleus, contained cells immunoreactive to NOS, suggesting that nitroxidergic innervation to pulley SM is mainly from the pterygopalatine ganglion. The SM suspensions of human and monkey EOM pulleys are similar and receive rich innervation involving multiple neurotransmitters. These complex

  20. Immunomodulation Stimulates the Innervation of Engineered Tooth Organ

    PubMed Central

    Kökten, Tunay; Bécavin, Thibault; Keller, Laetitia; Weickert, Jean-Luc; Kuchler-Bopp, Sabine; Lesot, Hervé

    2014-01-01

    The sensory innervation of the dental mesenchyme is essential for tooth function and protection. Sensory innervation of the dental pulp is mediated by axons originating from the trigeminal ganglia and is strictly regulated in time. Teeth can develop from cultured re-associations between dissociated dental epithelial and mesenchymal cells from Embryonic Day 14 mouse molars, after implantation under the skin of adult ICR mice. In these conditions however, the innervation of the dental mesenchyme did not occur spontaneously. In order to go further with this question, complementary experimental approaches were designed. Cultured cell re-associations were implanted together with trigeminal ganglia for one or two weeks. Although axonal growth was regularly observed extending from the trigeminal ganglia to all around the forming teeth, the presence of axons in the dental mesenchyme was detected in less than 2.5% of samples after two weeks, demonstrating a specific impairment of their entering the dental mesenchyme. In clinical context, immunosuppressive therapy using cyclosporin A was found to accelerate the innervation of transplanted tissues. Indeed, when cultured cell re-associations and trigeminal ganglia were co-implanted in cyclosporin A-treated ICR mice, nerve fibers were detected in the dental pulp, even reaching odontoblasts after one week. However, cyclosporin A shows multiple effects, including direct ones on nerve growth. To test whether there may be a direct functional relationship between immunomodulation and innervation, cell re-associations and trigeminal ganglia were co-implanted in immunocompromised Nude mice. In these conditions as well, the innervation of the dental mesenchyme was observed already after one week of implantation, but axons reached the odontoblast layer after two weeks only. This study demonstrated that immunodepression per se does stimulate the innervation of the dental mesenchyme. PMID:24465840

  1. Intrinsic cardiac neurons involved in cardiac regulation possess alpha 1-, alpha 2-, beta 1- and beta 2-adrenoceptors.

    PubMed

    Armour, J A

    1997-03-01

    To determine whether intrinsic cardiac neurons involved in cardiac regulation possess alpha 1-, alpha 2-, beta 1-, or beta 2-adrenoceptors. The alpha1-adrenoceptor agonist phenylephrine, the alpha 2-adrenoceptor agonist clonidine, the beta 1-adrenoceptor agonist prenaterol and the beta 2-adrenoceptor agonist terbutaline were administered individually to a population of spontaneously active intrinsic cardiac neurons either locally (10 microL of 100 microM solution; eight dogs) or via the local arterial blood supply (0.1 mL of 100 microM solution; 20 dogs) in artificially ventilated, open chest anesthetized dogs. Neuronal and cardiac effects induced by each of the adrenergic agonists were also tested in the presence of an antagonist selective to each adrenoceptor subtype studied. The activity of intrinsic cardiac neurons was modified by at least one of the adrenoceptor agonists tested, and 34% of the spontaneously active neurons were affected by all four agonists. Alpha-adrenoceptor agonists either increased or decreased neuronal activity, depending on the population of neurons studied. On the other hand, the activity generated by intrinsic cardiac neurons was augmented by beta-adrenoceptor agonists. Ventricular contractile force increased when intrinsic cardiac neurons were excited by adrenoceptor agonists. The spontaneous activity generated by neurons was suppressed by beta-adrenoceptor, but not alpha-adrenoceptor, blockade. Neuronal and cardiovascular responses were no longer elicited by an agonist in the presence of its selective antagonist; they were elicited in the presence of antagonists to the other receptor subtypes studied. Intrinsic cardiac neurons involved in cardiac regulation possess alpha 1-, alpha 2-, beta 1- or beta 2-adrenoceptors. Intrinsic cardiac adrenergic neurons receive tonic inputs via beta-, but not alpha-, adrenoceptors. These data indicate that adrenergic blockade may affect cardiac function, in part, via modification of the intrinsic

  2. [Localization of efferent sympathetic neurons and afferent neurons in dorsal root ganglia innervating the heart].

    PubMed

    Fateev, M M; Zaikina, M G

    1989-01-01

    The retrograde transport of horseradish peroxidase (HRP) has been used to study the localization and the number of neurons innervating the heart in the right stellate ganglion and accessory cervical ganglion, spinal cord and dorsal root ganglia of the cat. HRP was applied to the central cuts of anastomose of the stellate ganglion with the vagal nerve, of the vagosympathetic trunk caudal to anastomose and of the inferior cardiac nerve. HRP-labelled neurons were detected in the stellate ganglion in the regions which give off nerves, whereas in the accessory cervical ganglion labelled neurons were distributed throughout the whole ganglion. HRP-stained cells were found in the anastomose. In the spinal cord labelled neurons were detected in the lateral horn of T1-T5 segments. In the dorsal root ganglion the greatest number of neurons was observed in T2-T4 segments.

  3. Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias

    PubMed Central

    Jungen, Christiane; Scherschel, Katharina; Eickholt, Christian; Kuklik, Pawel; Klatt, Niklas; Bork, Nadja; Salzbrunn, Tim; Alken, Fares; Angendohr, Stephan; Klene, Christiane; Mester, Janos; Klöcker, Nikolaj; Veldkamp, Marieke W.; Schumacher, Udo; Willems, Stephan; Nikolaev, Viacheslav O.; Meyer, Christian

    2017-01-01

    The parasympathetic nervous system plays an important role in the pathophysiology of atrial fibrillation. Catheter ablation, a minimally invasive procedure deactivating abnormal firing cardiac tissue, is increasingly becoming the therapy of choice for atrial fibrillation. This is inevitably associated with the obliteration of cardiac cholinergic neurons. However, the impact on ventricular electrophysiology is unclear. Here we show that cardiac cholinergic neurons modulate ventricular electrophysiology. Mechanical disruption or pharmacological blockade of parasympathetic innervation shortens ventricular refractory periods, increases the incidence of ventricular arrhythmia and decreases ventricular cAMP levels in murine hearts. Immunohistochemistry confirmed ventricular cholinergic innervation, revealing parasympathetic fibres running from the atria to the ventricles parallel to sympathetic fibres. In humans, catheter ablation of atrial fibrillation, which is accompanied by accidental parasympathetic and concomitant sympathetic denervation, raises the burden of premature ventricular complexes. In summary, our results demonstrate an influence of cardiac cholinergic neurons on the regulation of ventricular function and arrhythmogenesis. PMID:28128201

  4. Cardiac Effects of Attenuating Gsα - Dependent Signaling

    PubMed Central

    Meyer, Sören; Ochs, Marco M.; Hagenmueller, Marco; Riffel, Johannes H.; Buss, Sebastian J.; Heger, Thomas; Katus, Hugo A.; Hardt, Stefan E.

    2016-01-01

    Aims Inhibition of β-adrenergic signalling plays a key role in treatment of heart failure. Gsα is essential for β-adrenergic signal transduction. In order to reduce side-effects of beta-adrenergic inhibition diminishing β-adrenergic signalling in the heart at the level of Gsα is a promising option. Methods and Results We analyzed the influence of Gsα on regulation of myocardial function and development of cardiac hypertrophy, using a transgenic mouse model (C57BL6/J mice) overexpressing a dominant negative Gsα-mutant under control of the α-MHC-promotor. Cardiac phenotype was characterized in vivo and in vitro and under acute and chronic β-adrenergic stimulation. At rest, Gsα-DN-mice showed bradycardia (602 ± 13 vs. 660 ± 17 bpm, p<0.05) and decreased dp/dtmax (5037 ± 546- vs. 6835 ± 505 mmHg/s, p = 0.02). No significant differences were found regarding ejection fraction, heart weight and cardiomyocyte size. β-blockade by propranolol revealed no baseline differences of hemodynamic parameters between wildtype and Gsα-DN-mice. Acute adrenergic stimulation resulted in decreased β-adrenergic responsiveness in Gsα-DN-mice. Under chronic adrenergic stimulation, wildtype mice developed myocardial hypertrophy associated with increase of LV/BW-ratio by 23% (4.4 ± 0.2 vs. 3.5 ± 0.1 mg/g, p<0.01) and cardiac myocyte size by 24% (14927 ± 442 px vs. 12013 ± 583 px, p<0.001). In contrast, both parameters were unchanged in Gsα-DN-mice after chronic isoproterenol stimulation. Conclusion Overexpression of a dominant negative mutant of Gsα leads to decreased β-adrenergic responsiveness and is protective against isoproterenol-induced hypertrophy. Thus, Gsα-DN-mice provide novel insights into β-adrenergic signal transduction and its modulation in myocardial overload and failure. PMID:26811901

  5. GIPC interacts with the beta1-adrenergic receptor and regulates beta1-adrenergic receptor-mediated ERK activation.

    PubMed

    Hu, Liaoyuan A; Chen, Wei; Martin, Negin P; Whalen, Erin J; Premont, Richard T; Lefkowitz, Robert J

    2003-07-11

    Beta1-adrenergic receptors, expressed at high levels in the human heart, have a carboxyl-terminal ESKV motif that can directly interact with PDZ domain-containing proteins. Using the beta1-adrenergic receptor carboxyl terminus as bait, we identified the novel beta1-adrenergic receptor-binding partner GIPC in a yeast two-hybrid screen of a human heart cDNA library. Here we demonstrate that the PDZ domain-containing protein, GIPC, co-immunoprecipitates with the beta1-adrenergic receptor in COS-7 cells. Essential for this interaction is the Ser residue of the beta1-adrenergic receptor carboxyl-terminal ESKV motif. Our data also demonstrate that beta1-adrenergic receptor stimulation activates the mitogen-activated protein kinase, ERK1/2. beta1-adrenergic receptor-mediated ERK1/2 activation was inhibited by pertussis toxin, implicating Gi, and was substantially decreased by the expression of GIPC. Expression of GIPC had no observable effect on beta1-adrenergic receptor sequestration or receptor-mediated cAMP accumulation. This GIPC effect was specific for the beta1-adrenergic receptor and was dependent on an intact PDZ binding motif. These data suggest that GIPC can regulate beta1-adrenergic receptor-stimulated, Gi-mediated, ERK activation while having no effect on receptor internalization or Gs-mediated cAMP signaling.

  6. Human myometrial adrenergic receptors: identification of the beta-adrenergic receptor by (/sup 3/H)dihydroalprenolol binding

    SciTech Connect

    Hayashida, D.N.; Leung, R.; Goldfien, A.; Roberts, J.M.

    1982-02-15

    The radioactive beta-adrenergic antagonist (/sup 3/H) dihydroalprenolol (DHA) binds to particulate preparations of human myometrium in a manner compatible with binding to the beta-adrenergic receptor. The binding of DHA is rapid (attaining equilibrium in 12 minutes), readily reversible (half time = 16 minutes), high affinity (K/sub D/ = 0.50 nM), low capacity (Bmax = 70 fmoles/mg of protein), and stereoselective ((-)-propranolol is 100 times as potent as (+) -propranolol in inhibiting DHA binding). Adrenergic agonists competed for DHA binding sites in a manner compatible with beta-adrenergic interactions and mirrored ..beta../sub 2/ pharmacologic potencies: isoproterenol > epinephrine >> norepinephrine. Studies in which zinterol, a ..beta../sub 2/-adrenergic agonist, competed for DHA binding sites in human myometrial particulate indicated that at least 87% of the beta-adrenergic receptors present are ..beta../sub 2/-adrenergic receptors. Binding of DHA to human myometrial beta-adrenergic receptors provides a tool which may be used in the examination of gonadal hormonal modification of adrenergic response in human uterus as well as in the analysis of beta-adrenergic agents as potentially useful tocolytic agents.

  7. Successful Implantation of Bioengineered, Intrinsically Innervated, Human Internal Anal Sphincter

    PubMed Central

    Raghavan, Shreya; Gilmont, Robert R.; Miyasaka, Eiichi A.; Somara, Sita; Srinivasan, Shanthi; Teitelbaum, Daniel H; Bitar, Khalil N.

    2011-01-01

    Background & Aims To restore fecal continence, the weakened pressure of the internal anal sphincter (IAS) must be increased. We bioengineered intrinsically innervated human IAS, to emulate sphincteric physiology, in vitro. Methods We co-cultured human IAS circular smooth muscle with immortomouse fetal enteric neurons. We investigated the ability of bioengineered innervated human IAS, implanted in RAG1−/− mice, to undergo neovascularization and preserve the physiology of the constituent myogenic and neuronal components. Results The implanted IAS was neovascularized in vivo; numerous blood vessels were observed with no signs of inflammation or infection. Real-time force acquisition from implanted and pre-implant IAS showed distinct characteristics of IAS physiology. Features included the development of spontaneous myogenic basal tone; relaxation of 100% of basal tone in response to inhibitory neurotransmitter vasoactive intestinal peptide (VIP) and direct electrical field stimulation of the intrinsic innervation; inhibition of nitrergic and VIPergic EFS-induced relaxation (by antagonizing nitric oxide synthesis or receptor interaction); contraction in response to cholinergic stimulation with acetylcholine; and intact electromechanical coupling (evidenced by direct response to potassium chloride). Implanted, intrinsically innervated bioengineered human IAS tissue preserved the integrity and physiology of myogenic and neuronal components. Conclusion Intrinsically innervated human IAS bioengineered tissue can be successfully implanted in mice. This approach might be used to treat patients with fecal incontinence. PMID:21463628

  8. Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration.

    PubMed

    Wang, E R; Jarrah, A A; Benard, L; Chen, J; Schwarzkopf, M; Hadri, L; Tarzami, S T

    2014-05-01

    Altered alpha- and beta-adrenergic receptor signaling is associated with cardiac hypertrophy and failure. Stromal cell-derived factor-1α (SDF-1α) and its cognate receptor CXCR4 have been reported to mediate cardioprotection after injury through the mobilization of stem cells into injured tissue. However, little is known regarding whether SDF-1/CXCR4 induces acute protection following pathological hypertrophy and if so, by what molecular mechanism. We have previously reported that CXCR4 physically interacts with the beta-2 adrenergic receptor and modulates its downstream signaling. Here we have shown that CXCR4 expression prevents beta-adrenergic receptor-induced hypertrophy. Cardiac beta-adrenergic receptors were stimulated with the implantation of a subcutaneous osmotic pump administrating isoproterenol and CXCR4 expression was selectively abrogated in cardiomyocytes using Cre-loxP-mediated gene recombination. CXCR4 knockout mice showed worsened fractional shortening and ejection fraction. CXCR4 ablation increased susceptibility to isoproterenol-induced heart failure, by upregulating apoptotic markers and reducing mitochondrial function; cardiac function decreases whereas fibrosis increases. In addition, CXCR4 expression was rescued with the use of cardiotropic adeno-associated viral-9 vectors. CXCR4 gene transfer reduced cardiac apoptotic signaling, improved mitochondrial function and resulted in a recovered cardiac function. Our results represent the first evidence that SDF-1/CXCR4 signaling mediates acute cardioprotection through modulating beta-adrenergic receptor signaling in vivo.

  9. Decreased Autophagy in Rat Heart Induced by Anti-β1-Adrenergic Receptor Autoantibodies Contributes to the Decline in Mitochondrial Membrane Potential

    PubMed Central

    Hao, Haihu; Li, Xiaoyu; Wang, Jie; Wang, Ke; Wang, Jin; Yan, Zi; Zhang, Suli; Du, Yunhui; Liu, Huirong

    2013-01-01

    It has been recognized that changes in mitochondrial structure plays a key role in development of cardiac dysfunction, and autophagy has been shown to exert maintenance of mitochondrial homeostasis effects. Our previous study found that anti-β1-adrenergic receptor autoantibodies (β1-AABs) could lead to cardiac dysfunction along with abnormalities in mitochondrial structure. The present study tested the hypothesis that β1-AABs may induce the decline in mitochondrial membrane potential (ΔΨm) by suppression of cardiac autophagy, which contributed to cardiac dysfunction. Male adult rats were randomized to receive a vehicle or peptide corresponding to the second extracellular loop of the β1 adrenergic receptor (β1-AAB group, 0.4 μg/g every two weeks for 12 weeks) and treated with rapamycin (RAPA, an autophagy agonist) at 5 mg/kg/day for two days before detection. At the 4th week, 8th week and 12th week of active immunization, the rats were sacrificed and cardiac function and the levels of cardiac LC3 and Beclin-1 were detected. ΔΨm in cardiac myocytes was determined by myocardial radionuclide imaging technology and JC-1 staining. In the present study, β1-AABs caused cardiac dysfunction, reduced ΔΨm and decreased cardiac autophagy. Treatment with RAPA markedly attenuated β1-AABs-induced cardiac injury evidenced by recovered ΔΨm. Taken together, these results suggested that β1-AABs exerted significant decreased ΔΨm, which may contribute to cardiac dysfunction, most likely by decreasing cardiac autophagy in vivo. Moreover, myocardial radionuclide imaging technology may be needed to assess the risk in developing cardiac dysfunction for the people who have β1-AABs in their blood. PMID:24278413

  10. Prevention of ventricular fibrillation, acute myocardial infarction (myocardial necrosis), heart failure, and mortality by bretylium: is ischemic heart disease primarily adrenergic cardiovascular disease?

    PubMed

    Bacaner, Marvin; Brietenbucher, James; LaBree, John

    2004-01-01

    It is widely, but mistakenly, believed that ischemic heart disease (IsHD) and its complications are the sole and direct result of reduced coronary blood flow by obstructive coronary artery disease (CAD). However, cardiac angina, acute myocardial infarction (AMI), and sudden cardiac death (SCD) occur in 15%-20% of patients with anatomically unobstructed and grossly normal coronaries. Moreover, severe obstructive coronary disease often occurs without associated pathologic myocardiopathy or prior symptoms, ie, unexpected sudden death, silent myocardial infarction, or the insidious appearance of congestive heart failure (CHF). The fact that catecholamines explosively augment oxidative metabolism much more than cardiac work is generally underappreciated. Thus, adrenergic actions alone are likely to be more prone to cause cardiac ischemia than reduced coronary blood flow per se. The autonomic etiology of IsHD raises contradictions to the traditional concept of anatomically obstructive CAD as the lone cause of cardiac ischemia and AMI. Actually, all the signs and symptoms of IsHD reflect autonomic nervous system imbalance, particularly adrenergic hyperactivity, which may by itself cause ischemia as in rest angina. Adrenergic activity causing ischemia signals cardiac pain to pain centers via sympathetic efferent pathways and tend to induce arrhythmogenic and necrotizing ischemic actions on the cardiovascular system. This may result in ischemia induced metabolic myocardiopathy not unlike that caused by anatomic or spasmogenic coronary obstruction. The clinical study and review presented herein suggest that adrenergic hyperactivity alone without CAD can be a primary cause of IsHD. Thus, adrenergic heart disease (AdHD), or actually adrenergic cardiovascular heart disease (ACVHD), appears to be a distinct entity, most commonly but not necessarily occurring in parallel with CAD. CAD certainly contributes to vulnerability as well as the progression of IsHD. This vicious cycle

  11. Hypoxia increases exercise heart rate despite combined inhibition of β-adrenergic and muscarinic receptors.

    PubMed

    Siebenmann, C; Rasmussen, P; Sørensen, H; Bonne, T C; Zaar, M; Aachmann-Andersen, N J; Nordsborg, N B; Secher, N H; Lundby, C

    2015-06-15

    Hypoxia increases the heart rate response to exercise, but the mechanism(s) remains unclear. We tested the hypothesis that the tachycardic effect of hypoxia persists during separate, but not combined, inhibition of β-adrenergic and muscarinic receptors. Nine subjects performed incremental exercise to exhaustion in normoxia and hypoxia (fraction of inspired O2 = 12%) after intravenous administration of 1) no drugs (Cont), 2) propranolol (Prop), 3) glycopyrrolate (Glyc), or 4) Prop + Glyc. HR increased with exercise in all drug conditions (P < 0.001) but was always higher at a given workload in hypoxia than normoxia (P < 0.001). Averaged over all workloads, the difference between hypoxia and normoxia was 19.8 ± 13.8 beats/min during Cont and similar (17.2 ± 7.7 beats/min, P = 0.95) during Prop but smaller (P < 0.001) during Glyc and Prop + Glyc (9.8 ± 9.6 and 8.1 ± 7.6 beats/min, respectively). Cardiac output was enhanced by hypoxia (P < 0.002) to an extent that was similar between Cont, Glyc, and Prop + Glyc (2.3 ± 1.9, 1.7 ± 1.8, and 2.3 ± 1.2 l/min, respectively, P > 0.4) but larger during Prop (3.4 ± 1.6 l/min, P = 0.004). Our results demonstrate that the tachycardic effect of hypoxia during exercise partially relies on vagal withdrawal. Conversely, sympathoexcitation either does not contribute or increases heart rate through mechanisms other than β-adrenergic transmission. A potential candidate is α-adrenergic transmission, which could also explain why a tachycardic effect of hypoxia persists during combined β-adrenergic and muscarinic receptor inhibition. Copyright © 2015 the American Physiological Society.

  12. β3-Adrenergic receptor antagonist improves exercise performance in pacing-induced heart failure

    PubMed Central

    Masutani, Satoshi; Cheng, Heng-Jie; Morimoto, Atsushi; Hasegawa, Hiroshi; Han, Qing-Hua; Little, William C.

    2013-01-01

    In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise. We have previously shown that in HF at rest stimulation of β3-adrenergic receptors by endogenous catecholamine depresses LV contraction and relaxation. β3-Adrenergic receptors are activated at higher concentrations of catecholamine. Thus exercise may cause increased stimulation of cardiac β3-adrenergic receptors and contribute to this abnormal response. We assessed the effect of L-748,337 (50 μg/kg iv), a selective β3-adrenergic receptor antagonist (β3-ANT), on LV dynamics during exercise in 12 chronically instrumented dogs with pacing-induced HF. Compared with HF at rest, exercise increased LV end-systolic pressure (PES), minimum LV pressure (LVPmin), and the time constant of LV relaxation (τ) with an upward shift of early diastolic portion of LV pressure-volume loop. LV contractility decreased and arterial elastance (EA) increased. LV arterial coupling (EES/EA) (0.40 vs. 0.51) was impaired. Compared with exercise in HF preparation, exercise after β3-ANT caused similar increases in heart rate and PES but significantly decreased τ (34.9 vs. 38.3 ms) and LVPmin with a downward shift of the early diastolic portion of LV pressure-volume loop and further augmented dV/dtmax. Both EES and EES/EA (0.68 vs. 0.40) were increased. LV mechanical efficiency improved from 0.39 to 0.53. In conclusion, after HF, β3-ANT improves LV diastolic filling; increases LV contractility, LV arterial coupling, and mechanical efficiency; and improves exercise performance. PMID:23873794

  13. Adrenergic, coagulation, and fibrinolytic responses to heat.

    PubMed

    Britton, B J; Hawkey, C; Wood, W G; Peele, M; Kaye, J; Irving, M H

    1974-10-19

    Two groups of volunteers were exposed to heat in a sauna bath-one group for 10 minutes and the other for 15. There was no change in plasma adrenaline concentration until the subjects emerged from the sauna bath, when there was a slight increase in concentration. Factor VIII and thrombo-elastograph patterns did not change but marked activation of fibrinolysis was stimulated by exposure to heat. These findings support the concept that fibrinolysis is not mediated by direct adrenergic activity.

  14. The influence of adrenergic stimulation on sex differences in left ventricular twist mechanics.

    PubMed

    Williams, Alexandra M; Shave, Rob E; Cheyne, William S; Eves, Neil D

    2017-06-15

    Sex differences in left ventricular (LV) mechanics occur during acute physiological challenges; however, it is unknown whether sex differences in LV mechanics are fundamentally regulated by differences in adrenergic control. Using two-dimensional echocardiography and speckle tracking analysis, this study compared LV mechanics in males and females matched for LV length during post-exercise ischaemia (PEI) and β1 -adrenergic receptor blockade. Our data demonstrate that while basal rotation was increased in males, LV twist was not significantly different between the sexes during PEI. In contrast, during β1 -adrenergic receptor blockade, LV apical rotation, twist and untwisting velocity were reduced in males compared to females. Significant relationships were observed between LV twist and LV internal diameter and sphericity index in females, but not males. These findings suggest that LV twist mechanics may be more sensitive to alterations in adrenergic stimulation in males, but more highly influenced by ventricular structure and geometry in females. Sex differences in left ventricular (LV) mechanics exist at rest and during acute physiological stress. Differences in cardiac autonomic and adrenergic control may contribute to sex differences in LV mechanics and LV haemodynamics. Accordingly, this study aimed to investigate sex differences in LV mechanics with altered adrenergic stimulation achieved through post-handgrip-exercise ischaemia (PEI) and β1 -adrenergic receptor (AR) blockade. Twenty males (23 ± 5 years) and 20 females (22 ± 3 years) were specifically matched for LV length (males: 8.5 ± 0.5 cm, females: 8.2 ± 0.6 cm, P = 0.163), and two-dimensional speckle-tracking echocardiography was used to assess LV structure and function at baseline, during PEI and following administration of 5 mg bisoprolol (β1 -AR antagonist). During PEI, LV end-diastolic volume and stroke volume were increased in both groups (P < 0.001), as was end-systolic wall

  15. Neuroprotection by Alpha 2-Adrenergic Agonists in Cerebral Ischemia

    PubMed Central

    Zhang, Yonghua; Kimelberg, Harold K.

    2005-01-01

    Ischemic brain injury is implicated in the pathophysiology of stroke and brain trauma, which are among the top killers worldwide, and intensive studies have been performed to reduce neural cell death after cerebral ischemia. Alpha 2-adrenergic agonists have been shown to improve the histomorphological and neurological outcome after cerebral ischemic injury when administered during ischemia, and recent studies have provided considerable evidence that alpha 2-adrenergic agonists can protect the brain from ischemia/reperfusion injury. Thus, alpha 2-adrenergic agonists are promising potential drugs in preventing cerebral ischemic injury, but the mechanisms by which alpha 2-adrenergic agonists exert their neuroprotective effect are unclear. Activation of both the alpha 2-adrenergic receptor and imidazoline receptor may be involved. This mini review examines the recent progress in alpha 2-adrenergic agonists - induced neuroprotection and its proposed mechanisms in cerebral ischemic injury. PMID:18369397

  16. Orphan nuclear receptor Nur77 affects cardiomyocyte calcium homeostasis and adverse cardiac remodelling.

    PubMed

    Medzikovic, Lejla; Schumacher, Cees A; Verkerk, Arie O; van Deel, Elza D; Wolswinkel, Rianne; van der Made, Ingeborg; Bleeker, Natascha; Cakici, Daniella; van den Hoogenhof, Maarten M G; Meggouh, Farid; Creemers, Esther E; Remme, Carol Ann; Baartscheer, Antonius; de Winter, Robbert J; de Vries, Carlie J M; Arkenbout, E Karin; de Waard, Vivian

    2015-10-21

    Distinct stressors may induce heart failure. As compensation, β-adrenergic stimulation enhances myocardial contractility by elevating cardiomyocyte intracellular Ca(2+) ([Ca(2+)]i). However, chronic β-adrenergic stimulation promotes adverse cardiac remodelling. Cardiac expression of nuclear receptor Nur77 is enhanced by β-adrenergic stimulation, but its role in cardiac remodelling is still unclear. We show high and rapid Nur77 upregulation in cardiomyocytes stimulated with β-adrenergic agonist isoproterenol. Nur77 knockdown in culture resulted in hypertrophic cardiomyocytes. Ventricular cardiomyocytes from Nur77-deficient (Nur77-KO) mice exhibited elevated diastolic and systolic [Ca(2+)]i and prolonged action potentials compared to wild type (WT). In vivo, these differences resulted in larger cardiomyocytes, increased expression of hypertrophic genes, and more cardiac fibrosis in Nur77-KO mice upon chronic isoproterenol stimulation. In line with the observed elevated [Ca(2+)]i, Ca(2+)-activated phosphatase calcineurin was more active in Nur77-KO mice compared to WT. In contrast, after cardiac pressure overload by aortic constriction, Nur77-KO mice exhibited attenuated remodelling compared to WT. Concluding, Nur77-deficiency results in significantly altered cardiac Ca(2+) homeostasis and distinct remodelling outcome depending on the type of insult. Detailed knowledge on the role of Nur77 in maintaining cardiomyocyte Ca(2+) homeostasis and the dual role Nur77 plays in cardiac remodelling will aid in developing personalized therapies against heart failure.

  17. Sex differences in alpha-adrenergic support of blood pressure.

    PubMed

    Schmitt, Judith A M; Joyner, Michael J; Charkoudian, Nisha; Wallin, B Gunnar; Hart, Emma C

    2010-08-01

    We tested whether the inter-individual variability in alpha-adrenergic support of blood pressure plays a critical role in the sex differences in tonic support of blood pressure by the autonomic nervous system. Blockade of the alpha-adrenergic receptors was achieved via phentolamine and showed a smaller (P < 0.05) decrease in blood pressure in women compared to men, implying that alpha-adrenergic support of blood pressure is less in women than in men.

  18. Release of acetylcholine by chick embryo heart before innervation

    PubMed Central

    Coraboeuf, E.; Le Douarin, G.; Obrecht-Coutris, G.

    1970-01-01

    1. In chick embryo hearts, 3-day-old and not yet innervated, repetitive direct stimulation causes a transitory inhibition of the spontaneous rhythm. 2. The degree of post-stimulation inhibition depends on the frequency and duration of the artificial stimulation and on the concentration of K and Ca ions in the extracellular solution. 3. After treatment with atropine (10-5 g/ml.) post-stimulation inhibition is no longer observed. The spontaneous rhythm is accelerated by atropine. The findings therefore suggest that an ACh-like substance is released from the non-innervated embryonic heart during activity. 4. By use of the dorsal muscle of the leech for biological assay the liberation of an ACh-like substance from the non-innervated embryonic heart was confirmed. ImagesPlate 1 PMID:5498489

  19. The Lesser Palatine Nerve Innervates the Levator Veli Palatini Muscle

    PubMed Central

    Matsuura, Yoshitaka; Kawai, Katsuya; Yamada, Shigehito; Suzuki, Shigehiko

    2016-01-01

    Summary: When the lesser palatine nerve (LPN) is supposed to be a branch of the trigeminal nerve and innervate sensation of the soft palate, whether the LPN contains motor fibers is unclear. In this study, we monitored the electromyogram of the levator veli palatini (LVP) muscle on stimulating the LPN during palatoplasty in 3 patients. The electromyogram of the muscles showed the myogenic potential induced by electrostimulation of the LPN. Taken together with the finding from our previous anatomical study that the motor fibers come from the facial nerve, this result supports the double innervation theory of the LVP, which posits that both the pharyngeal plexus and the facial nerve innervate it. Identifying and preserving the LPN during palatoplasty might improve postoperative speech results. PMID:27757354

  20. The innervation of the zebrafish pharyngeal jaws and teeth

    PubMed Central

    Crucke, Jeroen; Van de Kelft, Annelore; Huysseune, Ann

    2015-01-01

    Zebrafish ( Danio rerio) teeth are increasingly used as a model to study odontogenesis in non-mammalians. Using serial semi-thin section histology and immunohistochemistry, the nerves innervating the pharyngeal jaws and teeth have been identified. The last pair of branchial arches, which are non-gill bearing but which carry the teeth, are innervated by an internal branch of a post-trematic ramus of the vagal nerve. Another, external, branch is probably responsible for the motor innervation of the branchiomeric musculature. Nerve fibres appear in the pulp cavity of the teeth only late during cytodifferentiation, and are therefore likely not involved in early steps of tooth formation. The precise role of the nervous system during continuous tooth replacement remains to be determined. Nonetheless, this study provides the necessary morphological background information to address this question. PMID:26018453

  1. Improved myocardial beta-adrenergic responsiveness and signaling with exercise training in hypertension.

    PubMed

    MacDonnell, Scott M; Kubo, Hajime; Crabbe, Deborah L; Renna, Brian F; Reger, Patricia O; Mohara, Jun; Smithwick, L Ashley; Koch, Walter J; Houser, Steven R; Libonati, Joseph R

    2005-06-28

    Cardiac responses to beta-adrenergic receptor stimulation are depressed with pressure overload-induced cardiac hypertrophy. We investigated whether exercise training could modify beta-adrenergic receptor responsiveness in a model of spontaneous hypertension by modifying the beta-adrenergic receptor desensitizing kinase GRK2 and the abundance and phosphorylation of some key Ca2+ cycling proteins. Female spontaneously hypertensive rats (SHR; age, 4 months) were placed into a treadmill running (SHR-TRD; 20 m/min, 1 h/d, 5 d/wk, 12 weeks) or sedentary group (SHR-SED). Age-matched Wistar Kyoto (WKY) rats were controls. Mean blood pressure was higher in SHR versus WKY (P<0.01) and unaltered with exercise. Left ventricular (LV) diastolic anterior and posterior wall thicknesses were greater in SHR than WKY (P<0.001) and augmented with training (P<0.01). Langendorff LV performance was examined during isoproterenol (ISO) infusions (1x10(-10) to 1x10(-7) mol/L) and pacing stress (8.5 Hz). The peak LV developed pressure/ISO dose response was shifted rightward 100-fold in SHR relative to WKY. The peak ISO LV developed pressure response was similar between WKY and SHR-SED and increased in SHR-TRD (P<0.05). SHR-TRD showed the greatest lusitropic response to ISO (P<0.05) and offset the pacing-induced increase in LV end-diastolic pressure and the time constant of isovolumic relaxation (tau) observed in WKY and SHR-SED. Improved cardiac responses to ISO in SHR-TRD were associated with normalized myocardial levels of GRK2 (P<0.05). SHR displayed increased L-type Ca2+ channel and sodium calcium exchanger abundance compared with WKY (P<0.001). Training increased ryanodine receptor phosphorylation and phospholamban phosphorylation at both the Ser16 and Thr17 residues (P<0.05). Exercise training in hypertension improves the inotropic and lusitropic responsiveness to beta-adrenergic receptor stimulation despite augmenting LV wall thickness. A lower GRK2 abundance and an increased

  2. Remodelling sympathetic innervation in rat pancreatic islets ontogeny

    PubMed Central

    Cabrera-Vásquez, Siraam; Navarro-Tableros, Víctor; Sánchez-Soto, Carmen; Gutiérrez-Ospina, Gabriel; Hiriart, Marcia

    2009-01-01

    Background Pancreatic islets are not fully developed at birth and it is not clear how they are vascularised and innervated. Nerve Growth Factor (NGF) is required to guide sympathetic neurons that innervate peripheral organs and also in cardiovascular system and ovary angiogenesis. Pancreatic beta cells of a transgenic mouse that over-expressed NGF in attracts sympathetic hyper-innervation towards them. Moreover, we have previously demonstrated that adult beta cells synthesize and secrete NGF; however, we do not know how is NGF secreted during development, nor if it might be trophic for sympathetic innervation and survival in the pancreas. We analyzed sympathetic innervation and vasculature development in rat pancreatic islets at different developmental stages; foetal (F19), early postnatal (P1), weaning period (P20) and adults. We temporarily correlated these events to NGF secretion by islet cells. Results Sympathetic fibres reached pancreatic islets in the early postnatal period, apparently following blood vessels. The maximal number of sympathetic fibres (TH immunopositive) in the periphery of the islets was observed at P20, and then fibres entered the islets and reached the core where beta cells are mainly located. The number of fibres decreased from that stage to adulthood. At all stages studied, islet cells secreted NGF and also expressed the high affinity receptor TrkA. Foetal and neonatal isolated islet cells secreted more NGF than adults. TrkA receptors were expressed at all stages in pancreatic sympathetic fibres and blood vessels. These last structures were NGF–immunoreactive only at early stages (foetal and P0). Conclusion The results suggest that NGF signalling play an important role in the guidance of blood vessels and sympathetic fibres toward the islets during foetal and neonatal stages and could also preserve innervation at later stages of life. PMID:19534767

  3. Oesophageal epithelial innervation in health and reflux oesophagitis

    PubMed Central

    Newton, M; Kamm, M; Soediono, P; Milner, P; Burnham, W; Burnstock, G

    1999-01-01

    BACKGROUND—The response of the oesophagus to refluxed gastric contents is likely to depend on intact neural mechanisms in the oesophageal mucosa. The epithelial innervation has not been systematically evaluated in health or reflux disease. 
AIMS—To study oesophageal epithelial innervation in controls, and also inflamed and non-inflamed mucosa in patients with reflux oesophagitis and healed oesophagitis. 
PATIENTS—Ten controls, nine patients with reflux oesophagitis, and five patients with healed oesophagitis. 
METHODS—Oesophageal epithelial biopsy specimens were obtained at endoscopy. The distribution of the neuronal marker protein gene product 9.5 (PGP), and the neuropeptides calcitonin gene related peptide (CGRP), neuropeptide Y (NPY), substance P (SP), and vasoactive intestinal peptide (VIP) were investigated by immunohistochemistry. Density of innervation was assessed by the proportion of papillae in each oesophageal epithelial biopsy specimen containing immunoreactive fibres (found in the subepithelium and epithelial papillae, but not penetrating the epithelium). 
RESULTS—The proportion of papillae positive for PGP immunoreactive nerve fibres was significantly increased in inflamed tissue when compared with controls, and non-inflamed and healed tissue. There was also a significant increase in VIP immunoreactive fibres within epithelial papillae. Other neuropeptides showed no proportional changes in inflammation. 
CONCLUSIONS—Epithelial biopsy specimens can be used to assess innervation in the oesophagus. The innervation of the oesophageal mucosa is not altered in non-inflamed tissue of patients with oesophagitis but alters in response to inflammation, where there is a selective increase (about three- to fourfold) in VIP containing nerves. 

 Keywords: gastro-oesophageal reflux; reflux oesophagitis; innervation; neuropeptides; inflammation PMID:10026314

  4. Degeneration and regeneration of perivascular innervation in arterial grafts.

    PubMed

    Heikki, Penttilä; Timo, Waris; Nureddin, Ashammakhi; Sampsa, Vanhatalo

    2004-07-01

    Because the understanding of postoperative changes in arterial graft innervation is limited, this study was performed to characterize neuronal degeneration and regeneration events immunohistochemically in femoral arterial grafts transplanted to carotid arteries in rats. Specimens taken 1 day, 3 days, 7 days, 1 month, 3 months, and 5 months after surgery were assessed for vasoactive intestinal peptide, neurofilaments, growth-associated protein 43, tyrosine hydroxylase, and nitric oxide synthase isoenzymes. During neuronal degeneration, vasoactive intestinal peptide disappeared within 1 day, transmitter-synthesizing enzymes (nitric oxide synthase and tyrosine hydroxylase) had vanished by day 7, and neurofilaments (cytoskeletal markers) had essentially disappeared after 1 week. In the regeneration phase, the most robust axonal growth, as visualized by growth-associated protein 43, was observed at 1 month, followed by a gradual increase in neurotransmitter markers at 1 and 3 months, whereas the neurofilaments increased gradually up to the end of the 5-month observation period. Reinnervation proceeded from the proximal carotid (host) trunk distally to the graft. Axonal re-growth occurred mainly in arterial adventitia. Innervation density, as visually assessed, was denser in the graft than in the host. These findings suggest that 1) the main sequence of degeneration and regeneration follows that reported in other models of neuronal degeneration; 2) reinnervation of the arterial grafts comes mainly from the host arteries; and 3) the innervation density in the graft may differ from that in the host, which may suggest target-derived regulation of innervation. The latter finding may have clinical implications. It suggests that for a good outcome it would be beneficial to choose a sparsely innervated graft rather than a densely innervated one.

  5. Homologous beta-adrenergic desensitization in isolated rat hepatocytes.

    PubMed Central

    García-Sáinz, J A; Michel, B

    1987-01-01

    Hepatocytes from hypothyroid rats have a marked beta-adrenergic responsiveness. Preincubation of these hepatocytes with isoprenaline induced a time-dependent and concentration-dependent desensitization of the beta-adrenergic responsiveness without altering that to glucagon (homologous desensitization). The desensitization was evidenced both in the cyclic AMP accumulation and in the stimulation of ureagenesis induced by the beta-adrenergic agonists. Under the same conditions, preincubation with glucagon induced no desensitization. Propranolol was also unable to induce desensitization, but blocked that induced by isoprenaline. Pertussis-toxin treatment did not alter the homologous beta-adrenergic desensitization induced by isoprenaline. PMID:2825633

  6. Opioid peptide receptor stimulation reverses beta-adrenergic effects in rat heart cells.

    PubMed

    Xiao, R P; Pepe, S; Spurgeon, H A; Capogrossi, M C; Lakatta, E G

    1997-02-01

    Opioid peptide receptor (OPR) agonists are co-released with the beta-adrenergic receptor (beta-AR) agonist norepinephrine (NE) from nerve terminals in the heart during sympathetic stimulation. Whereas recent studies indicate that OPR and beta-AR coexist on the surface of cardiac myocytes, whether significant "cross talk" occurs between OPR and beta-AR signaling cascades within heart cells is unknown. In the present study we demonstrate a marked effect of delta-OPR stimulation to modulate beta-adrenergic responses in single isolated rat ventricular myocytes. Nanomolar concentrations (10(-8) M) of the OPR agonist leucine enkephalin (LE), a naturally occurring delta-opioid peptide, inhibited NE-induced increases in sarcolemmal L-type Ca2+ current, cytosolic Ca2+ transient, and contraction. The antiadrenergic effect of LE was pertussis toxin sensitive and abolished by naloxone, an opioid receptor antagonist. In contrast, LE was unable to inhibit the positive inotropic effects induced by equipotent concentrations of 8-(4 chlorophenylthio)-adenosine 3',5'-cyclic monophosphate, a cell-permeant adenosine 3',5'-cyclic monophosphate analog, or by the non-receptor-induced increase in contraction by elevated bathing Ca2+ concentration. These results indicate that an interaction of the OPR and beta-AR systems occurs proximal to activation of the adenosine 3',5'-cyclic monophosphate-dependent protein kinase of the beta-AR intracellular signaling pathway. This modulation of beta-adrenergic effects by OPR activation at the myocyte level may have important implications in the regulation of cardiac Ca2+ metabolism and contractility, particularly during the myocardial response to stress.

  7. The innervation of the muscle spindle: a personal history.

    PubMed

    Banks, Robert W

    2015-08-01

    I present a brief review of current understanding of the innervation of the mammalian muscle spindle, from a personal historical perspective. The review begins with comparative studies on the numbers of spindle afferents and considers how their relative abundance may best be assessed. This is followed by an examination of the distribution and some functional properties of the motor innervation. The primary ending is the subject of the final section, in particular, I look at what can be learned from serial sectioning and volumetric reconstruction, and present new results on a model and simulations concerning sensory terminal deformation during stretch.

  8. The innervation of the muscle spindle: a personal history

    PubMed Central

    Banks, Robert W

    2015-01-01

    I present a brief review of current understanding of the innervation of the mammalian muscle spindle, from a personal historical perspective. The review begins with comparative studies on the numbers of spindle afferents and considers how their relative abundance may best be assessed. This is followed by an examination of the distribution and some functional properties of the motor innervation. The primary ending is the subject of the final section, in particular, I look at what can be learned from serial sectioning and volumetric reconstruction, and present new results on a model and simulations concerning sensory terminal deformation during stretch. PMID:26095428

  9. [Genetic polymorphism of beta-adrenergic receptors and mortality in ischemic heart disease].

    PubMed

    Jaillon, Patrice; Simon, Tabassome

    2007-01-01

    The genetic polymorphism of beta-2 adrenergic receptors (B2AR) could play a major role in the prognostic of patients with a coronary heart disease. Two recent epidemiological studies could support this hypothesis. In 597 patients treated by a beta-blocker and followed for 3 years after a myocardial infarction or an acute coronary syndrome, the death rate was 5.4 times higher in homozygous Arg 16 and Gln 27 B2AR genotypes than in heterozygous or homozygous Gly 16 and Glu 27 B2AR genotypes. The beta-1 adrenergic receptor (B1AR) genetic polymorphism did not modify mortality. In a second study, in a prospective cohort of 5249 patients aged > or =65 years, the incidence of sudden cardiac death was 1.56 times higher in patients with homozygous Gln 27 B2AR than in heterozygous or homozygous Glu 27 B2AR genotype. This result was confirmed by a case-control study (155 cases of sudden cardiac death versus 144 control subjects). These data suggest that B2AR genetic polymorphism should be systematically studied in clinical trials in myocardial ischemia, with or without congestive heart failure.

  10. GSK-3α directly regulates β-adrenergic signaling and the response of the heart to hemodynamic stress in mice

    PubMed Central

    Zhou, Jibin; Lal, Hind; Chen, Xiongwen; Shang, Xiying; Song, Jianliang; Li, Yingxin; Kerkela, Risto; Doble, Bradley W.; MacAulay, Katrina; DeCaul, Morgan; Koch, Walter J.; Farber, John; Woodgett, James; Gao, Erhe; Force, Thomas

    2010-01-01

    The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases consists of 2 highly related isoforms, α and β. Although GSK-3β has an important role in cardiac development, much remains unknown about the function of either GSK-3 isoform in the postnatal heart. Herein, we present what we believe to be the first studies defining the role of GSK-3α in the mouse heart using gene targeting. Gsk3a–/– mice over 2 months of age developed progressive cardiomyocyte and cardiac hypertrophy and contractile dysfunction. Following thoracic aortic constriction in young mice, we observed enhanced hypertrophy that rapidly transitioned to ventricular dilatation and contractile dysfunction. Surprisingly, markedly impaired β-adrenergic responsiveness was found at both the organ and cellular level. This phenotype was reproduced by acute treatment of WT cardiomyocytes with a small molecule GSK-3 inhibitor, confirming that the response was not due to a chronic adaptation to LV dysfunction. Thus, GSK-3α appears to be the central regulator of a striking range of essential processes, including acute and direct positive regulation of β-adrenergic responsiveness. In the absence of GSK-3α, the heart cannot respond effectively to hemodynamic stress and rapidly fails. Our findings identify what we believe to be a new paradigm of regulation of β-adrenergic signaling and raise concerns given the rapid expansion of drug development targeting GSK-3. PMID:20516643

  11. Sensory recovery of the breast after innervated and non-innervated autologous breast reconstructions: A systematic review.

    PubMed

    Beugels, J; Cornelissen, A J M; Spiegel, A J; Heuts, E M; Piatkowski, A; van der Hulst, R R W J; Tuinder, S M H

    2017-09-01

    The sensory recovery of the reconstructed breast is an undervalued topic in the field of autologous breast reconstruction. This systematic review aimed to evaluate the available literature on the sensory recovery of the breast after innervated and non-innervated autologous breast reconstructions and to assess the possible benefits of sensory nerve coaptation compared to spontaneous reinnervation of the flap. A comprehensive literature search was conducted in PubMed, Embase and the Cochrane Library to identify all eligible studies regarding the sensory recovery of all types of innervated and non-innervated autologous breast reconstructions. The search yielded 334 hits, of which 32 studies concerning 1177 breast reconstructions were included. The amount of heterogeneity between the studies was high, which made the pooling of data difficult. The studies indicated that spontaneous reinnervation of autologous breast reconstructions occurred to a variable extent, depending on how and when it was measured. Despite these variable results, the sensory recovery of innervated flaps, however, was superior, started earlier and gradually improved over time with a higher chance of approaching normal values than non-innervated flaps. There is a lack of studies that assess the return of erogenous sensation and quality of life. The current evidence shows that nerve coaptation results in superior sensory recovery of the reconstructed breast compared to spontaneous reinnervation of the flap. This review illustrates that more standardised, high-quality studies with adequate sample sizes are needed to objectively evaluate the sensory recovery of the breast after autologous breast reconstructions. Copyright © 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. All rights reserved.

  12. The pineal gland: A model for adrenergic modulation of ubiquitin ligases

    PubMed Central

    Liu, Wenjun; Reiter, Russel J.

    2017-01-01

    responsive, in vitro, to treatment with a cyclic AMP analog, and norepinephrine. All previously described 24-hour rhythms in the pineal require an intact sympathetic input from the superior cervical ganglia. Conclusions The Hartley dataset thus provides evidence that the pineal gland is a highly useful model for studying adrenergically dependent mechanisms regulating variations in ubiquitin ligases, ubiquitin conjugases, and deubiquitinases, mechanisms that may be physiologically relevant not only in the pineal gland, but in all adrenergically innervated tissue. PMID:28212404

  13. Alpha-adrenergic modulation of synaptic transmission in rabbit pancreatic ganglia.

    PubMed

    Yi, Eunyoung; Love, Jeffrey A

    2005-10-30

    Pancreatic ganglia contain noradrenergic nerve terminals whose role in ganglionic transmission is unknown. Intracellular recordings from rabbit pancreatic neurons were used to study the effects of alpha-adrenergic agonists and antagonists on ganglionic transmission and to determine if endogenously released norepinephrine contributed to synaptic depression. Significant regional differences in alpha adrenergic effects were observed. In neurons from ganglia of the head/neck region norepinephrine or selective alpha(2) agonists presynaptically inhibited ganglionic transmission and this effect was antagonized by the alpha(2) antagonist yohimbine. In the majority of cells membrane hyperpolarization accompanied presynaptic inhibition during superfusion of alpha(2) agonists. Repetitive nerve stimulation evoked a presynaptic post-train depression (PTD) of ganglionic transmission in all neurons tested. A combination of nisoxetine (selective inhibitor of the norepinephrine transporter) and tyramine (releaser of endogenous catecholamines) increased PTD. Pretreatment with clonidine inhibited synaptic transmission and abolished PTD while yohimbine did not affect it. Pretreatment with guanethidine (>or=3.5 h) also failed reduce PTD while neurons unresponsive to alpha(2) adrenoceptor agonists routinely exhibited PTD, implying the presence of other inhibitory neurotransmitters sharing a common presynaptic mechanism with alpha(2) agonists. In the majority of neurons from ganglia of the body region superfusion of norepinephrine or the selective alpha(1) agonist phenylephrine evoked membrane depolarization and facilitated ganglionic transmission. These effects were antagonized by the alpha(1) antagonist prazosin. The remaining neurons exhibited either alpha(2)-mediated synaptic inhibition or no-response. In conclusion, inhibitory alpha(2) and excitatory alpha(1) adrenoceptors exist in pancreatic ganglia and predominate in the head/neck and body, respectively. Norepinephrine, released

  14. β2-Adrenergic receptor supports prolonged theta tetanus-induced LTP.

    PubMed

    Qian, Hai; Matt, Lucas; Zhang, Mingxu; Nguyen, Minh; Patriarchi, Tommaso; Koval, Olha M; Anderson, Mark E; He, Kaiwen; Lee, Hey-Kyoung; Hell, Johannes W

    2012-05-01

    The widespread noradrenergic innervation in the brain promotes arousal and learning by molecular mechanisms that remain largely undefined. Recent work shows that the β(2)-adrenergic receptor (β(2)AR) is linked to the AMPA-type glutamate receptor subunit GluA1 via stargazin and PSD-95 (Joiner ML, Lise MF, Yuen EY, Kam AY, Zhang M, Hall DD, Malik ZA, Qian H, Chen Y, Ulrich JD, Burette AC, Weinberg RJ, Law PY, El-Husseini A, Yan Z, Hell JW. EMBO J 29: 482-495, 2010). We now demonstrate that the β(2)AR plays a prominent role in long-term potentiation (LTP) induced by a train of 900 stimuli at 5 Hz (prolonged theta-tetanus-LTP, or PTT-LTP) in the hippocampal CA1 region in mice, which requires simultaneous β-adrenergic stimulation. Although PTT-LTP was impaired in hippocampal slices from β(1)AR and β(2)AR knockout (KO) mice, only β(2)AR-selective stimulation with salbutamol supported this PTT-LTP in wild-type (WT) slices, whereas β(1)AR-selective stimulation with dobutamine (+ prazosin) did not. Furthermore, only the β(2)AR-selective antagonist ICI-118551 and not the β(1)AR-selective antagonist CGP-20712 inhibited PTT-LTP and phosphorylation of GluA1 on its PKA site S845 in WT slices. Our analysis of S845A knockin (KI) mice indicates that this phosphorylation is relevant for PTT-LTP. These results identify the β(2)AR-S845 signaling pathway as a prominent regulator of synaptic plasticity.

  15. β2-Adrenergic receptor supports prolonged theta tetanus-induced LTP

    PubMed Central

    Qian, Hai; Matt, Lucas; Zhang, Mingxu; Nguyen, Minh; Patriarchi, Tommaso; Koval, Olha M.; Anderson, Mark E.; He, Kaiwen; Lee, Hey-Kyoung

    2012-01-01

    The widespread noradrenergic innervation in the brain promotes arousal and learning by molecular mechanisms that remain largely undefined. Recent work shows that the β2-adrenergic receptor (β2AR) is linked to the AMPA-type glutamate receptor subunit GluA1 via stargazin and PSD-95 (Joiner ML, Lise MF, Yuen EY, Kam AY, Zhang M, Hall DD, Malik ZA, Qian H, Chen Y, Ulrich JD, Burette AC, Weinberg RJ, Law PY, El-Husseini A, Yan Z, Hell JW. EMBO J 29: 482–495, 2010). We now demonstrate that the β2AR plays a prominent role in long-term potentiation (LTP) induced by a train of 900 stimuli at 5 Hz (prolonged theta-tetanus-LTP, or PTT-LTP) in the hippocampal CA1 region in mice, which requires simultaneous β-adrenergic stimulation. Although PTT-LTP was impaired in hippocampal slices from β1AR and β2AR knockout (KO) mice, only β2AR-selective stimulation with salbutamol supported this PTT-LTP in wild-type (WT) slices, whereas β1AR-selective stimulation with dobutamine (+ prazosin) did not. Furthermore, only the β2AR-selective antagonist ICI-118551 and not the β1AR-selective antagonist CGP-20712 inhibited PTT-LTP and phosphorylation of GluA1 on its PKA site S845 in WT slices. Our analysis of S845A knockin (KI) mice indicates that this phosphorylation is relevant for PTT-LTP. These results identify the β2AR-S845 signaling pathway as a prominent regulator of synaptic plasticity. PMID:22338020

  16. Development of the intrinsic and extrinsic innervation of the gut.

    PubMed

    Uesaka, Toshihiro; Young, Heather M; Pachnis, Vassilis; Enomoto, Hideki

    2016-09-15

    The gastrointestinal (GI) tract is innervated by intrinsic enteric neurons and by extrinsic efferent and afferent nerves. The enteric (intrinsic) nervous system (ENS) in most regions of the gut consists of two main ganglionated layers; myenteric and submucosal ganglia, containing numerous types of enteric neurons and glial cells. Axons arising from the ENS and from extrinsic neurons innervate most layers of the gut wall and regulate many gut functions. The majority of ENS cells are derived from vagal neural crest cells (NCCs), which proliferate, colonize the entire gut, and first populate the myenteric region. After gut colonization by vagal NCCs, the extrinsic nerve fibers reach the GI tract, and Schwann cell precursors (SCPs) enter the gut along the extrinsic nerves. Furthermore, a subpopulation of cells in myenteric ganglia undergoes a radial (inward) migration to form the submucosal plexus, and the intrinsic and extrinsic innervation to the mucosal region develops. Here, we focus on recent progress in understanding the developmental processes that occur after the gut is colonized by vagal ENS precursors, and provide an up-to-date overview of molecular mechanisms regulating the development of the intrinsic and extrinsic innervation of the GI tract. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Changes in uterine innervation in pregnancy and during labour.

    PubMed

    Tingåker, Berith K; Irestedt, Lars

    2010-06-01

    The present review highlights recent findings focusing on effects on the cervical innervation exerted by term pregnancy and labour. The corpus uteri is almost denervated in term pregnancy, as demonstrated in both humans and rodents, whereas the cervical innervation remains dense throughout pregnancy and labour. In rats, fewer connections between sensory subdivisions in spinal cord segments and the cervix have been observed in late pregnancy as compared with the nonpregnant state. In term pregnancy an increased excitability of mechanosensitive afferents innervating the cervix has been demonstrated. The reasons for these seemingly contradictory findings may be clarified in further studies. Transient receptor potential vanilloid receptor, a key molecule in nociception, has been identified in the human cervix uteri in the nonpregnant state and during pregnancy and labour as opposed to the corpus, in which transient receptor potential vanilloid receptor disappears during pregnancy. These findings add evidence to the hypothesis that the uterine cervix is the main site from where labour pain propagates. The conservation of the cervical innervation in term pregnancy and labour, in contrast to the corpus, and the large number of mediators involved in cervical ripening clearly indicate that the cervix plays a crucial role in pregnancy maintenance, labour initiation, labour pain and parturition.

  18. Adaptive plasticity of vaginal innervation in term pregnant rats.

    PubMed

    Liao, Zhaohui; Smith, Peter G

    2011-12-01

    Changes in reproductive status place varied functional demands on the vagina. These include receptivity to male intromission and sperm transport in estrus, barrier functions during early pregnancy, and providing a conduit for fetal passage at parturition. Peripheral innervation regulates vaginal function, which in turn may be influenced by circulating reproductive hormones. We assessed vaginal innervation in diestrus and estrus (before and after the estrous cycle surge in estrogen), and in the early (low estrogen) and late (high estrogen) stages in pregnancy. In vaginal sections from cycling rats, axons immunoreactive for the pan-neuronal marker protein gene product 9.5 (PGP 9.5) showed a small reduction at estrus relative to diestrus, but this difference did not persist after correcting for changes in target size. No changes were detected in axons immunoreactive for tyrosine hydroxylase (sympathetic), vesicular acetylcholine transporter (parasympathetic), or calcitonin gene-related peptide and transient receptor potential vanilloid type 1 (TRPV-1; sensory nociceptors). In rats at 10 days of pregnancy, innervation was similar to that observed in cycling rats. However, at 21 days of pregnancy, axons immunoreactive for PGP 9.5 and each of the subpopulation-selective markers were significantly reduced both when expressed as percentage of sectional area or after correcting for changes in target size. Because peripheral nerves regulate vaginal smooth muscle tone, blood flow, and pain sensitivity, reductions in innervation may represent important adaptive mechanisms facilitating parturition.

  19. Functional Reconstruction of Sarcoma Defects Utilising Innervated Free Flaps

    PubMed Central

    Grinsell, Damien; Di Bella, Claudia; Choong, Peter F. M.

    2012-01-01

    Soft-tissue reconstruction following preoperative radiotherapy and wide resection of soft tissue sarcoma remains a challenge. Pedicled and free tissue transfers are an essential part of limb sparing surgery. We report 22 cases of sarcoma treated with radiotherapy and wide excision followed by one-stage innervated free or pedicled musculocutaneous flap transfers. The resection involved the upper limb in 3 cases, the lower limb in 17, and the abdominal wall in 2. The flaps used for the reconstruction were mainly latissimus dorsi and gracilis. The range of motion was restored fully in 14 patients. The muscle strength of the compartment reconstructed was of grades 4 and 5 in all patients except one. The overall function was excellent in all the cases with functional scores of 71.2% in the upper limb and 84% in the lower limb. The only 2 major complications were flap necrosis, both revised with another flap, one of which was innervated with restoration of function. Innervated flaps are valuable alternatives for reconstruction after sarcoma resection in the extremity and in the abdominal wall. The excellent functional results are encouraging, and we believe that innervated muscle reconstruction should be encouraged in the treatment of sarcoma after radiotherapy and wide resection. PMID:22969309

  20. The EGFR Is Required for Proper Innervation to the Skin

    PubMed Central

    Maklad, Adel; Nicolai, Jodi R.; Bichsel, Kyle J.; Evenson, Jackie E.; Lee, Tang-Cheng; Threadgill, David W.; Hansen, Laura A.

    2008-01-01

    EGFR family members are essential for proper peripheral nervous system development. A role for EGFR itself in peripheral nervous system development in vivo, however, has not been reported. We investigated whether EGFR is required for cutaneous innervation using Egfr null and skin-targeted Egfr mutant mice. Neuronal markers; including PGP9.5, GAP-43, acetylated tubulin, and neurofilaments; revealed that Egfr null dorsal skin was hyperinnervated with a disorganized pattern of innervation. In addition, receptor subtypes such as lanceolate endings were disorganized and immature. To determine whether the hyperinnervation phenotype resulted from a target-derived effect of loss of EGFR, mice lacking EGFR expression in the cutaneous epithelium were examined. These mice retained other aspects of the cutaneous Egfr null phenotype but exhibited normal innervation. The sensory deficits in Egfr null dorsal skin were not associated with any abnormality in the morphology or density of dorsal root ganglion (DRG) neurons or Schwann cells. However, explant and dissociated cell cultures of DRG revealed more extensive branching in Egfr null cultures. These data demonstrate that EGFR is required for proper cutaneous innervation during development and suggest that it limits axonal outgrowth and branching in a DRG-autonomous manner. PMID:18830272

  1. Follicle Microstructure and Innervation Vary between Pinniped Micro- and Macrovibrissae.

    PubMed

    Mattson, Erin E; Marshall, Christopher D

    2016-01-01

    Histological data from terrestrial, semiaquatic, and fully aquatic mammal vibrissa (whisker) studies indicate that follicle microstructure and innervation vary across the mystacial vibrissal array (i.e. medial microvibrissae to lateral macrovibrissae). However, comparative data are lacking, and current histological studies on pinniped vibrissae only focus on the largest ventrolateral vibrissae. Consequently, we investigated the microstructure, medial-to-lateral innervation, and morphometric trends in harp seal (Pagophilus groenlandicus) vibrissal follicle-sinus complexes (F-SCs). The F-SCs were sectioned either longitudinally or in cross-section and stained with a modified Masson's trichrome stain (microstructure) or Bodian's silver stain (innervation). All F-SCs exhibited a tripartite blood organization system. The dermal capsule thickness, the distribution of major branches of the deep vibrissal nerve, and the hair shaft design were more symmetrical in medial F-SCs, but these features became more asymmetrical as the F-SCs became more lateral. Overall, the mean axon count was 1,221 ± 422.3 axons/F-SC and mean axon counts by column ranged from 550 ± 97.4 axons/F-SC (medially, column 11) to 1,632 ± 173.2 axons/F-SC (laterally, column 2). These values indicate a total of 117,216 axons innervating the entire mystacial vibrissal array. The mean axon count of lateral F-SCs was 1,533 ± 192.9 axons/ F-SC, which is similar to values reported in the literature for other pinniped F-SCs. Our data suggest that conventional studies that only examine the largest ventrolateral vibrissae may overestimate the total innervation by ∼20%. However, our study also accounts for variation in quantification methods and shows that conventional analyses likely only overestimate innervation by ∼10%. The relationship between axon count and cross-sectional F-SC surface area was nonlinear, and axon densities were consistent across the snout. Our data indicate that harp seals exhibit

  2. Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment.

    PubMed

    Kim-Fuchs, Corina; Le, Caroline P; Pimentel, Matthew A; Shackleford, David; Ferrari, Davide; Angst, Eliane; Hollande, Frédéric; Sloan, Erica K

    2014-08-01

    Pancreatic cancer cells intimately interact with a complex microenvironment that influences pancreatic cancer progression. The pancreas is innervated by fibers of the sympathetic nervous system (SNS) and pancreatic cancer cells have receptors for SNS neurotransmitters which suggests that pancreatic cancer may be sensitive to neural signaling. In vitro and non-orthotopic in vivo studies showed that neural signaling modulates tumour cell behavior. However the effect of SNS signaling on tumor progression within the pancreatic microenvironment has not previously been investigated. To address this, we used in vivo optical imaging to non-invasively track growth and dissemination of primary pancreatic cancer using an orthotopic mouse model that replicates the complex interaction between pancreatic tumor cells and their microenvironment. Stress-induced neural activation increased primary tumor growth and tumor cell dissemination to normal adjacent pancreas. These effects were associated with increased expression of invasion genes by tumor cells and pancreatic stromal cells. Pharmacological activation of β-adrenergic signaling induced similar effects to chronic stress, and pharmacological β-blockade reversed the effects of chronic stress on pancreatic cancer progression. These findings indicate that neural β-adrenergic signaling regulates pancreatic cancer progression and suggest β-blockade as a novel strategy to complement existing therapies for pancreatic cancer.

  3. Sympathetic Nervous System Control of Carbon Tetrachloride-Induced Oxidative Stress in Liver through α-Adrenergic Signaling.

    PubMed

    Lin, Jung-Chun; Peng, Yi-Jen; Wang, Shih-Yu; Lai, Mei-Ju; Young, Ton-Ho; Salter, Donald M; Lee, Herng-Sheng

    2016-01-01

    In addition to being the primary organ involved in redox cycling, the liver is one of the most highly innervated tissues in mammals. The interaction between hepatocytes and sympathetic, parasympathetic, and peptidergic nerve fibers through a variety of neurotransmitters and signaling pathways is recognized as being important in the regulation of hepatocyte function, liver regeneration, and hepatic fibrosis. However, less is known regarding the role of the sympathetic nervous system (SNS) in modulating the hepatic response to oxidative stress. Our aim was to investigate the role of the SNS in healthy and oxidatively stressed liver parenchyma. Mice treated with 6-hydroxydopamine hydrobromide were used to realize chemical sympathectomy. Carbon tetrachloride (CCl4) injection was used to induce oxidative liver injury. Sympathectomized animals were protected from CCl4 induced hepatic lipid peroxidation-mediated cytotoxicity and genotoxicity as assessed by 4-hydroxy-2-nonenal levels, morphological features of cell damage, and DNA oxidative damage. Furthermore, sympathectomy modulated hepatic inflammatory response induced by CCl4-mediated lipid peroxidation. CCl4 induced lipid peroxidation and hepatotoxicity were suppressed by administration of an α-adrenergic antagonist. We conclude that the SNS provides a permissive microenvironment for hepatic oxidative stress indicating the possibility that targeting the hepatic α-adrenergic signaling could be a viable strategy for improving outcomes in patients with acute hepatic injury.

  4. Sympathetic Nervous System Control of Carbon Tetrachloride-Induced Oxidative Stress in Liver through α-Adrenergic Signaling

    PubMed Central

    Lin, Jung-Chun; Peng, Yi-Jen; Wang, Shih-Yu; Young, Ton-Ho; Salter, Donald M.; Lee, Herng-Sheng

    2016-01-01

    In addition to being the primary organ involved in redox cycling, the liver is one of the most highly innervated tissues in mammals. The interaction between hepatocytes and sympathetic, parasympathetic, and peptidergic nerve fibers through a variety of neurotransmitters and signaling pathways is recognized as being important in the regulation of hepatocyte function, liver regeneration, and hepatic fibrosis. However, less is known regarding the role of the sympathetic nervous system (SNS) in modulating the hepatic response to oxidative stress. Our aim was to investigate the role of the SNS in healthy and oxidatively stressed liver parenchyma. Mice treated with 6-hydroxydopamine hydrobromide were used to realize chemical sympathectomy. Carbon tetrachloride (CCl4) injection was used to induce oxidative liver injury. Sympathectomized animals were protected from CCl4 induced hepatic lipid peroxidation-mediated cytotoxicity and genotoxicity as assessed by 4-hydroxy-2-nonenal levels, morphological features of cell damage, and DNA oxidative damage. Furthermore, sympathectomy modulated hepatic inflammatory response induced by CCl4-mediated lipid peroxidation. CCl4 induced lipid peroxidation and hepatotoxicity were suppressed by administration of an α-adrenergic antagonist. We conclude that the SNS provides a permissive microenvironment for hepatic oxidative stress indicating the possibility that targeting the hepatic α-adrenergic signaling could be a viable strategy for improving outcomes in patients with acute hepatic injury. PMID:26798417

  5. Adrenergic stimulation sensitizes TRPV1 through upregulation of cystathionine β-synthetase in a rat model of visceral hypersensitivity.

    PubMed

    Zhu, Liyan; Zhao, Liting; Qu, Ruobing; Zhu, Hong-Yan; Wang, Yongmeng; Jiang, Xinghong; Xu, Guang-Yin

    2015-11-03

    The pathogenesis of pain in irritable bowel syndrome (IBS) is poorly understood and treatment remains difficult. The present study was designed to investigate roles of adrenergic signaling and the endogenous hydrogen sulfide producing enzyme cystathionine β-synthetase (CBS) in a previously validated rat model of IBS induced by neonatal colonic inflammation (NCI). Here we showed that NCI-induced visceral hypersensitivity (VH) was significantly attenuated by β2 subunit inhibitor but not by β1 or β3 or α subunit inhibitor. NCI markedly elevated plasma norepinephrine (NE) concentration without alteration in expression of β2 subunit receptors in dorsal root ganglion (DRGs) innervating the colon. In addition, NCI markedly enhanced TRPV1 and CBS expression in the colon DRGs. CBS inhibitor AOAA reversed the upregulation of TRPV1 in NCI rats. In vitro experiments showed that incubation of DRG cells with NE markedly enhanced expression of TRPV1, which was reversed by application of AOAA. Incubation of DRG cells with the H2S donor NaHS greatly enhanced TRPV1 expression. Collectively, these data suggest that activation of adrenergic signaling by NCI sensitizes TRPV1 channel activity, which is likely mediated by upregulation of CBS expression in peripheral sensory neurons, thus contributing to chronic visceral hypersensitivity.

  6. Adrenergic stimulation sensitizes TRPV1 through upregulation of cystathionine β-synthetase in a rat model of visceral hypersensitivity

    PubMed Central

    Zhu, Liyan; Zhao, Liting; Qu, Ruobing; Zhu, Hong-Yan; Wang, Yongmeng; Jiang, Xinghong; Xu, Guang-Yin

    2015-01-01

    The pathogenesis of pain in irritable bowel syndrome (IBS) is poorly understood and treatment remains difficult. The present study was designed to investigate roles of adrenergic signaling and the endogenous hydrogen sulfide producing enzyme cystathionine β-synthetase (CBS) in a previously validated rat model of IBS induced by neonatal colonic inflammation (NCI). Here we showed that NCI-induced visceral hypersensitivity (VH) was significantly attenuated by β2 subunit inhibitor but not by β1 or β3 or α subunit inhibitor. NCI markedly elevated plasma norepinephrine (NE) concentration without alteration in expression of β2 subunit receptors in dorsal root ganglion (DRGs) innervating the colon. In addition, NCI markedly enhanced TRPV1 and CBS expression in the colon DRGs. CBS inhibitor AOAA reversed the upregulation of TRPV1 in NCI rats. In vitro experiments showed that incubation of DRG cells with NE markedly enhanced expression of TRPV1, which was reversed by application of AOAA. Incubation of DRG cells with the H2S donor NaHS greatly enhanced TRPV1 expression. Collectively, these data suggest that activation of adrenergic signaling by NCI sensitizes TRPV1 channel activity, which is likely mediated by upregulation of CBS expression in peripheral sensory neurons, thus contributing to chronic visceral hypersensitivity. PMID:26527188

  7. [Mivazerol and other benzylimidazoles with alpha-2 adrenergic properties].

    PubMed

    Cossement, E; Geerts, J P; Michel, P; Motte, G; Noyer, M

    1994-01-01

    4-Benzyl-imidazole compounds derived from Salbutanol are evaluated for potential adrenergic activities. The prevalent property of a series of new bioisosteres of catecholamines either of the saligenol-(ucb LO61) or benzamide-(Mivazerol) type is a selective alpha-adrenergic agonism, at the presynaptic level. The present study stresses the structural features responsible for the alpha-2-agonistic property.

  8. Roles of innervation in developing and regenerating orofacial tissues.

    PubMed

    Pagella, Pierfrancesco; Jiménez-Rojo, Lucia; Mitsiadis, Thimios A

    2014-06-01

    The head is innervated by 12 cranial nerves (I-XII) that regulate its sensory and motor functions. Cranial nerves are composed of sensory, motor, or mixed neuronal populations. Sensory neurons perceive generally somatic sensations such as pressure, pain, and temperature. These neurons are also involved in smell, vision, taste, and hearing. Motor neurons ensure the motility of all muscles and glands. Innervation plays an essential role in the development of the various orofacial structures during embryogenesis. Hypoplastic cranial nerves often lead to abnormal development of their target organs and tissues. For example, Möbius syndrome is a congenital disease characterized by defective innervation (i.e., abducens (VI) and facial (VII) nerves), deafness, tooth anomalies, and cleft palate. Hence, it is obvious that the peripheral nervous system is needed for both development and function of orofacial structures. Nerves have a limited capacity to regenerate. However, neural stem cells, which could be used as sources for neural tissue maintenance and repair, have been found in adult neuronal tissues. Similarly, various adult stem cell populations have been isolated from almost all organs of the human body. Stem cells are tightly regulated by their microenvironment, the stem cell niche. Deregulation of adult stem cell behavior results in the development of pathologies such as tumor formation or early tissue senescence. It is thus essential to understand the factors that regulate the functions and maintenance of stem cells. Yet, the potential importance of innervation in the regulation of stem cells and/or their niches in most organs and tissues is largely unexplored. This review focuses on the potential role of innervation in the development and homeostasis of orofacial structures and discusses its possible association with stem cell populations during tissue repair.

  9. Eph/ephrin interactions modulate vascular sympathetic innervation.

    PubMed

    Damon, Deborah H; teRiele, Jaclyn A; Marko, Stephen B

    2010-12-08

    Ephs and ephrins are membrane-bound proteins that interact to modulate axon growth and neuronal function. We tested the hypothesis that eph/ephrin interactions affected the growth and function of vascular sympathetic innervation. Using RT-PCR analyses, we detected both classes of ephs (A and B) and both classes of ephrins (A and B) in sympathetic ganglia from neonatal and adult rats. Both classes of ephs (A and B) and both classes of ephrins (A and B) bound to the cell bodies and neurites of dissociated postganglionic sympathetic neurons. Messenger RNAs encoding for both classes of ephs (A and B) and both classes of ephrins (A and B) were also detected in sympathetically innervated arteries from neonatal and adult rats. These data suggest that ephrins/ephs on nerve fibers of postganglionic sympathetic neurons could interact with ephs/ephrins on cells in innervated arteries. We found that ephA4 reduced reinnervation of denervated femoral arteries. Reinnervation in the presence of ephA4-Fc (38.9±6.6%) was significantly less than that in the presence of IgG-Fc (62±10%; n=5; p<0.05; one-tailed unpaired t-test). These data indicate that eph/ephrin interactions modulated the growth of vascular sympathetic innervation. We also found that ephA4 increased basal release of norepinephrine from nerve terminals of isolated tail arteries. These data indicate that eph/ephrin interactions affect the growth and function of vascular sympathetic innervation.

  10. Adrenergic urticaria: review of the literature and proposed mechanism.

    PubMed

    Hogan, Sara R; Mandrell, Joshua; Eilers, David

    2014-04-01

    Adrenergic urticaria is a rare type of stress-induced physical urticaria characterized by transient outbreaks of red papules surrounded by halos of hypopigmented, vasoconstricted skin. First described in 1985, there are 10 reported cases of adrenergic urticaria in the English-language medical literature. Episodes are caused by various triggers, including emotional upset, coffee, and chocolate, during which serum catecholamines and IgE are elevated, whereas histamine and serotonin levels remain within normal limits. The precise mechanisms leading to the pathogenesis of adrenergic urticaria have yet to be elucidated. Diagnosis can be made by intradermal injection of epinephrine or norepinephrine, which reproduces the characteristic rash, or by clinical observation. Trigger avoidance and oral propranolol are currently the best known treatments for adrenergic urticaria. Nonspecific therapies, including tranquilizers and antihistamines, may also ease symptoms. This article explores the pathophysiology of adrenergic urticaria and proposes a mechanism by which propranolol treats the condition.

  11. Epinephrine administration increases neural impulses propagated along the vagus nerve: Role of peripheral beta-adrenergic receptors.

    PubMed

    Miyashita, T; Williams, C L

    2006-03-01

    A significant number of animal and human studies demonstrate that memories for new experiences are encoded more effectively under environmental or laboratory conditions which elevate peripheral concentrations of the hormone epinephrine and in turn, induce emotional arousal. Although this phenomenon has been replicated across several learning paradigms, understanding of how this arousal related hormone affects memory processing remains obscure because epinephrine does not freely enter into the central circulation to produce any direct effects on the brain. This study examined whether epinephrine's actions on the CNS may be mediated by the initial activation of peripheral vagal fibers that project to the brain. The vagus was selected as a candidate for this role since it is densely embedded with beta-adrenergic receptors and the peripheral endings of this nerve innervate a broad spectrum of sensory organs that are directly affected by epinephrine release. Electrophysiological recordings of cervical vagal activity was measured over 110 min in urethane-anesthetized Sprague-Dawley rats given saline, epinephrine (0.3 mg/kg), the peripherally acting beta-adrenergic antagonist sotalol (2.0 mg/kg), or a combination of sotalol followed 15 min later by an injection of epinephrine. Epinephrine produced a significant increase in vagal nerve firing 10 min post-injection (p < .05) relative to controls and neural impulses recorded from the vagus remained significantly elevated for the remaining 55 min collection period. The excitatory actions of epinephrine were not observed in groups given an identical dose of the hormone after peripheral beta-adrenergic receptor blockade with sotalol. These findings demonstrate that neural discharge in vagal afferent fibers is increased by elevations in peripheral concentrations of epinephrine and the significance of these findings in understanding how epinephrine modulates brain limbic structures to encode and store new information into memory

  12. Variations of lumbrical muscle innervation patterns in the hand, focusing on the dual innervation of the third lumbrical muscle.

    PubMed

    Hur, Mi-Sun

    2017-02-01

    This study was conducted to clarify the innervation patterns of the lumbrical muscles by identifying the origin of the nerve fascicles innervating these muscles. The lumbricals in the hand were investigated in 50 specimens of embalmed Korean adult cadavers. Dual innervation of the third lumbrical was most frequently observed in 64.0%. The third lumbrical was innervated by a branch arising from the median nerve (MN) distal to site at which the superficial branch of the ulnar nerve (sUN) joins the MN in 34%. When separating and tracing the nerve fascicles from the MN distal to the communicating branch from the sUN to MN, the fascicles contained parts of the MN and sUN in 18% and part of the MN in 16%. These results will be helpful for accurate diagnoses, surgical procedures, and electrophysiological examinations in lesions of the MN and ulnar nerve in the hand. Muscle Nerve, 2016 Muscle Nerve 55: 160-165, 2017. © 2016 Wiley Periodicals, Inc.

  13. Mild metabolic acidosis impairs the β-adrenergic response in isolated human failing myocardium

    PubMed Central

    2012-01-01

    Introduction Pronounced extracellular acidosis reduces both cardiac contractility and the β-adrenergic response. In the past, this was shown in some studies using animal models. However, few data exist regarding how the human end-stage failing myocardium, in which compensatory mechanisms are exhausted, reacts to acute mild metabolic acidosis. The aim of this study was to investigate the effect of mild metabolic acidosis on contractility and the β-adrenergic response of isolated trabeculae from human end-stage failing hearts. Methods Intact isometrically twitching trabeculae isolated from patients with end-stage heart failure were exposed to mild metabolic acidosis (pH 7.20). Trabeculae were stimulated at increasing frequencies and finally exposed to increasing concentrations of isoproterenol (0 to 1 × 10-6 M). Results A mild metabolic acidosis caused a depression in twitch-force amplitude of 26% (12.1 ± 1.9 to 9.0 ± 1.5 mN/mm2; n = 12; P < 0.01) as compared with pH 7.40. Force-frequency relation measurements yielded no further significant differences of twitch force. At the maximal isoproterenol concentration, the force amplitude was comparable in each of the two groups (pH 7.40 versus pH 7.20). However, the half-maximal effective concentration (EC50) was significantly increased in the acidosis group, with an EC50 of 5.834 × 10-8 M (confidence interval (CI), 3.48 × 10-8 to 9.779 × 10-8; n = 9), compared with the control group, which had an EC50 of 1.056 × 10-8 M (CI, 2.626 × 10-9 to 4.243 × 10-8; n = 10; P < 0.05), indicating an impaired β-adrenergic force response. Conclusions Our data show that mild metabolic acidosis reduces cardiac contractility and significantly impairs the β-adrenergic force response in human failing myocardium. Thus, our results could contribute to the still-controversial discussion about the therapy regimen of acidosis in patients with critical heart failure. PMID:22889236

  14. [The adrenergic mechanisms are involved in the pulmonary hemodynamics changes following experimental myocardial ischemia in rabbits].

    PubMed

    Evlakhov, V I; Poiasov, I Z

    2012-05-01

    In acute experiments in anesthetized rabbits the changes of the pulmonary hemodynamics following myocardial ischemia in the region of the descendent left coronary artery were studied in control animals and after the blockade of alpha-adrenoreceptors by phentolamine or N-cholinoreceptors of autonomic ganglia by hexamethonium. Following myocardial ischemia in control animals the pulmonary artery pressure and flow decreased, the pulmonary vascular resistance was elevated not significantly, the cardiac output decreased more than pulmonary artery flow. Following myocardial ischemia after the blockade of alpha-adrenoreceptors the pulmonary artery flow and cardiac output decreased in the same level and the pulmonary vascular resistance was decreased. In these conditions the pulmonary artery pressure decreased more than in control animals, meanwhile the pulmonary artery flow was decreased in the same level as in the last case. Following myocardial ischemia after the blockade of N-cholinoreceptors the pulmonary hemodynamics changes were the same as they were following myocardial ischemia in the control rabbits, the cardiac output decreased more than pulmonary artery flow. The disbalance of the cardiac output and pulmonary artery flow changes in the case of myocardial ischemia was caused by the pulmonary vessel reactions following activations of the humoral adrenergic mechanisms.

  15. Targeted disruption of the mouse beta1-adrenergic receptor gene: developmental and cardiovascular effects.

    PubMed Central

    Rohrer, D K; Desai, K H; Jasper, J R; Stevens, M E; Regula, D P; Barsh, G S; Bernstein, D; Kobilka, B K

    1996-01-01

    At least three distinct beta-adrenergic receptor (beta-AR) subtypes exist in mammals. These receptors modulate a wide variety of processes, from development and behavior, to cardiac function, metabolism, and smooth muscle tone. To understand the roles that individual beta-AR subtypes play in these processes, we have used the technique of gene targeting to create homozygous beta 1-AR null mutants (beta 1-AR -/-) in mice. The majority of beta 1-AR -/- mice die prenatally, and the penetrance of lethality shows strain dependence. Beta l-AR -/- mice that do survive to adulthood appear normal, but lack the chronotropic and inotropic responses seen in wild-type mice when beta-AR agonists such as isoproterenol are administered. Moreover, this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice. These findings occur despite persistent cardiac beta 2-AR expression, demonstrating the importance of beta 1-ARs for proper mouse development and cardiac function, while highlighting functional differences between beta-AR subtypes. Images Fig. 1 Fig. 3 PMID:8693001

  16. Phosphoinositide metabolism and adrenergic receptors in astrocytes

    SciTech Connect

    Noble, E.P.; Ritchie, T.; de Vellis, J.

    1986-03-01

    Agonist-induced phosphoinositide (PI) breakdown functions as a signal generating system. Diacylglycerol, one breakdown product of phosphotidylinositol-4,5-diphosphate hydrolysis, can stimulate protein kinase C, whereas inositol triphosphate, the other product, has been proposed to be a second messenger for Ca/sup + +/ mobilization. Using purified astrocyte cultures from neonatal rat brain, the effects of adrenergic agonists and antagonists at 10/sup -5/ M were measured on PI breakdown. Astrocytes grown in culture were prelabeled with (/sup 3/H)inositol, and basal (/sup 3/H) inositol phosphate (IP/sub 1/) accumulation was measured in the presence of Li/sup +/. Epinephrine > norepinephrine (NE) were the most active stimulants of IP/sub 1/ production. The ..cap alpha../sub 1/ adrenoreceptor blockers, phentolamine and phenoxybenzamine, added alone had no effect on IP/sub 1/ production was reduced below basal levels. Propranolol partially blocked the effects of NE. Clonidine and isoproterenol, separately added, reduced IP/sub 1/ below basal levels and when added together diminished IP/sub 1/ accumulation even further. The role of adrenergic stimulation in the production of c-AMP.

  17. beta. -Adrenergic stimulation of brown adipocyte proliferation

    SciTech Connect

    Geloeen, A.; Collet, A.J.; Guay, G.; Bukowiecki, L.J. Laboratoire de Thermoregulation et Metabolisme Energetique, Lyon )

    1988-01-01

    The mechanisms of brown adipose tissue (BAT) growth were studied by quantitative photonic radioautography using tritiated thymidine to follow mitotic activity. To identify the nature of the adrenergic pathways mediating brown adipocyte proliferation and differentiation, the effects of cold exposure (4 days at 4{degree}C) on BAT growth were compared with those induced by treating rats at 25{degree}C with norepinephrine (a mixed agonist), isoproterenol (a {beta}-agonist), and phenylephrine (an {alpha}-agonist). Norepinephrine mimicked the effects of cold exposure, not only on the mitotic activity, but also on the distribution of the labeling among the various cellular types. Isoproterenol entirely reproduced the effects of norepinephrine both on the labeling index and on the cellular type labeling frequency. These results demonstrate that norepinephrine triggers a coordinated proliferation of brown adipocytes and endothelial cells in warm-exposed rats that is similar to that observed after cold exposure. They also suggest that cold exposure stimulates BAT growth by increasing the release of norepinephrine from sympathetic nerves and that the neurohormone activates mitoses in BAT precursor cells via {beta}-adrenergic pathways.

  18. Adrenergic regulation of innate immunity: a review

    PubMed Central

    Scanzano, Angela; Cosentino, Marco

    2015-01-01

    The sympathetic nervous system has a major role in the brain-immune cross-talk, but few information exist on the sympathoadrenergic regulation of innate immune system. The aim of this review is to summarize available knowledge regarding the sympathetic modulation of the innate immune response, providing a rational background for the possible repurposing of adrenergic drugs as immunomodulating agents. The cells of immune system express adrenoceptors (AR), which represent the target for noradrenaline and adrenaline. In human neutrophils, adrenaline and noradrenaline inhibit migration, CD11b/CD18 expression, and oxidative metabolism, possibly through β-AR, although the role of α1- and α2-AR requires further investigation. Natural Killer express β-AR, which are usually inhibitory. Monocytes express β-AR and their activation is usually antiinflammatory. On murine Dentritic cells (DC), β-AR mediate sympathetic influence on DC-T cells interactions. In human DC β2-AR may affect Th1/2 differentiation of CD4+ T cells. In microglia and in astrocytes, β2-AR dysregulation may contribute to neuroinflammation in autoimmune and neurodegenerative disease. In conclusion, extensive evidence supports a critical role for adrenergic mechanisms in the regulation of innate immunity, in peripheral tissues as well as in the CNS. Sympathoadrenergic pathways in the innate immune system may represent novel antiinflammatory and immunomodulating targets with significant therapeutic potential. PMID:26321956

  19. The influence of hyperthyroidism and hypothyroidism on alpha- and beta-adrenergic receptor systems and adrenergic responsiveness.

    PubMed

    Bilezikian, J P; Loeb, J N

    1983-01-01

    A detailed review has been conducted of studies addressing dressing the subject of the influence of thyroid hormone on alpha- and beta-adrenergic receptors and adrenergic responsiveness in a wide range of experimental animals and tissues. The studies summarized in the present article have been restricted to those in which explicit measurements of receptor number were made by the use of appropriate radioligands. Particular emphasis is given to an examination of the relationship between thyroid hormone-induced changes in alpha- and beta-adrenergic receptor number and accompanying changes in adenylate cyclase activity and more distal adrenergic responses. Although in many instances thyroid hormone-induced changes in receptor number are reflected in coordinate changes in adrenergic sensitivity, this is shown to be by no means uniformly the case. In contrasting instances, modifications at other more distal sites in the sequence of events mediating catecholamine hormone action are responsible for biochemical and physiological changes in catecholamine responsiveness induced by thyroid hormone.

  20. Cardiac cAMP: production, hydrolysis, modulation and detection

    PubMed Central

    Boularan, Cédric; Gales, Céline

    2015-01-01

    Cyclic adenosine 3′,5′-monophosphate (cAMP) modulates a broad range of biological processes including the regulation of cardiac myocyte contractile function where it constitutes the main second messenger for β-adrenergic receptors' signaling to fulfill positive chronotropic, inotropic and lusitropic effects. A growing number of studies pinpoint the role of spatial organization of the cAMP signaling as an essential mechanism to regulate cAMP outcomes in cardiac physiology. Here, we will briefly discuss the complexity of cAMP synthesis and degradation in the cardiac context, describe the way to detect it and review the main pharmacological arsenal to modulate its availability. PMID:26483685

  1. Influence of parasympathetic non-adrenergic, non-cholinergic mechanisms on [3H]thymidine uptake in rat parotid salivary glands in response to mastication following upon a liquid regimen.

    PubMed

    Ekström, J; Reinhold, A C

    2001-12-01

    A role for parasympathetic non-adrenergic, non-cholinergic (NANC) mechanisms in parotid gland cell hyperplasia in response to mastication was investigated. Following a liquid regimen for 1 week, aiming at glandular inactivity, rats were offered hard chow for 2 h to throw their parotid glands into secretory activity. In response to the increasing demands, [3H]thymidine incorporation into the trichloroacetic acid-insoluble material increased by 76% in normally innervated glands, while there was no increase in glands parasympathetically denervated in advance. In innervated glands of rats pretreated with atropine and alpha- and beta-adrenoceptor blockers the increase was 46%. The results suggest a potential contribution of parasympathetic NANC mechanisms to the mitotic response of the parotid gland under natural feeding conditions.

  2. Cardiovascular and metabolic alterations in mice lacking both beta1- and beta2-adrenergic receptors.

    PubMed

    Rohrer, D K; Chruscinski, A; Schauble, E H; Bernstein, D; Kobilka, B K

    1999-06-11

    The activation state of beta-adrenergic receptors (beta-ARs) in vivo is an important determinant of hemodynamic status, cardiac performance, and metabolic rate. In order to achieve homeostasis in vivo, the cellular signals generated by beta-AR activation are integrated with signals from a number of other distinct receptors and signaling pathways. We have utilized genetic knockout models to test directly the role of beta1- and/or beta2-AR expression on these homeostatic control mechanisms. Despite total absence of beta1- and beta2-ARs, the predominant cardiovascular beta-adrenergic subtypes, basal heart rate, blood pressure, and metabolic rate do not differ from wild type controls. However, stimulation of beta-AR function by beta-AR agonists or exercise reveals significant impairments in chronotropic range, vascular reactivity, and metabolic rate. Surprisingly, the blunted chronotropic and metabolic response to exercise seen in beta1/beta2-AR double knockouts fails to impact maximal exercise capacity. Integrating the results from single beta1- and beta2-AR knockouts as well as the beta1-/beta2-AR double knock-out suggest that in the mouse, beta-AR stimulation of cardiac inotropy and chronotropy is mediated almost exclusively by the beta1-AR, whereas vascular relaxation and metabolic rate are controlled by all three beta-ARs (beta1-, beta2-, and beta3-AR). Compensatory alterations in cardiac muscarinic receptor density and vascular beta3-AR responsiveness are also observed in beta1-/beta2-AR double knockouts. In addition to its ability to define beta-AR subtype-specific functions, this genetic approach is also useful in identifying adaptive alterations that serve to maintain critical physiological setpoints such as heart rate, blood pressure, and metabolic rate when cellular signaling mechanisms are perturbed.

  3. Cardiac catheterization - discharge

    MedlinePlus

    Catheterization - cardiac - discharge; Heart catheterization - discharge: Catheterization - cardiac; Heart catheterization; Angina - cardiac catheterization discharge; CAD - cardiac catheterization discharge; Coronary artery disease - cardiac catheterization ...

  4. Norepinephrine regulates cocaine-primed reinstatement via α1-adrenergic receptors in the medial prefrontal cortex.

    PubMed

    Schmidt, Karl T; Schroeder, Jason P; Foster, Stephanie L; Squires, Katherine; Smith, Brilee M; Pitts, Elizabeth G; Epstein, Michael P; Weinshenker, David

    2017-06-01

    Drug-primed reinstatement of cocaine seeking in rats is thought to reflect relapse-like behavior and is mediated by the integration of signals from mesocorticolimbic dopaminergic projections and corticostriatal glutamatergic innervation. Cocaine-primed reinstatement can also be attenuated by systemic administration of dopamine β-hydroxylase (DBH) inhibitors, which prevent norepinephrine (NE) synthesis, or by α1-adrenergic receptor (α1AR) antagonists, indicating functional modulation by the noradrenergic system. In the present study, we sought to further discern the role of NE in cocaine-seeking behavior by determining whether α1AR activation can induce reinstatement on its own or is sufficient to permit cocaine-primed reinstatement in the absence of all other AR signaling, and identifying the neuroanatomical substrate within the mesocorticolimbic reward system harboring the critical α1ARs. We found that while intracerebroventricular infusion of the α1AR agonist phenylephrine did not induce reinstatement on its own, it did overcome the blockade of cocaine-primed reinstatement by the DBH inhibitor nepicastat. Furthermore, administration of the α1AR antagonist terazosin in the medial prefrontal cortex (mPFC), but not the ventral tegmental area (VTA) or nucleus accumbens (NAc) shell, attenuated cocaine-primed reinstatement. Combined, these data indicate that α1AR activation in the mPFC is required for cocaine-primed reinstatement, and suggest that α1AR antagonists merit further investigation as pharmacotherapies for cocaine dependence. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Chemistry, physiology, and pharmacology of β-adrenergic mechanisms in the heart. Why are β-blocker antiarrhythmics superior?

    PubMed

    Szentmiklosi, A József; Szentandrássy, Norbert; Hegyi, Bence; Horvath, Balázs; Magyar, János; Bányász, Tamás; Nanasi, Peter P

    2015-01-01

    Stimulation of β-adrenergic receptors in the heart is the most effective endogenous way to increase the mechanical performance of cardiac tissues to meet the requirements of a fight-or-flight situation or stress. On the other hand, sustained activation of cardiac β-receptors initiates maladaptive remodeling of the myocardium leading to cardiomyopathies and heart failure. Since both acute and chronic stimulation of β-adrenoceptors are arrhythmogenic, the application of β-receptor blockers exerts effective antiarrhytmic actions at both short and long time scale. Compared to other classes of antiarrhythmic agents, β-blockers are the class of antiarrhythmics that was shown to decrease mortality in postinfarct patients. Chemical, physiological, and pharmacological properties of the β-adrenoceptor related signaling, the role of β-1, β-2, and β-3 receptor subtypes, consequences of acute and long term β-adrenergic stimulation and the underlying proarrhythmic mechanisms, including the changes in cardiac ion currents and Ca(2+) handling, are reviewed in this paper together with the clinical relevance of cardioprotective β-blocking therapy.

  6. Adrenergic Signaling Regulates Mitochondrial Ca2+ Uptake Through Pyk2-Dependent Tyrosine Phosphorylation of the Mitochondrial Ca2+ Uniporter

    PubMed Central

    Jhun, Bong Sook; Xu, Shangcheng; Hurst, Stephen; Raffaello, Anna; Liu, Xiaoyun; Yi, Bing; Zhang, Huiliang; Gross, Polina; Mishra, Jyotsna; Ainbinder, Alina; Kettlewell, Sarah; Smith, Godfrey L.; Dirksen, Robert T.; Wang, Wang; Rizzuto, Rosario

    2014-01-01

    Abstract Aims: Mitochondrial Ca2+ homeostasis is crucial for balancing cell survival and death. The recent discovery of the molecular identity of the mitochondrial Ca2+ uniporter pore (MCU) opens new possibilities for applying genetic approaches to study mitochondrial Ca2+ regulation in various cell types, including cardiac myocytes. Basal tyrosine phosphorylation of MCU was reported from mass spectroscopy of human and mouse tissues, but the signaling pathways that regulate mitochondrial Ca2+ entry through posttranslational modifications of MCU are completely unknown. Therefore, we investigated α1-adrenergic-mediated signal transduction of MCU posttranslational modification and function in cardiac cells. Results: α1-adrenoceptor (α1-AR) signaling translocated activated proline-rich tyrosine kinase 2 (Pyk2) from the cytosol to mitochondrial matrix and accelerates mitochondrial Ca2+ uptake via Pyk2-dependent MCU phosphorylation and tetrametric MCU channel pore formation. Moreover, we found that α1-AR stimulation increases reactive oxygen species production at mitochondria, mitochondrial permeability transition pore activity, and initiates apoptotic signaling via Pyk2-dependent MCU activation and mitochondrial Ca2+ overload. Innovation: Our data indicate that inhibition of α1-AR-Pyk2-MCU signaling represents a potential novel therapeutic target to limit or prevent mitochondrial Ca2+ overload, oxidative stress, mitochondrial injury, and myocardial death during pathophysiological conditions, where chronic adrenergic stimulation is present. Conclusion: The α1-AR-Pyk2-dependent tyrosine phosphorylation of the MCU regulates mitochondrial Ca2+ entry and apoptosis in cardiac cells. Antioxid. Redox Signal. 21, 863–879. PMID:24800979

  7. TNFα reverse signaling promotes sympathetic axon growth and target innervation

    PubMed Central

    Kisiswa, Lilian; Osório, Catarina; Erice, Clara; Vizard, Thomas; Wyatt, Sean; Davies, Alun M

    2013-01-01

    Reverse signaling via members of the tumor necrosis factor (TNF) superfamily is increasingly recognized among cells of the immune system where it controls multiple aspects of immune function. Here we document TNFα reverse signaling in the nervous system for the first time and show that it plays a crucial role in establishing sympathetic innervation. During postnatal development, sympathetic axons express TNFα as they grow and branch in their target tissues which in turn express TNFR1. In culture, soluble forms of TNFR1 act directly on postnatal sympathetic axons to promote growth and branching by a mechanism that depends on membrane integrated TNFα and downstream MEK/ERK activation. Sympathetic innervation density is significantly reduced in several tissues in postnatal and adult mice lacking either TNFα or TNFR1. These findings reveal that target-derived TNFR1 acts as a reverse signaling ligand for membrane-integrated TNFα to promote sympathetic axon growth and branching. PMID:23749144

  8. Structure and innervation of extraocular muscles of Carassius.

    PubMed Central

    Davey, D F; Mark, R F; Marotte, L R; Proske, U

    1975-01-01

    The extraocular muscles of the carp Carassius contain two types of muscle fibre. Large white fibres have ribbon-shaped peripheral myofibrils and triads located at the Z line. Small red fibres, rich in mitochondria, have polygonal-shaped myofibrils and triads at the A-I junction. Silver- and cholinesterase-stained preparations show that the large fibres are innervated by axons which spiral around them and exhibit intense cholinesterase activity over long distances. Axons supplying small muscle fibres run across bundles of fibres, making one contact with each fibre. By electron microscopy the nerve endings on each fibre type appear identical, both having a smooth post-junctional muscle membrane. The differences in structure and innervation pattern of the two fibre types are discussed in relation to their possible functional roles. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 PMID:1184453

  9. The ischiourethralis muscle of the rat: anatomy, innervation, and function.

    PubMed

    Dail, W G; Sachs, B D

    1991-02-01

    The ischiourethralis (IU), a striated perineal muscle presumed to be involved in sexual reflexes, was studied in the rat. The paired muscle arises from the penile crus and the penile bulb and unites in a raphe over the deep dorsal vein of the penis. Retrograde tracing studies show that the muscle is innervated by neurons in the dorsolateral nucleus of the lumbar spinal cord, a pudendal nerve motor nucleus which also innervates the ischiocavernosus muscle. Excision of the IU muscle did not interfere with the ability of males to display normal copulatory behavior, nor did it affect significantly the number and intensity of reflexive erections. It nevertheless remains possible that the IU may contribute to intense glans erection by compressing the deep dorsal vein.

  10. The innervated free toe web flap for clitoris reconstruction.

    PubMed

    Dabernig, Jörg; Shelley, Odhran P; Schaff, Jürgen

    2007-01-01

    Clitoris reconstruction is often used in transgender reassignment. Most techniques now reconstruct the clitoris using glans pedicled on the dorsal phallic neurovascular bundle. Other techniques of clitoris reconstruction re-shape retained elements of the proximal segment of the corpora cavernosa, as well as techniques mobilising local flaps. We are presenting a new technique for clitoris reconstruction using an innervated free web space flap. The operative technique and outcome are illustrated and discussed in this case report.

  11. The Histology and Histopathology of the Dental Innervation

    PubMed Central

    Bradlaw, Robert

    1939-01-01

    The presence of a perivascular neural plexus in the periodontal membrane suggests that the dental structures have both sensory and autonomic nerve supply. The fibres described by Mummery are unaffected by section of the inferior dental nerve although there is marked degeneration in all demonstrable nerves. Nerve-fibres have been observed describing simple and complex looping in the odontogenetic zone and others which, running tangentially between the odontoblast layer and the dentine, form a very definite nerve plexus. Attached to these nerve-fibres are numerous round or pear-shaped bodies which may be either nerve-cells or end-organs. Definite nerve-fibres have been traced into the dentine. The convoluted forms described by growing nerve-fibres approaching transplanted teeth did not resemble the nerve-loops previously reported in the periodontal membrane of monkey and man. Plexiform nerve-fibres have been seen in the gum of the cat and varicose nerve-fibres in the gum of the sheep. In man, intra-epithelial fibres have been observed which pass from the intra-papillary neural coils to terminate near the surface of the epithelium in knob-like endings. No abnormality of innervation has been found in supernumerary teeth and teeth from cleft palates, dentigerous and ovarian cysts, and in the pulps of denticles from compound odontomes. Since there is no difference in the innervation of heterogenous and autogenous tooth-germ transplants, whether of normal or abnormal form, it would seem that abnormalities of form are not due to abnormal innervation. The development and degeneration of the peripheral nerves and the changes produced in the dental innervation by local and general disease in man and experimental animals are described and discussed. ImagesFig. 8Fig. 9Fig. 10Fig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 11Fig. 12Fig. 13Fig. 14Fig. 15Fig. 16Fig. 17 PMID:19992023

  12. Sympathetic innervation of the ileocecal junction in horses.

    PubMed

    Russo, D; Bombardi, C; Grandis, A; Furness, J B; Spadari, A; Bernardini, C; Chiocchetti, R

    2010-10-01

    The distribution and chemical phenotypes of sympathetic and dorsal root ganglion (DRG) neurons innervating the equine ileocecal junction (ICJ) were studied by combining retrograde tracing and immunohistochemistry. Immunoreactivity (IR) for tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), neuronal nitric oxide synthase (nNOS), calcitonin gene-related peptide (CGRP), substance P (SP), and neuropeptide Y (NPY) was investigated. Sympathetic neurons projecting to the ICJ were distributed within the celiac (CG), cranial mesenteric (CranMG), and caudal mesenteric (CaudMG) ganglia, as well as in the last ganglia of the thoracic sympathetic chain and in the splanchnic ganglia. In the CG and CranMG 91 +/- 8% and 93 +/- 12% of the neurons innervating the ICJ expressed TH- and DBH-IR, respectively. In the CaudMG 90 +/- 15% and 94 +/- 5% of ICJ innervating neurons were TH- and DBH-IR, respectively. Sympathetic (TH-IR) fibers innervated the myenteric and submucosal ganglia, ileal blood vessels, and the muscle layers. They were more concentrated at the ICJ level and were also seen encircling myenteric plexus (MP) and submucosal plexus (SMP) descending neurons that were retrogradely labeled from the ICJ. Among the few retrogradely labeled DRG neurons, nNOS-, CGRP-, and SP-IR nerve cells were observed. Dense networks of CGRP-, nNOS-, and SP-IR varicosities were seen around retrogradely labeled prevertebral ganglia neurons. The CGRP-IR fibers are probably the endings of neurons projecting from the intestine to the prevertebral ganglia. These findings indicate that this crucial region of the intestinal tract is strongly influenced by the sympathetic system and that sensory information of visceral origin influences the sympathetic control of the ICJ.

  13. Ovarian innervation develops before initiation of folliculogenesis in the rat.

    PubMed

    Malamed, S; Gibney, J A; Ojeda, S R

    1992-10-01

    Sympathetic neurotransmitters have been shown to be present in the ovary of the rat during early postnatal development and to affect steroidogenesis before the ovary becomes responsive to gonadotropins, and before the first primordial follicles are formed. This study was undertaken to determine if development of the ovarian innervation is an event that antedates the initiation of folliculogenesis in the rat, Rattus norvegicus. Serial sections of postnatal ovaries revealed a negligible frequency of follicles 24 h after birth (about 1 primordial follicle per ovary). Twelve hours later there were about 500 follicles per ovary, a number that more than doubled to about 1300 during the subsequent 12 h, indicating that an explosive period of follicular differentiation occurs between the end of postnatal days 1 and 2. Electron microscopy demonstrated that before birth the ovaries are already innervated by fibers containing clear and dense-core vesicles. Immunohistochemistry performed on either fetal (day 19) or newborn (less than 15h after birth) ovaries showed the presence of catecholaminergic nerves, identified by their content of immunoreactive tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. While some of these fibers innervate blood vessels, others are associated with primordial ovarian cells, thereby suggesting their participation in non-vascular functions. Since prefollicular ovaries are insensitive to gonadotropins, the results suggest that the developing ovary becomes subjected to direct neurogenic influences before it acquires responsiveness to gonadotropins.

  14. Genetics-based manipulation of adipose tissue sympathetic innervation.

    PubMed

    François, Marie; Qualls-Creekmore, Emily; Berthoud, Hans-Rudolf; Münzberg, Heike; Yu, Sangho

    2017-08-28

    There is renewed interest in leveraging the thermogenic capacity of brown adipose tissue (BAT) and browning of white adipose tissue (WAT) to improve energy balance and prevent obesity. In addition to these effects on energy expenditure, both BAT and WAT secrete large numbers of hormones and cytokines that play important roles in maintaining metabolic health. Both BAT and WAT are densely innervated by the sympathetic nervous system (SNS) and this innervation is crucial for BAT thermogenesis and WAT browning, making it a potentially interesting target for manipulating energy balance and treatment of obesity and metabolic disease. Peripheral neuromodulation in the form of electrical manipulation of the SNS and parasympathetic nervous system (PSNS) has been used for the management of pain and many other conditions, but progress is hampered by lack of detailed knowledge of function-specific neurons and nerves innervating particular organs and tissues. Therefore, the goal of the National Institutes of Health (NIH) Common Fund project "Stimulating Peripheral Activity to Relieve Conditions (SPARC)" is to comprehensively map both anatomical and neurochemical aspects of the peripheral nervous system in animal model systems to ultimately guide optimal neuromodulation strategies in humans. Compared to electrical manipulation, neuron-specific opto- and chemogenetic manipulation, now being extensively used to decode the function of brain circuits, will further increase the functional specificity of peripheral neuromodulation. Copyright © 2017. Published by Elsevier Inc.

  15. Adrenergic receptors in human fetal liver membranes

    SciTech Connect

    Falkay, G.; Kovacs, L. )

    1990-01-01

    The adrenergic receptor binding capacities in human fetal and adult livers were measured to investigate the mechanism of the reduced alpha-1 adrenoreceptor response of the liver associated with a reciprocal increase in beta-adrenoreceptor activity in a number of conditions. Alpha-1 and beta-adrenoreceptor density were determined using {sup 3}H-prazosin and {sup 3}H-dihydroalprenolol, respectively, as radioligand. Heterogeneous populations of beta-adrenoreceptors were found in fetal liver contrast to adult. Decreased alpha-1 and increased beta-receptor density were found which may relate to a decreased level in cellular differentiation. These findings may be important for the investigation of perinatal hypoglycemia of newborns after treatment of premature labor with beta-mimetics. This is the first demonstration of differences in the ratio of alpha-1 and beta-adrenoceptors in human fetal liver.

  16. Effect of cardiopulmonary bypass on beta adrenergic receptor-adenylate cyclase system on surfaces of peripheral lymphocytes.

    PubMed

    Luo, A; Tian, Y; Jin, S

    2000-01-01

    The experimental results showed that the level of CAMP, the ratio of cAPM to cGMP, IL-2R expression and IL-2 production in vitro in lymphocytes immediate and 2 weeks after cardiopulmonary bypass (CPB) were significantly lower than those before anesthetics in the patients undergoing cardiac surgery with CPB. These findings suggested that CPB could cause serious damage to adrenergic beta receptor-adenylate cyclase system on circulating lymphocytes surfaces, which might be one of the mechanisms resulting in immunosuppression after open heart surgery with CPB.

  17. Adrenergic Polymorphism and the Human Stress Response

    PubMed Central

    Rao, Fangwen; Zhang, Lian; Wessel, Jennifer; Zhang, Kuixing; Wen, Gen; Kennedy, Brian P.; Rana, Brinda K.; Das, Madhusudan; Rodriguez-Flores, Juan L.; Smith, Douglas W.; Cadman, Peter E.; Salem, Rany M.; Mahata, Sushil K.; Schork, Nicholas J.; Taupenot, Laurent; Ziegler, Michael G.; O’Connor, Daniel T.

    2009-01-01

    Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. Does common genetic variation at human TH alter autonomic activity and predispose to cardiovascular disease? We undertook systematic polymorphism discovery at the TH locus, and then tested variants for contributions to sympathetic function and blood pressure. We resequenced 80 ethnically diverse individuals across the TH locus. One hundred seventy-two twin pairs were evaluated for sympathetic traits, including catecholamine production and environmental (cold) stress responses. To evaluate hypertension, we genotyped subjects selected from the most extreme diastolic blood pressure percentiles in the population. Human TH promoter haplotype/reporter plasmids were transfected into chromaffin cells. Forty-nine single nucleotide polymorphisms (SNPs) and one tetranucleotide repeat were discovered, but coding region polymorphism did not account for common phenotypic variation. A block of linkage disequilibrium spanned four common variants in the proximal promoter. Catecholamine secretory traits were significantly heritable, as were stress-induced blood pressure changes. In the TH promoter, significant associations were found for urinary catecholamine excretion, as well as blood pressure response to stress. TH promoter haplotype #2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. In hypertension, a case–control study (1266 subjects, 53% women) established the effect of C-824T in determination of blood pressure. We conclude that human catecholamine secretory traits are heritable, displaying joint genetic determination (pleiotropy) with autonomic activity and finally with blood pressure in the population. Catecholamine secretion is influenced by genetic variation in the adrenergic pathway encoding catecholamine synthesis, especially at the classically rate-limiting step, TH. The results suggest novel pathophysiological links between a key

  18. Postsynaptic α1-Adrenergic Vasoconstriction Is Impaired in Young Patients With Vasovagal Syncope and Is Corrected by Nitric Oxide Synthase Inhibition.

    PubMed

    Stewart, Julian M; Suggs, Melissa; Merchant, Sana; Sutton, Richard; Terilli, Courtney; Visintainer, Paul; Medow, Marvin S

    2016-08-01

    Syncope is a sudden transient loss of consciousness and postural tone with spontaneous recovery; the most common form is vasovagal syncope (VVS). During VVS, gravitational pooling excessively reduces central blood volume and cardiac output. In VVS, as in hemorrhage, impaired adrenergic vasoconstriction and venoconstriction result in hypotension. We hypothesized that impaired adrenergic responsiveness because of excess nitric oxide can be reversed by reducing nitric oxide. We recorded cardiopulmonary dynamics in supine syncope patients and healthy volunteers (aged 15-27 years) challenged with a dose-response using the α1-agonist phenylephrine (PE), with and without the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine, monoacetate salt (L-NMMA). Systolic and diastolic pressures among control and VVS were the same, although they increased after L-NMMA and saline+PE (volume and pressor control for L-NMMA). Heart rate was significantly reduced by L-NMMA (P<0.05) for control and VVS compared with baseline, but there was no significant difference in heart rate between L-NMMA and saline+PE. Cardiac output and splanchnic blood flow were reduced by L-NMMA for control and VVS (P<0.05) compared with baseline, while total peripheral resistance increased (P<0.05). PE dose-response for splanchnic flow and resistance were blunted for VVS compared with control after saline+PE, but enhanced after L-NMMA (P<0.001). Postsynaptic α1-adrenergic vasoconstrictive impairment was greatest in the splanchnic vasculature, and splanchnic blood flow was unaffected by PE. Forearm and calf α1-adrenergic vasoconstriction were unimpaired in VVS and unaffected by L-NMMA. Impaired postsynaptic α1-adrenergic vasoconstriction in young adults with VVS can be corrected by nitric oxide synthase inhibition, demonstrated with our use of L-NMMA. © 2016 American Heart Association, Inc.

  19. Identification of motoneurons supplying multiply- or singly-innervated extraocular muscle fibers in the rat.

    PubMed

    Eberhorn, A C; Büttner-Ennever, J A; Horn, A K E

    2006-02-01

    In mammals, the extraocular muscle fibers can be categorized in singly-innervated and multiply-innervated muscle fibers. In the monkey oculomotor, trochlear and abducens nucleus the motoneurons of multiply-innervated muscle fibers lie separated from those innervating singly-innervated muscle fibers and show different histochemical properties. In order to discover, if this organization is a general feature of the oculomotor system, we investigated the location of singly-innervated muscle fiber and multiply-innervated muscle fiber motoneurons in the rat using combined tract-tracing and immunohistochemical techniques. The singly-innervated muscle fiber and multiply-innervated muscle fiber motoneurons of the medial and lateral rectus muscle were identified by retrograde tracer injections into the muscle belly or the distal myotendinous junction. The belly injections labeled the medial rectus muscle subgroup of the oculomotor nucleus or the greatest part of abducens nucleus, including some cells outside the medial border of abducens nucleus. In contrast, the distal injections labeled only a subset of the medial rectus muscle motoneurons and exclusively cells outside the medial border of abducens nucleus. The tracer detection was combined with immunolabeling using antibodies for perineuronal nets (chondroitin sulfate proteoglycan) and non-phosphorylated neurofilaments. In monkeys both antibodies permit a distinction between singly-innervated muscle fiber and multiply-innervated muscle fiber motoneurons. The experiments revealed that neurons labeled from a distal injection lack both markers and are assumed to represent multiply-innervated muscle fiber motoneurons, whereas those labeled from a belly injection are chondroitin sulfate proteoglycan- and non-phosphorylated neurofilament-immunopositive and assumed to represent singly-innervated muscle fiber motoneurons. The overall identification of multiply-innervated muscle fiber and singly-innervated muscle fiber motoneurons

  20. Beta-adrenergic receptor sensitivity, autonomic balance and serotonergic activity in practitioners of Transcendental Meditation

    SciTech Connect

    Hill, D.A.

    1989-01-01

    The aim of this thesis was to investigate the acute autonomic effects of the Transcendental Meditation Program (TM) and resolve the conflict arising from discrepant neurochemical and psychophysiological data. Three experimental investigations were performed. The first examined beta{sub 2}-adrenergic receptors (AR's) on peripheral blood lymphocytes, via (I{sup 125})iodocyanopindolol binding, in 10 male mediating and 10 age matched non-meditating control subjects, to test the hypothesis that the long-term practice of TM and the TM Sidhi Program (TMSP) reduces end organ sensitivity to adrenergic agonists. The second investigated respiratory sinus arrhythmia (an indirect measure of cardiac Parasympathetic Nervous System tone), and skin resistance (a measure of Sympathetic Nervous System tone) during periods of spontaneous respiratory apneusis, a phenomenon occurring during TM that is known to mark the subjective experience of transcending. The third was within subject investigation of the acute effects of the TMSP on 5-hydroxytryptamine (5-HT) activity. Platelet 5-HT was assayed by high pressure liquid chromatography with electrochemical detection, plasma prolactin (PL) and lutenizing hormone (LH) by radioimmunoassay, tryptophan by spectrofluorimetry, and alpha-1-acid glycoprotein (AGP, a modulator of 5-HT uptake) by radial immunodiffusion assay.

  1. The structural basis for agonist and partial agonist action on a β(1)-adrenergic receptor.

    PubMed

    Warne, Tony; Moukhametzianov, Rouslan; Baker, Jillian G; Nehmé, Rony; Edwards, Patricia C; Leslie, Andrew G W; Schertler, Gebhard F X; Tate, Christopher G

    2011-01-13

    β-adrenergic receptors (βARs) are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins upon binding catecholamine agonist ligands such as adrenaline and noradrenaline. Synthetic ligands have been developed that either activate or inhibit βARs for the treatment of asthma, hypertension or cardiac dysfunction. These ligands are classified as either full agonists, partial agonists or antagonists, depending on whether the cellular response is similar to that of the native ligand, reduced or inhibited, respectively. However, the structural basis for these different ligand efficacies is unknown. Here we present four crystal structures of the thermostabilized turkey (Meleagris gallopavo) β(1)-adrenergic receptor (β(1)AR-m23) bound to the full agonists carmoterol and isoprenaline and the partial agonists salbutamol and dobutamine. In each case, agonist binding induces a 1 Å contraction of the catecholamine-binding pocket relative to the antagonist bound receptor. Full agonists can form hydrogen bonds with two conserved serine residues in transmembrane helix 5 (Ser(5.42) and Ser(5.46)), but partial agonists only interact with Ser(5.42) (superscripts refer to Ballesteros-Weinstein numbering). The structures provide an understanding of the pharmacological differences between different ligand classes, illuminating how GPCRs function and providing a solid foundation for the structure-based design of novel ligands with predictable efficacies.

  2. Thalamocortical Innervation Pattern in Mouse Auditory and Visual Cortex: Laminar and Cell-Type Specificity.

    PubMed

    Ji, Xu-Ying; Zingg, Brian; Mesik, Lukas; Xiao, Zhongju; Zhang, Li I; Tao, Huizhong W

    2016-06-01

    Despite many previous studies, the functional innervation pattern of thalamic axons and their target specificity remains to be investigated thoroughly. Here, in primary auditory cortical slices, we examined thalamic innervation patterns for excitatory and different types of inhibitory neurons across laminae, by optogenetically stimulating axons from the medial geniculate body. We found that excitatory cells and parvalbumin (PV)-expressing inhibitory neurons across layer 2/3 (L2/3) to L6 are directly innervated by thalamic projections, with the strongest innervation occurring in L4. The innervation of PV neurons is stronger than that of excitatory neurons in the same layer, with a relatively constant ratio between their innervation strengths across layers. For somatostatin and vasoactive intestinal peptide inhibitory neurons, essentially only L4 neurons were innervated by thalamic axons and the innervation was much weaker compared with excitatory and PV cells. In addition, more than half of inhibitory neurons in L1 were innervated, relatively strongly, by thalamic axons. Similar innervation patterns were also observed in the primary visual cortex. Thus, thalamic information can be processed independently and differentially by different cortical layers, in addition to the generally thought hierarchical processing starting from L4. This parallel processing is likely shaped by feedforward inhibition from PV neurons in each individual lamina, and may extend the computation power of sensory cortices.

  3. The innervation of the adrenal gland. IV. Innervation of the rat adrenal medulla from birth to old age. A descriptive and quantitative morphometric and biochemical study of the innervation of chromaffin cells and adrenal medullary neurons in Wistar rats.

    PubMed Central

    Tomlinson, A; Coupland, R E

    1990-01-01

    The innervation of the adrenal medulla has been investigated in normal Wistar rats from birth to old age and ultrastructural findings compared with biochemical markers of the cholinergic innervation of the adrenal gland and catecholamine storage. Morphological evidence of the immaturity of the innervation during the first postnatal week is provided and using quantitative morphometry the innervation of chromaffin cells is shown to reach a mean total of 5.4 synapses per chromaffin cell during the period 26 days to 12 weeks of age. The variation in contents of synaptic profiles is discussed in the light of recent work that demonstrates a major sensory as well as visceral efferent innervation of the gland. Adrenal medullary neurons usually occur in closely packed groups, intimately associated with Schwann cells. Axodendritic and axosomatic synapses on these neurons are described and the likely origin of axonal processes innervating the neurons discussed. In old age the density of innervation remains the same as in young adult animals even though the medulla shows evidence of hyperplasia and hypertrophy of individual chromaffin cells. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 Fig. 14 Fig. 15 Fig. 16 Fig. 17 Fig. 18 Fig. 19 Fig. 20 Fig. 21 Fig. 22 Fig. 23 Fig. 24 Fig. 25 PMID:2384334

  4. Exercise Testing, Training, and Beta-Adrenergic Blockade.

    ERIC Educational Resources Information Center

    Wilmore, Jack H.

    1988-01-01

    This article summarizes the current knowledge on the effects of beta-adrenergic blocking drugs, used widely for treatment of cardiovascular diseases, on exercise performance, training benefits, and exercise prescription. (IAH)

  5. Exercise Testing, Training, and Beta-Adrenergic Blockade.

    ERIC Educational Resources Information Center

    Wilmore, Jack H.

    1988-01-01

    This article summarizes the current knowledge on the effects of beta-adrenergic blocking drugs, used widely for treatment of cardiovascular diseases, on exercise performance, training benefits, and exercise prescription. (IAH)

  6. Pharmacologic specificity of alpha-2 adrenergic receptor subtypes

    SciTech Connect

    Petrash, A.; Bylund, D.

    1986-03-01

    The authors have defined alpha-2 adrenergic receptor subtypes in human and rat tissues using prazosin as a subtype selective drug. Prazosin has a lower affinity (250 nM) at alpha-2A receptor and a higher affinity (5 nM) at alpha-2B receptors. In order to determine if other adrenergic drugs are selective for one or the other subtypes, the authors performed (/sup 3/H)yohimbine inhibition experiments with various adrenergic drugs in tissues containing alpha-2A, alpha-2B or both subtypes. Oxymetazoline, WB4101 and yohimbine were found to be 80-, 20- and 10-fold more potent at alpha-2A receptors than at alpha-2B receptors. Phentolamine, adazoxan, (+)- and (-)-mianserin, clonidine, (+)-butaclamol, (-)- and (+)-norepinephrine, epinephrine, dopamine and thioridazine were found to have equal affinities for the two subtypes. These results further validate the subdivision of alpha-2 adrenergic receptors into alpha-2A and alpha-2B subtypes.

  7. Vagal modulation of cardiac ventricular arrhythmia.

    PubMed

    Ng, G André

    2014-02-01

    What is the topic of this review? This article addresses the relationship between vagus nerve activity and malignant ventricular arrhythmias. It focuses on the clinical association of an impaired vagal tone in cardiac disease states with high mortality from sudden cardiac death and the potential underlying mechanisms. What advances does it highlight? The article summarizes the mounting evidence that vagal innervation in the cardiac ventricle plays a key direct role in the prevention of the initiation of ventricular fibrillation. Data are presented on the role that nitric oxide plays in mediating the effects of vagal protection against ventricular fibrillation, supporting the notion that a separate non-muscarinic, nitrergic population of vagal neurons is responsible for this protection. Sudden cardiac death remains a significant unresolved clinical problem, with many of the deaths being due to malignant ventricular arrhythmias. Markers of abnormal autonomic function have been shown to be strong prognostic predictors, highlighting the important relationship between reduced vagal tone and malignant ventricular arrhythmias, such as ventricular fibrillation, in cardiac patients. Exploring the mechanisms underlying the autonomic modulation of ventricular fibrillation, my group has shown that vagus nerve stimulation protects against ventricular fibrillation in the innervated isolated heart preparation. We have provided direct evidence that nitric oxide is released in the ventricle with cervical vagus nerve stimulation and NO mediates the antifibrillatory actions of vagus nerve stimulation in the ventricle. Classical physiology teaches that vagal postganglionic nerves modulate the heart via acetylcholine acting at muscarinic receptors and, dogmatically, that there is little vagal effect in the ventricle, as innervation was believed to be sparse. Mounting evidence from many species now supports the presence of a rich vagal innervation in the ventricle. Data from my group

  8. Novel arylpiperazines as selective alpha1-adrenergic receptor antagonists.

    PubMed

    Li, X; Murray, W V; Jolliffe, L; Pulito, V

    2000-05-15

    A novel series of arylpiperazines has been synthesized and identified as antagonists of alpha1a adrenergic receptor (alpha1a-AR) implicated in benign prostatic hyperplasia. These compounds selectively bind to membrane bound alpha1a-AR with K(i)s as low as 0.66 nM. As such, these potentially represent a viable treatment for BPH without the side effects associated with known alpha1-adrenergic antagonists.

  9. Study of alteration of adrenergic receptor response by chronic use of lisinopril: an ACE inhibitor.

    PubMed

    Abrar, Hina; Aftab, Muhammad Tariq

    2013-03-01

    Unpredictable outcomes of life saving drugs have been seen in patients who receive different cardioselective drugs for longer periods. Many studies have been conducted to explore these responses. This study shows the down regulation of adrenergic receptors due to chronic use of lisinopril, an ACE inhibitor as a cause of poor response of adrenaline. Langendroff's technique was used. The data obtained from ten rabbits shows that effective dose of lisinopril (10mg/kg daily orally) reduces the inotropic and chronotropic effects of adrenaline significantly (P<0.05).Therefore it is suggested to use higher doses of adrenaline in cardiac units in patients who have used therapeutic doses of lisinopril for longer periods provided it is supported by clinical studies.

  10. Beta-adrenergic receptor antagonists and chronic heart failure in children

    PubMed Central

    Filippo, Sylvie Di

    2007-01-01

    Chronic congestive heart failure (HF) occurs in infants and children as a result of systemic ventricle incompetence. Neurohormonal activation is thought to be the main consequence of cardiac pump failure and cause of further worsening. Several large multicenter randomized trials have demonstrated that beta-adrenergic blocking agents can improve ventricular ejection fraction, symptoms, and survival in adults with chronic congestive HF. Current literature about pediatric HF is very scarce. The only large, multicenter, randomized, placebo-controlled pediatric trial failed to demonstrate any beneficial effect of beta-blockers in infants and children with chronic HF. Other small-size reports showed significant improvement in ejection fraction and/or clinical outcomes. The HF pediatric population is characterized by wide heterogeneicity regarding causes, underlying cardiac disease, drug pharmacokinetics, and interactions, which may account for divergences. Further large-scale studies are needed to elucidate the optimal use (indications and dosages) of beta-blockers in the management of HF in children, with particular attention to the underlying cardiac disease. PMID:18473008

  11. β-Adrenergic receptor antagonism in mice: a model for pediatric heart disease.

    PubMed

    Sucharov, Carmen C; Hijmans, Jamie G; Sobus, Rebecca D; Melhado, William F A; Miyamoto, Shelley D; Stauffer, Brian L

    2013-10-01

    Children with heart failure are treated with similar medical therapy as adults with heart failure. In contrast to adults with heart failure, these treatment regiments are not associated with improved outcomes in children. Recent studies have demonstrated age-related pathophysiological differences in the molecular mechanisms of heart failure between children and adults. There are no animal models of pediatric cardiomyopathy to allow mechanistic studies. The purpose of the current experiments was to develop a mouse model of pediatric heart disease and test whether the influence of β-adrenergic receptor (β-AR) antagonism could be modeled in this system. We hypothesized that isoproterenol treatment of young mice would provide a model system of cardiac pathology, and that nonselective β-AR blockade would provide benefit in adult, but not young, mice, similar to clinical trial data. We found that isoproterenol treatment (through osmotic minipump implantation) of young and adult mice produced similar degrees of cardiac hypertrophy and recapitulated several age-related molecular abnormalities in human heart failure, including phospholamban phosphorylation and β-AR expression. We also found that nonselective β-AR blockade effectively prevented pathological cardiac growth and collagen expression in the adult but not young mice, and that selective β1-AR blockade was effective in both young and adult isoproterenol-treated mice. In conclusion, we have developed the first model system for β-AR-mediated pediatric heart disease. Furthermore, we have generated novel data suggesting beneficial effects of selective β1-AR blockade in the pediatric heart.

  12. Cardiac Fibroblasts Regulate Sympathetic Nerve Sprouting and Neurocardiac Synapse Stability

    PubMed Central

    Mias, Céline; Coatrieux, Christelle; Denis, Colette; Genet, Gaël; Seguelas, Marie-Hélène; Laplace, Nathalie; Rouzaud-Laborde, Charlotte; Calise, Denis; Parini, Angelo; Cussac, Daniel; Pathak, Atul; Sénard, Jean-Michel; Galés, Céline

    2013-01-01

    Sympathetic nervous system (SNS) plays a key role in cardiac homeostasis and its deregulations always associate with bad clinical outcomes. To date, little is known about molecular mechanisms regulating cardiac sympathetic innervation. The aim of the study was to determine the role of fibroblasts in heart sympathetic innervation. RT-qPCR and western-blots analysis performed in cardiomyocytes and fibroblasts isolated from healthy adult rat hearts revealed that Pro-Nerve growth factor (NGF) and pro-differentiating mature NGF were the most abundant neurotrophins expressed in cardiac fibroblasts while barely detectable in cardiomyocytes. When cultured with cardiac fibroblasts or fibroblast-conditioned medium, PC12 cells differentiated into/sympathetic-like neurons expressing axonal marker Tau-1 at neurites in contact with cardiomyocytes. This was prevented by anti-NGF blocking antibodies suggesting a paracrine action of NGF secreted by fibroblasts. When co-cultured with cardiomyocytes to mimic neurocardiac synapse, differentiated PC12 cells exhibited enhanced norepinephrine secretion as quantified by HPLC compared to PC12 cultured alone while co-culture with fibroblasts had no effect. However, when supplemented to PC12-cardiomyocytes co-culture, fibroblasts allowed long-term survival of the neurocardiac synapse. Activated fibroblasts (myofibroblasts) isolated from myocardial infarction rat hearts exhibited significantly higher mature NGF expression than normal fibroblasts and also promoted PC12 cells differentiation. Within the ischemic area lacking cardiomyocytes and neurocardiac synapses, tyrosine hydroxylase immunoreactivity was increased and associated with local anarchical and immature sympathetic hyperinnervation but tissue norepinephrine content was similar to that of normal cardiac tissue, suggesting depressed sympathetic function. Collectively, these findings demonstrate for the first time that fibroblasts are essential for the setting of cardiac sympathetic

  13. 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(+) (KATP) 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 β1-AR blocker atenolol, but not the β2-AR blocker ICI 118,551, providing evidence that wheel running reduced the sensitivity of the β1-AR. At 10 Hz, the KATP 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 β1-AR responsiveness and KATP 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 KATP 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

  14. Adrenergic receptor control mechanism for growth hormone secretion.

    PubMed

    Blackard, W G; Heidingsfelder, S A

    1968-06-01

    The influence of catecholamines on growth hormone secretion has been difficult to establish previously, possibly because of the suppressive effect of the induced hyperglycemia on growth hormone concentrations. In this study, an adrenergic receptor control mechanism for human growth hormone (HGH) secretion was uncovered by studying the effects of alpha and beta receptor blockade on insulin-induced growth hormone elevations in volunteer subjects. Alpha adrenergic blockade with phentolamine during insulin hypoglycemia, 0.1 U/kg, inhibited growth hormon elevations to 30-50% of values in the same subjects during insulin hypoglycemia without adrenergic blockade. More complete inhibition by phentolamine could not be demonstrated at a lower dose of insulin (0.05 U/kg). Beta adrenergic blockade with propranolol during insulin hypoglycemia significantly enhanced HGH concentrations in paired experiments. The inhibiting effect of alpha adrenergic receptor blockade on HGH concentrations could not be attributed to differences in blood glucose or free fatty acid values; however, more prolonged hypoglycemia and lower plasma free fatty acid values may have been a factor in the greater HGH concentrations observed during beta blockade. In the absence of insulin induced hypoglycemia, neither alpha nor beta adrenergic receptor blockade had a detectable effect on HGH concentrations. Theophylline, an inhibitor of cyclic 3'5'-AMP phosphodiesterase activity, also failed to alter plasma HGH concentrations. These studies demonstrate a stimulatory effect of alpha receptors and a possible inhibitory effect of beta receptors on growth hormone secretion.

  15. Amiloride interacts with renal. cap alpha. - and. beta. -adrenergic receptors

    SciTech Connect

    Howard, M.J.; Mullen, M.D.; Insel, P.A.

    1987-07-01

    The authors have used radioligand binding techniques to assess whether amiloride and certain analogues of amiloride (ethylisopropyl amiloride and benzamil) can bind to adrenergic receptors in the kidney. They found that amiloride could compete for (/sup 3/H)rauwolscine (..cap alpha../sub 2/-adrenergic receptors), (/sup 3/H)prazosin (..cap alpha../sub 1/-adrenergic receptors), and (/sup 125/I)iodocyanopindolol (..beta..-adrenergic receptors) binding in rat renal cortical membranes with inhibitor constants of 13.6 /plus minus/ 5.7, 24.4 /plus minus/ 7.4, and 8.36 /plus minus/ 13.5 ..mu..M, respectively. Ethylisopropyl amiloride and benzamil were from 2- to 25-fold more potent than amiloride in competing for radioligand binding sites in studies with these membranes. In addition, amiloride and the two analogues competed for (/sup 3/H)prazosin sites on intact Madin-Darby canine kidney cells and amiloride blocked epinephrine-stimulated prostaglandin E/sub 2/ production in these cells. They conclude that amiloride competes for binding to several classes of renal adrenergic receptors with a rank order of potency of ..cap alpha../sub 2/ > ..cap alpha../sub 1/ > ..beta... Binding to, and antagonism of, adrenergic receptors occurs at concentrations of amiloride that are lower than previously observed nonspecific interactions of this agent.

  16. Attenuation of Choroidal Neovascularization by β2-Adrenergic Receptor Antagonism

    PubMed Central

    Lavine, Jeremy A.; Sang, Yanzhi; Wang, Shoujian; Ip, Michael S.; Sheibani, Nader

    2013-01-01

    Objectives To determine if β-adrenergic blockade inhibits choroidal neovascularization (CNV) in a mouse model of laser-induced CNV, and to investigate the mechanism by which β-adrenoreceptor antagonism blunts CNV. Methods The impact of β-adrenoreceptor blockade on CNV was determined using the laser-induced CNV model. Briefly, mice were subjected to laser burns, inducing CNV, and treated with daily intraperitoneal injections of propranolol. Neovascularization was measured on choroidal-sclera flat mounts using intercellular adhesion molecule-2 immunofluorescence staining. The impact of β-adrenergic receptor signaling on expression of vascular endothelial growth factor (VEGF) was investigated using primary mouse choroidal endothelial cells (ChEC) and retinal pigment epithelial (RPE) cells. These cells were incubated with β-adrenoreceptor agonists and/or antagonists, and assayed for VEGF mRNA and protein levels. Results Propranolol-treated mice demonstrated a 50% reduction in laser-induced CNV. Norepinephrine treatment stimulated VEGF mRNA expression and protein secretion in both ChEC and RPE cells. This effect was blocked by β2-adrenoreceptor antagonism and mimicked by β2-adrenergic receptor agonists. Conclusions and Clinical Relevance β-Adrenergic blockade attenuated CNV. β2-Adrenergic receptors regulated VEGF expression in ChEC and RPE cells. Antagonists of β-adrenergic receptors are safe and well tolerated in patients with glaucoma and cardiovascular disease. Thus, blockade of β-adrenoreceptors may provide a new avenue to inhibit VEGF expression in CNV. PMID:23303344

  17. Monovalent cation and amiloride analog modulation of adrenergic ligand binding to the unglycosylated alpha 2B-adrenergic receptor subtype

    SciTech Connect

    Wilson, A.L.; Seibert, K.; Brandon, S.; Cragoe, E.J. Jr.; Limbird, L.E. )

    1991-04-01

    The unglycosylated alpha 2B subtype of the alpha 2-adrenergic receptor found in NG-108-15 cells possesses allosteric regulation of adrenergic ligand binding by monovalent cations and 5-amino-substituted amiloride analogs. These findings demonstrate that allosteric modulation of adrenergic ligand binding is not a property unique to the alpha 2A subtype. The observation that amiloride analogs as well as monovalent cations can modulate adrenergic ligand binding to the nonglycosylated alpha 2B subtype indicates that charge shielding due to carbohydrate moieties does not play a role in this allosteric modulation but, rather, these regulatory effects result from interactions of cations and amiloride analogs with the protein moiety of the receptor. Furthermore, the observation that both alpha 2A and alpha 2B receptor subtypes are modulated by amiloride analogs suggests that structural domains that are conserved between the two are likely to be involved in this allosteric modulation.

  18. Decreased adrenergic tone in acromegaly: evidence from direct recording of muscle sympathetic nerve activity.

    PubMed

    Seravalle, G; Carzaniga, C; Attanasio, R; Grassi, G; Lonati, L; Facchini, C; Cozzi, R; Fatti, L M; Montini, M; Vitale, G; Sciortino, G; Damanti, S; Brambilla, G; Cavagnini, F; Mancia, G; Scacchi, M

    2012-08-01

    Sympathovagal imbalance has been shown in acromegaly by indirect measurements of adrenergic tone. Data regarding direct measurement of sympathetic activity are lacking as yet. Aim of this study was to assess the adrenergic tone through direct recording of muscle sympathetic nerve activity (MSNA) in acromegalic patients. Fifteen patients (age 26-66 years, eight women) with newly diagnosed active acromegaly without hyperprolactinaemia, pituitary hormone deficiencies, obstructive sleep apnoea and cardiac hypertrophy, and 15 healthy subjects matched for age, sex and body mass index were recruited. After evaluating anthropometric and echocardiographic parameters, anterior pituitary function, glucose and lipid metabolism, and measuring plasma leptin, direct recording of sympathetic outflow via the microneurographic technique was performed. For similar anthropometric and metabolic parameters in patients and controls, HOMA index was significantly increased in the former (4·2 ± 2·39 vs 1·6 ± 0·19, P < 0·001). Surprisingly, this finding of insulin resistance was accompanied by a marked sympathetic inhibition (MSNA 18·3 ± 8·10 vs 37·3 ± 6·48 bursts/min, P < 0·0001, respectively in patients and controls). A reduction in plasma leptin (1·6 ± 1·04 vs 6·5 ± 2·01 μg/l, P < 0·0001) was also recorded in the patients. MSNA was positively correlated with leptin (P < 0·0001). Newly diagnosed acromegalic patients without cardiac hypertrophy display a decreased sympathetic outflow in spite of insulin resistance. This finding might be related to hypoleptinaemia. © 2012 Blackwell Publishing Ltd.

  19. Exercise mitigates homocysteine - β2-adrenergic receptor interactions to ameliorate contractile dysfunction in diabetes

    PubMed Central

    Mishra, Paras Kumar; Awe, Olubusayo; Metreveli, Naira; Qipshidze, Natia; Joshua, Irving G; Tyagi, Suresh C

    2011-01-01

    We tested the hypothesis that exercise ameliorates contractile dysfunction by interfering with homocysteine - β2-adrenergic receptor (AR) interactions, inducing β2-adrenergic response and Gs (stimulatory G adenylyl cyclase dependent protein kinase), and lowering homocysteine level in diabetes. The effect of homocysteine on β2-AR was determined by (a) scoring the β2-AR in the cardiomyocytes treated with high dose of homocysteine using flow cytometry, and (b) co-localizing homocysteine with Gs (an inducer of β2-AR) in the cardiomyocytes obtained from C57BL/ 6J (WT) and db/ db mice using confocal microscopy. The effect of exercise on the protein-protein interactions of homocysteine and β2-AR in diabetes was evaluated by co-immunoprecipitation in the four groups of db/db mice: (1) sedentary, (2) treated with salbutamol (a β2-AR agonist), (3) swimming exercise, and (4) swimming + salbutamol treatment. The effect of exercise on β2-AR was determined by RT-PCR and Western blotting while cardiac dysfunction was assessed by echocardiography, and contractility and calcium transient of cardiomyocytes from the above four groups. The results revealed that elevated level of homocysteine decreases the number of β2-AR and inhibits Gs in diabetes. However, exercise mitigates the interactions of homocysteine with β2-AR and induces β2-AR. Exercise also ameliorates cardiac dysfunction by enhancing the calcium transient of cardiomyocytes. To our knowledge, this is the first report showing mechanism of homocysteine mediated attenuation of β2-AR response in diabetes and effect of exercise on homocysteine - β2-AR interactions. PMID:21760968

  20. Mapping genetic variants associated with beta-adrenergic responses in inbred mice.

    PubMed

    Hersch, Micha; Peter, Bastian; Kang, Hyun Min; Schüpfer, Fanny; Abriel, Hugues; Pedrazzini, Thierry; Eskin, Eleazar; Beckmann, Jacques S; Bergmann, Sven; Maurer, Fabienne

    2012-01-01

    β-blockers and β-agonists are primarily used to treat cardiovascular diseases. Inter-individual variability in response to both drug classes is well recognized, yet the identity and relative contribution of the genetic players involved are poorly understood. This work is the first genome-wide association study (GWAS) addressing the values and susceptibility of cardiovascular-related traits to a selective β(1)-blocker, Atenolol (ate), and a β-agonist, Isoproterenol (iso). The phenotypic dataset consisted of 27 highly heritable traits, each measured across 22 inbred mouse strains and four pharmacological conditions. The genotypic panel comprised 79922 informative SNPs of the mouse HapMap resource. Associations were mapped by Efficient Mixed Model Association (EMMA), a method that corrects for the population structure and genetic relatedness of the various strains. A total of 205 separate genome-wide scans were analyzed. The most significant hits include three candidate loci related to cardiac and body weight, three loci for electrocardiographic (ECG) values, two loci for the susceptibility of atrial weight index to iso, four loci for the susceptibility of systolic blood pressure (SBP) to perturbations of the β-adrenergic system, and one locus for the responsiveness of QTc (p<10(-8)). An additional 60 loci were suggestive for one or the other of the 27 traits, while 46 others were suggestive for one or the other drug effects (p<10(-6)). Most hits tagged unexpected regions, yet at least two loci for the susceptibility of SBP to β-adrenergic drugs pointed at members of the hypothalamic-pituitary-thyroid axis. Loci for cardiac-related traits were preferentially enriched in genes expressed in the heart, while 23% of the testable loci were replicated with datasets of the Mouse Phenome Database (MPD). Altogether these data and validation tests indicate that the mapped loci are relevant to the traits and responses studied.

  1. IGF-1 Prevents Diastolic and Systolic Dysfunction Associated with Cardiomyopathy and Preserves Adrenergic Sensitivity

    PubMed Central

    Roof, Steve R.; Boslett, James; Russell, Duncan; del Rio, Carlos; Alecusan, Joe; Zweier, Jay L.; Ziolo, Mark T.; Hamlin, Robert; Mohler, Peter J.; Curran, Jerry

    2015-01-01

    Aims Insulin-like growth factor 1 (IGF-1)-dependent signaling promotes exercise-induced physiological cardiac hypertrophy. However, the in vivo therapeutic potential of IGF-1 for heart disease is not well established. Here we test the potential therapeutic benefits of IGF-1 on cardiac function using an in vivo model of chronic catecholamine-induced cardiomyopathy. Methods Rats were perfused with isoproterenol via osmotic pump (1 mg/kg/day) and treated with 2 mg/kg IGF-1 (2 mg/kg/day, 6 days a week) for 2 or 4 weeks. Echocardiography, ECG, and blood pressure were assessed. In vivo pressure-volume loop studies were conducted at 4 weeks. Heart sections were analyzed for fibrosis and apoptosis, and relevant biochemical signaling cascades were assessed. Results After 4 weeks, diastolic function (EDPVR, EDP, tau, E/A ratio), systolic function (PRSW, ESPVR, dP/dtmax), and structural remodeling (LV chamber diameter, wall thickness) were all adversely affected in isoproterenol-treated rats. All these detrimental effects were attenuated in rats treated with Iso+IGF-1. Isoproterenol-dependent effects on BP were attenuated by IGF-1 treatment. Adrenergic sensitivity was blunted in isoproterenol-treated rats but was preserved by IGF-1 treatment. Immunoblots indicate that cardioprotective p110α signaling and activated Akt are selectively upregulated in Iso+IGF-1 treated hearts. Expression of iNOS was significantly increased in both the Iso and Iso+IGF-1 groups, however tetrahydrobiopterin (BH4) levels were decreased in the Iso group and maintained by IGF-1 treatment. Conclusion IGF-1 treatment attenuates diastolic and systolic dysfunction associated with chronic catecholamine-induced cardiomyopathy while preserving adrenergic sensitivity and promoting BH4 production. These data support the potential use of IGF-1 therapy for clinical applications for cardiomyopathies. PMID:26399932

  2. Isoproterenol-produced damage in amphibian heart could be mediated by adrenergic receptors located in the heart muscle.

    PubMed

    Cano-Martínez, Agustina; Vargas-González, Alvaro; Guarner-Lans, Verónica; Prado-Zayago, Esteban

    2004-01-01

    In mammals, isoproterenol may produce heart damage in part by binding to adrenergic receptors in the coronary arteries. Previously we showed evidence that isoproterenol produces cellular necrosis and interstitial fibrosis in the ventricle of the heart of an amphibian, which has no coronary arteries. The present study examines responses to 3-adrenergic receptor stimulation in the heart of urodele amphibians. The hearts from three amphibians; Ambystoma mexicanum, A. tigrinum and A. dumerilii were mounted in an organ bath at 16+/-2 degrees C. The spontaneous isometric contractions (heart rate and isometric tension) were recorded using a tension transducer connected to polygraph. Concentration-response to isoproterenol in the presence and absence of propranolol (10(-6)) was recorded. The basal heart rate in the A. mexicanum heart was 19+/-2 beats/min and in A. tigrinum and A. dumerilii was 14+/-2 beats/min. The auricular tension was 284+/-15, 190+/-10, 140+/-8 mg, while the ventricular tension was of 62+/-3, 55+/-2 and 29+/-2 mg for A. mexicanum, A. tigrinum and A. dumenrilii respectively. Isoproterenol (10(-9), 10(-6), 10(-3) M) increased the heart rate and tension in a dose-dependent manner, and the effect was reversed in presence of propranolol. Our results indicate that isoproterenol-induced heart damage in urodele amphibians can be mediated by beta-adrenergic receptors located in the heart muscle. In the future, it will be necessary to characterize adrenergic receptor subtypes directly in these species, in order to understand the mechanism underlying the use of isoproterenol in experimental models of cardiac injury in non- mammalian vertebrates.

  3. Egr3 Dependent Sympathetic Target Tissue Innervation in the Absence of Neuron Death

    PubMed Central

    Li, Lin; Eldredge, Laurie C.; Quach, David H.; Honasoge, Avinash; Gruner, Katherine; Tourtellotte, Warren G.

    2011-01-01

    Nerve Growth Factor (NGF) is a target tissue derived neurotrophin required for normal sympathetic neuron survival and target tissue innervation. NGF signaling regulates gene expression in sympathetic neurons, which in turn mediates critical aspects of neuron survival, axon extension and terminal axon branching during sympathetic nervous system (SNS) development. Egr3 is a transcription factor regulated by NGF signaling in sympathetic neurons that is essential for normal SNS development. Germline Egr3-deficient mice have physiologic dysautonomia characterized by apoptotic sympathetic neuron death and abnormal innervation to many target tissues. The extent to which sympathetic innervation abnormalities in the absence of Egr3 is caused by altered innervation or by neuron death during development is unknown. Using Bax-deficient mice to abrogate apoptotic sympathetic neuron death in vivo, we show that Egr3 has an essential role in target tissue innervation in the absence of neuron death. Sympathetic target tissue innervation is abnormal in many target tissues in the absence of neuron death, and like NGF, Egr3 also appears to effect target tissue innervation heterogeneously. In some tissues, such as heart, spleen, bowel, kidney, pineal gland and the eye, Egr3 is essential for normal innervation, whereas in other tissues such as lung, stomach, pancreas and liver, Egr3 appears to have little role in innervation. Moreover, in salivary glands and heart, two tissues where Egr3 has an essential role in sympathetic innervation, NGF and NT-3 are expressed normally in the absence of Egr3 indicating that abnormal target tissue innervation is not due to deregulation of these neurotrophins in target tissues. Taken together, these results clearly demonstrate a role for Egr3 in mediating sympathetic target tissue innervation that is independent of neuron survival or neurotrophin deregulation. PMID:21980528

  4. β Adrenergic Receptor Kinase C-Terminal Peptide Gene-Therapy Improves β2-Adrenergic Receptor-Dependent Neoangiogenesis after Hindlimb Ischemia.

    PubMed

    Cannavo, Alessandro; Liccardo, Daniela; Lymperopoulos, Anastasios; Gambino, Giuseppina; D'Amico, Maria Loreta; Rengo, Franco; Koch, Walter J; Leosco, Dario; Ferrara, Nicola; Rengo, Giuseppe

    2016-02-01

    After hindlimb ischemia (HI), increased catecholamine levels within the ischemic muscle can cause dysregulation of β2-adrenergic receptor (β2AR) signaling, leading to reduced revascularization. Indeed, in vivo β2AR overexpression via gene therapy enhances angiogenesis in a rat model of HI. G protein-coupled receptor kinase 2 (GRK2) is a key regulator of βAR signaling, and β adrenergic receptor kinase C-terminal peptide (βARKct), a peptide inhibitor of GRK2, has been shown to prevent βAR down-regulation and to protect cardiac myocytes and stem cells from ischemic injury through restoration of β2AR protective signaling (i.e., protein kinase B/endothelial nitric oxide synthase). Herein, we tested the potential therapeutic effects of adenoviral-mediated βARKct gene transfer in an experimental model of HI and its effects on βAR signaling and on endothelial cell (EC) function in vitro. Accordingly, in this study, we surgically induced HI in rats by femoral artery resection (FAR). Fifteen days of ischemia resulted in significant βAR down-regulation that was paralleled by an approximately 2-fold increase in GRK2 levels in the ischemic muscle. Importantly, in vivo gene transfer of the βARKct in the hindlimb of rats at the time of FAR resulted in a marked improvement of hindlimb perfusion, with increased capillary and βAR density in the ischemic muscle, compared with control groups. The effect of βARKct expression was also assessed in vitro in cultured ECs. Interestingly, ECs expressing the βARKct fenoterol, a β2AR-agonist, induced enhanced β2AR proangiogenic signaling and increased EC function. Our results suggest that βARKct gene therapy and subsequent GRK2 inhibition promotes angiogenesis in a model of HI by preventing ischemia-induced β2AR down-regulation.

  5. The spatiotemporal development of innervation in spinal ligaments of chickens.

    PubMed Central

    Jiang, H; Moreau, M; Greidanus, N; Bilo, J; Russell, G; Raso, J; Bagnall, K

    1996-01-01

    The development of the innervation of both central and lateral (intertransverse) spinal ligaments was investigated in chickens between the time of hatching and 13 wk of age. A total of 36 White Leghorn chickens in 4 groups of 9 at ages 0, 2, 7, and 13 wk were used. The spinal ligaments were dissected, serially sectioned and labelled with a monoclonal antibody against neurofilament protein and observed using either conventional fluorescence or confocal microscopy. Only a few nerve elements were found in the ligaments at hatching and these consisted simply of single nerve fibres and small nerve bundles. The number of nerve elements increased rapidly up to 7 wk of age when large nerve bundles and Ruffini corpuscles were also found. The number of nerve elements decreased between 7 and 13 wk birds when the ligaments had begun to ossify and the amount of collagenous ligamentous tissue was significantly reduced. The fluctuation in numbers of neural elements was due to changes in numbers of single nerve fibres and small nerve bundles rather than large nerve bundles and Ruffini corpuscles which remained constant. In contrast to this significant increase in numbers of nerve elements, the innervation density of the ligaments decreased because of the overwhelming increase of the ligament volume due to growth. There were no differences between ligaments on the left and right sides of the body, but there was an unequal distribution of the neural elements within the ligaments; most were found in the cranial third of the intertransverse ligaments. These results show that significant changes in innervation of spinal ligaments occur during development and reflect the possibility that damage to the ligaments during this time could produce significant and permanent damage, especially in relation to the maintenance of an erect spine. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:8771396

  6. The spatiotemporal development of innervation in spinal ligaments of chickens.

    PubMed

    Jiang, H; Moreau, M; Greidanus, N; Bilo, J; Russell, G; Raso, J; Bagnall, K

    1996-08-01

    The development of the innervation of both central and lateral (intertransverse) spinal ligaments was investigated in chickens between the time of hatching and 13 wk of age. A total of 36 White Leghorn chickens in 4 groups of 9 at ages 0, 2, 7, and 13 wk were used. The spinal ligaments were dissected, serially sectioned and labelled with a monoclonal antibody against neurofilament protein and observed using either conventional fluorescence or confocal microscopy. Only a few nerve elements were found in the ligaments at hatching and these consisted simply of single nerve fibres and small nerve bundles. The number of nerve elements increased rapidly up to 7 wk of age when large nerve bundles and Ruffini corpuscles were also found. The number of nerve elements decreased between 7 and 13 wk birds when the ligaments had begun to ossify and the amount of collagenous ligamentous tissue was significantly reduced. The fluctuation in numbers of neural elements was due to changes in numbers of single nerve fibres and small nerve bundles rather than large nerve bundles and Ruffini corpuscles which remained constant. In contrast to this significant increase in numbers of nerve elements, the innervation density of the ligaments decreased because of the overwhelming increase of the ligament volume due to growth. There were no differences between ligaments on the left and right sides of the body, but there was an unequal distribution of the neural elements within the ligaments; most were found in the cranial third of the intertransverse ligaments. These results show that significant changes in innervation of spinal ligaments occur during development and reflect the possibility that damage to the ligaments during this time could produce significant and permanent damage, especially in relation to the maintenance of an erect spine.

  7. Leptin-sensitive sensory nerves innervate white fat

    PubMed Central

    Murphy, Keegan T.; Schwartz, Gary J.; Nguyen, Ngoc Ly T.; Mendez, Jennifer M.; Ryu, Vitaly

    2013-01-01

    Leptin, the primary white adipose tissue (WAT) adipokine, is thought to convey lipid reserve information to the brain via the circulation. Because WAT responds to environmental/internal signals in a fat pad-specific (FPS) manner, systemic signals such as leptin would fail to communicate such distinctive information. Saturation of brain leptin transport systems also would fail to convey increased lipid levels beyond that point. WAT possesses sensory innervation exemplified by proven sensory-associated peptides in nerves within the tissue and by viral sensory nerve-specific transneuronal tract tracer, H129 strain of herpes simplex virus 1 labeling of dorsal root ganglia (DRG) pseudounipolar neurons, spinal cord and central sensory circuits. Leptin as a paracrine factor activating WAT sensory innervation could supply the brain with FPS information. Therefore, we tested for and found the presence of the long form of the leptin receptor (Ob-Rb) on DRG pseudounipolar neurons immunohistochemically labeled after injections of Fluorogold, a retrograde tract tracer, into inguinal WAT (IWAT). Intra-IWAT leptin injections (300 ng) significantly elevated IWAT nerve spike rate within 5 min and persisted for at least 30 min. Intra-IWAT leptin injections also induced significant c-Fos immunoreactivity (ir), indicating neural activation across DRG pseudounipolar sensory neurons labeled with Fluorogold IWAT injections. Intraperitoneal leptin injection did not increase c-Fos-ir in DRG or the arcuate nucleus, nor did it increase arcuate signal transducer and activator of transcription 3 phosphorylation-ir. Collectively, these results strongly suggest that endogenous leptin secreted from white adipocytes functions as a paracrine factor to activate spinal sensory nerves innervating the tissue. PMID:23612999

  8. Innervated reverse dorsal digital island flap for fingertip reconstruction.

    PubMed

    Takeishi, Meisei; Shinoda, Akihiko; Sugiyama, Atsuki; Ui, Keito

    2006-09-01

    Various methods of fingertip reconstruction with a sensory flap have been reported. Digital island flaps or cross-finger flaps have to be used for large defects; however, the digital artery is sacrificed when creating conventional homodigital island flaps and 2 surgeries are required for the cross-finger flap. We describe our experience with an innervated reverse dorsal digital island flap that does not require sacrifice of the digital artery. We used innervated reverse dorsal digital flaps for fingertip reconstruction in 8 patients. The flap was supplied by the vascular network between the dorsal digital artery (the terminal branch of the dorsal metacarpal artery) and the dorsal branch of the digital artery. Venous drainage was through the cutaneous veins and the venous network associated with the dorsal arterial network. The flap was designed on either the dorsal proximal or the dorsal middle phalangeal region. The flap was harvested with the dorsal branch of the digital nerve (for the dorsal middle phalanx), the dorsal digital nerve (for the dorsal proximal phalanx), or the superficial branch of the radial nerve (for the thumb), which was anastomosed to the distal end of the digital nerve. After flap transfer the donor site was covered with a full-thickness skin graft. Of the 8 flaps, 6 survived completely, 1 had partial epithelial skin necrosis, and 1 showed central compression skin necrosis. Three flaps showed congestive changes from the first to the fifth day after surgery, which resolved by massage. All patients achieved satisfactory recovery of sensation; the static 2-point discrimination ranged from 3 mm to 5 mm and the Semmes-Weinstein test results ranged from 0.036 g to 0.745 g. The innervated reverse dorsal digital island flap provides another option for homodigital tip coverage. The advantages are that the digital artery is not sacrificed and only 1 surgery is needed. A disadvantage is the potential for venous congestion for the first 4 or 5 days after

  9. Dopaminergic innervation of interneurons in the rat basolateral amygdala

    PubMed Central

    Pinard, Courtney R.; Muller, Jay F.; Mascagni, Franco; McDonald, Alexander J.

    2008-01-01

    The basolateral nuclear complex of the amygdala (BLC) receives a dense dopaminergic innervation that plays a critical role in the formation of emotional memory. Dopamine has been shown to influence the activity of BLC GABAergic interneurons, which differentially control the activity of pyramidal cells. However, little is known about how dopaminergic inputs interface with different interneuronal subpopulations in this region. To address this question, dual-labeling immunohistochemical techniques were used at the light and electron microscopic levels to examine inputs from tyrosine hydroxylase-immunoreactive (TH+) dopaminergic terminals to two different interneuronal populations in the rat basolateral nucleus labeled using antibodies to parvalbumin (PV) or calretinin (CR). The basolateral nucleus exhibited a dense innervation by TH+ axons. Partial serial section reconstruction of TH+ terminals found that at least 43–50% of these terminals formed synaptic junctions in the basolateral nucleus. All of the synapses examined were symmetrical. In both TH/PV and TH/CR preparations the main targets of TH+ terminals were spines and distal dendrites of unlabeled cells. In sections dual-labeled for TH/PV 59% of the contacts of TH+ terminals with PV+ neurons were synapses, whereas in sections dual-labeled for TH/CR only 13% of the contacts of TH+ terminals with CR+ cells were synapses. In separate preparations examined in complete serial sections for TH+ basket-like innervation of PV+ perikarya, most (76.2%) of TH+ terminal contacts with PV+ perikarya were synapses. These findings suggest that PV+ interneurons, but not CR+ interneurons, are prominent synaptic targets of dopaminergic terminals in the BLC. PMID:18948174

  10. Frequency of isoproterenol hydrochloride-induced cardiac arrhythmia in 19 patients with chronic obstructive pulmonary disease: a prospective study.

    PubMed

    Assael, R; Martt, J M; Okeson, G C

    1975-06-01

    The incidence of adrenergic-induced arrhythmias was studied in 19 patients with chronic obstructive lung disease uncomplicated by respiratory failure or cardiac desease. The effects of isoproterenol hydrochloride and a placebo were studied, using a randomized double blind technique and continuous monitoring of the cardiac rhythm. Two of the patients had episodes of arrhythmia associated only with nebulization of isoproterenol hydrochloride. Ten patients had no abnormality associated with isoproterenol hydrochloride or placebo nebulizations. In the remainder, episodes of arrhythmia occurred but could not be consistently correlated with placebo or drug nrbulizations. None of the patients was aware of any cardiac irregularity. A chi square analysis of the dataindicated no relationship between the isoproterenol nebulizations and cardiac arrhythmias. In our patients with uncomplicated chronic obstructive lung disease, nebulization of adrenergic bronchodilators seemed an infrequent cause of cardiac arrhythmias.

  11. Evidence that antidromically stimulated vagal afferents activate inhibitory neurones innervating guinea-pig trachealis.

    PubMed Central

    Canning, B J; Undem, B J

    1994-01-01

    1. We recently described a capsaicin-sensitive vagal pathway mediating non-adrenergic, non-cholinergic (NANC) relaxations of an isolated, innervated rostral guinea-pig tracheal preparation. These afferent fibres are carried by the superior laryngeal nerves and relaxations elicited by their activation are insensitive to autonomic ganglion blockers such as hexamethonium. In the present study this vagal relaxant pathway was further characterized. 2. Relaxations of the trachealis elicited by electrical stimulation of capsaicin-sensitive vagal afferents were mimicked by bath application of capsaicin. Relaxations elicited by both methods were abolished when the tissue between the trachea and the adjacent oesophagus was disrupted. Indeed, separating the trachea from the oesophagus uncovered a contractile effect of capsaicin administration on the trachealis. 3. Capsaicin-induced, oesophagus-dependent relaxations of the trachealis were blocked by pretreatment with the fast sodium channel blocker tetrodotoxin (TTX). By contrast, capsaicin-induced contractions of the trachealis (obtained in the absence of the oesophagus) were unaffected by tetrodotoxin. 4. Substance P, neurokinin A (NKA) and neurokinin B (NKB) also elicited NANC relaxations of precontracted trachealis that were abolished by separating the trachea from the oesophagus or by TTX pretreatment. Like capsaicin, the tachykinins elicited only contractions of the trachealis following TTX pretreatment or separation of the trachea from the adjacent oesophagus. 5. Relaxations elicited by stimulation of the capsaicin-sensitive nerves were unaffected by a concentration of the tachykinin NK2 receptor-selective antagonist, SR 48968, that is selective for NK2 receptor blockade and were not mimicked by the NK2 receptor-selective agonist [beta-Ala8]-NKA(4-10). This suggests that NK2 receptors are not responsible for these relaxations. By contrast, the NK3 receptor-selective agonist, senktide analogue, and the NK1 receptor

  12. The oculomotor nucleus, not the abducent, innervates the muscles which advance the nictitating membrane in birds.

    PubMed

    Bravo, H; Inzunza, O

    1985-01-01

    The topographic distribution of the neurones that innervate the muscles that advance the nictitating membrane in birds was studied using intra-axonal retrograde transport of horseradish peroxidase. The motor neurones are distributed in the oculomotor complex of the ipsilateral and contralateral sides. In the ipsilateral side, the neurones innervating the pyramidalis muscles were located in the dorsolateral, dorsomedial and ventromedial subnuclei, while those neurones innervating the quadratus muscle were found in the dorsomedial and dorsolateral subnuclei. In the contralateral side the neurones innervating both the pyramidalis and quadratus were distributed in the ventromedial and ventrolateral subnuclei. The sensory neurones were found in the trigeminal ganglion and trigeminal mesencephalic nucleus.

  13. Localization of motoneurons innervating individual abdominal muscles of the cat

    NASA Technical Reports Server (NTRS)

    Miller, Alan D.

    1987-01-01

    The paper presents the results of a systematic investigation of the innervation of the cat's individual abdominal muscles. The segmental distribution of the different motor pools was determined by using electrical microstimulation of the ventral horn to produce visible localized muscle twitches and by retrograde transport of horseradish peroxidase injected into individual muscles. The segmental distribution of each motor pool was as follows: rectus abdominis, T4-L3; external oblique, T6-L3; transverse abdominis, T9-L3; and internal oblique, T13-L3.

  14. Localization of motoneurons innervating individual abdominal muscles of the cat

    NASA Technical Reports Server (NTRS)

    Miller, Alan D.

    1987-01-01

    The paper presents the results of a systematic investigation of the innervation of the cat's individual abdominal muscles. The segmental distribution of the different motor pools was determined by using electrical microstimulation of the ventral horn to produce visible localized muscle twitches and by retrograde transport of horseradish peroxidase injected into individual muscles. The segmental distribution of each motor pool was as follows: rectus abdominis, T4-L3; external oblique, T6-L3; transverse abdominis, T9-L3; and internal oblique, T13-L3.

  15. Spinally projecting preproglucagon axons preferentially innervate sympathetic preganglionic neurons

    PubMed Central

    Llewellyn-Smith, I.J.; Marina, N.; Manton, R.N.; Reimann, F.; Gribble, F.M.; Trapp, S.

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) affects central autonomic neurons, including those controlling the cardiovascular system, thermogenesis, and energy balance. Preproglucagon (PPG) neurons, located mainly in the nucleus tractus solitarius (NTS) and medullary reticular formation, produce GLP-1. In transgenic mice expressing glucagon promoter-driven yellow fluorescent protein (YFP), these brainstem PPG neurons project to many central autonomic regions where GLP-1 receptors are expressed. The spinal cord also contains GLP-1 receptor mRNA but the distribution of spinal PPG axons is unknown. Here, we used two-color immunoperoxidase labeling to examine PPG innervation of spinal segments T1–S4 in YFP-PPG mice. Immunoreactivity for YFP identified spinal PPG axons and perikarya. We classified spinal neurons receiving PPG input by immunoreactivity for choline acetyltransferase (ChAT), nitric oxide synthase (NOS) and/or Fluorogold (FG) retrogradely transported from the peritoneal cavity. FG microinjected at T9 defined cell bodies that supplied spinal PPG innervation. The deep dorsal horn of lower lumbar cord contained YFP-immunoreactive neurons. Non-varicose, YFP-immunoreactive axons were prominent in the lateral funiculus, ventral white commissure and around the ventral median fissure. In T1–L2, varicose, YFP-containing axons closely apposed many ChAT-immunoreactive sympathetic preganglionic neurons (SPN) in the intermediolateral cell column (IML) and dorsal lamina X. In the sacral parasympathetic nucleus, about 10% of ChAT-immunoreactive preganglionic neurons received YFP appositions, as did occasional ChAT-positive motor neurons throughout the rostrocaudal extent of the ventral horn. YFP appositions also occurred on NOS-immunoreactive spinal interneurons and on spinal YFP-immunoreactive neurons. Injecting FG at T9 retrogradely labeled many YFP-PPG cell bodies in the medulla but none of the spinal YFP-immunoreactive neurons. These results show that brainstem PPG neurons

  16. Spinally projecting preproglucagon axons preferentially innervate sympathetic preganglionic neurons.

    PubMed

    Llewellyn-Smith, I J; Marina, N; Manton, R N; Reimann, F; Gribble, F M; Trapp, S

    2015-01-22

    Glucagon-like peptide-1 (GLP-1) affects central autonomic neurons, including those controlling the cardiovascular system, thermogenesis, and energy balance. Preproglucagon (PPG) neurons, located mainly in the nucleus tractus solitarius (NTS) and medullary reticular formation, produce GLP-1. In transgenic mice expressing glucagon promoter-driven yellow fluorescent protein (YFP), these brainstem PPG neurons project to many central autonomic regions where GLP-1 receptors are expressed. The spinal cord also contains GLP-1 receptor mRNA but the distribution of spinal PPG axons is unknown. Here, we used two-color immunoperoxidase labeling to examine PPG innervation of spinal segments T1-S4 in YFP-PPG mice. Immunoreactivity for YFP identified spinal PPG axons and perikarya. We classified spinal neurons receiving PPG input by immunoreactivity for choline acetyltransferase (ChAT), nitric oxide synthase (NOS) and/or Fluorogold (FG) retrogradely transported from the peritoneal cavity. FG microinjected at T9 defined cell bodies that supplied spinal PPG innervation. The deep dorsal horn of lower lumbar cord contained YFP-immunoreactive neurons. Non-varicose, YFP-immunoreactive axons were prominent in the lateral funiculus, ventral white commissure and around the ventral median fissure. In T1-L2, varicose, YFP-containing axons closely apposed many ChAT-immunoreactive sympathetic preganglionic neurons (SPN) in the intermediolateral cell column (IML) and dorsal lamina X. In the sacral parasympathetic nucleus, about 10% of ChAT-immunoreactive preganglionic neurons received YFP appositions, as did occasional ChAT-positive motor neurons throughout the rostrocaudal extent of the ventral horn. YFP appositions also occurred on NOS-immunoreactive spinal interneurons and on spinal YFP-immunoreactive neurons. Injecting FG at T9 retrogradely labeled many YFP-PPG cell bodies in the medulla but none of the spinal YFP-immunoreactive neurons. These results show that brainstem PPG neurons

  17. β-Adrenergic stimulation activates protein kinase Cε and induces extracellular signal-regulated kinase phosphorylation and cardiomyocyte hypertrophy.

    PubMed

    Li, Lin; Cai, Hongyan; Liu, Hua; Guo, Tao

    2015-06-01

    The cardiac adrenergic signaling pathway is important in the induction of cardiac hypertrophy. The cardiac adrenergic pathway involves two main branches, phospholipase C (PLC)/protein kinase C (PKC) and the adenylate cyclase (cAMPase)/protein kinase A (PKA) signaling pathways. It is hypothesized that PLC/PKC and cAMPase/PKA are activated by the α‑adrenergic receptor (αAR) and the β‑adrenergic receptor (βAR), respectively. Previous studies have demonstrated that exchange protein directly activated by cAMP (Epac), a guanine exchange factor, activates phospholipase Cε. It is possible that there are βAR‑activated PKC pathways mediated by Epac and PLC. In the present study, the role of Epac and PLC in βAR activated PKC pathways in cardiomyocytes was investigated. It was found that PKCε activation and translocation were induced by the βAR agonist, isoproterenol (Iso). Epac agonist 8‑CPT‑2'OMe‑cAMP also enhanced PKCε activation. βAR stimulation activated PKCε in the cardiomyocytes and was regulated by Epac. Iso‑induced change in PKCε was not affected in the cardiomyocytes, which were infected with adenovirus coding rabbit muscle cAMP‑dependent protein kinase inhibitor. However, Iso‑induced PKCε activation was inhibited by the PLC inhibitor, U73122. The results suggested that Iso‑induced PKCε activation was independent of PKA, but was regulated by PLC. To further investigate the downstream signal target of PKCε activation, the expression of phosphorylated extracellular signal‑regulated kinase (pERK)1/2 and the levels of ERK phosphorylation was analyzed. The results revealed that Iso‑induced PKCε activation led to an increase in the expression of pERK1/2. ERK phosphorylation was inhibited by the PKCε inhibitor peptide. Taken together, these data demonstrated that the βAR is able to activate PKCε dependent on Epac and PLC, but independent of PKA.

  18. Adrenergic receptor and catecholamine distribution in rat cerebral cortex: binding studies with [3H]prazosin, [3H]idazoxan and [3H]dihydroalprenolol.

    PubMed

    Diop, L; Brière, R; Grondin, L; Reader, T A

    1987-02-03

    The tritiated adrenergic antagonists [3H]dihydroalprenolol ([3H]DHA; beta-receptors), [3H]prazosin ([3H]PRZ; alpha 1-receptors), and [3H]idazoxan ([3H]IDA; alpha 2-receptors) were used to determine the distribution of these sites in 5 defined areas of the adult rat cerebral cortex. The highest density of [3H]PRZ binding was found in the prefrontal cortex, with a lower and homogeneous distribution for the frontal, parietal, occipital and temporal areas. The [3H]IDA binding sites were fairly uniform for all areas, except for the temporal cortex where it was very dense. In contrast, beta-adrenoceptors labelled by [3H]DHA were very homogeneous for all the regions examined. The functional significance of the distribution of alpha 1, alpha 2 and beta-adrenoceptors is discussed in relation to the catecholamine innervation and monoamine contents measured by high performance liquid chromatography.

  19. Partial cardiac sympathetic denervation after bilateral thoracic sympathectomy in humans.

    PubMed

    Moak, Jeffrey P; Eldadah, Basil; Holmes, Courtney; Pechnik, Sandra; Goldstein, David S

    2005-06-01

    Upper thoracic sympathectomy is used to treat several disorders. Sympathetic nerve fibers emanating from thoracic ganglia innervate the heart. Whether unilateral or bilateral upper thoracic sympathectomy affects cardiac sympathetic innervation in humans in vivo has been unclear. The purpose of this study was to assess whether thoracic sympathectomy decreases cardiac sympathetic innervation, as indicated by positron emission tomographic scanning after intravenous injection of the sympathoneural imaging agent 6-[18F]fluorodopamine. Nine patients with previous upper thoracic sympathectomies (four right-sided, one left-sided, four bilateral) underwent thoracic 6-[18F]fluorodopamine scanning between 1 and 2 hours after injection of the imaging agent. In each case, a low rate of entry of norepinephrine into the arm venous drainage (norepinephrine spillover) verified upper limb sympathectomy. Data were compared with those from the interventricular septum of patients with cardiac sympathetic denervation associated with pure autonomic failure and from normal volunteers. All four patients with bilateral sympathectomy had low septal myocardial 6-[18F]fluorodopamine-derived radioactivity (2,673 +/- 92 nCi-kg/cc-mCi at an average of 89 minutes after injection) compared with normal volunteers (3,634 +/- 311 nCi-kg/cc-mCi at 83 minutes, N = 22, P = .007) and higher radioactivity than in patients with pure autonomic failure (1,320 +/- 300 nCi-kg/cc-mCi at 83 minutes, N = 7, P = .003). Patients with unilateral sympathectomy had normal 6-[18F]fluorodopamine-derived radioactivity (3,971 +/- 337 nCi-kg/cc-mCi at 87 minutes). Bilateral upper thoracic sympathectomy partly decreases cardiac sympathetic innervation density.

  20. Contrasting effects of presynaptic alpha2-adrenergic autoinhibition and pharmacologic augmentation of presynaptic inhibition on sympathetic heart rate control.

    PubMed

    Miyamoto, Tadayoshi; Kawada, Toru; Yanagiya, Yusuke; Akiyama, Tsuyoshi; Kamiya, Atsunori; Mizuno, Masaki; Takaki, Hiroshi; Sunagawa, Kenji; Sugimachi, Masaru

    2008-11-01

    Presynaptic alpha2-adrenergic receptors are known to exert feedback inhibition on norepinephrine release from the sympathetic nerve terminals. To elucidate the dynamic characteristics of the inhibition, we stimulated the right cardiac sympathetic nerve according to a binary white noise signal while measuring heart rate (HR) in anesthetized rabbits (n = 6). We estimated the transfer function from cardiac sympathetic nerve stimulation to HR and the corresponding step response of HR, with and without the blockade of presynaptic inhibition by yohimbine (1 mg/kg followed by 0.1 mg.kg(-1).h(-1) iv). We also examined the effect of the alpha2-adrenergic receptor agonist clonidine (0.3 and 1.5 mg.kg(-1).h(-1) iv) in different rabbits (n = 5). Yohimbine increased the maximum step response (from 7.2 +/- 0.8 to 12.2 +/- 1.7 beats/min, means +/- SE, P < 0.05) without significantly affecting the initial slope (0.93 +/- 0.23 vs. 0.94 +/- 0.22 beats.min(-1).s(-1)). Higher dose but not lower dose clonidine significantly decreased the maximum step response (from 6.3 +/- 0.8 to 6.8 +/- 1.0 and 2.8 +/- 0.5 beats/min, P < 0.05) and also reduced the initial slope (from 0.56 +/- 0.07 to 0.51 +/- 0.04 and 0.22 +/- 0.06 beats.min(-1).s(-1), P < 0.05). Our findings indicate that presynaptic alpha2-adrenergic autoinhibition limits the maximum response without significantly compromising the rapidity of effector response. In contrast, pharmacologic augmentation of the presynaptic inhibition not only attenuates the maximum response but also results in a sluggish effector response.

  1. Hypoxia sensing through β-adrenergic receptors

    PubMed Central

    Cheong, Hoi I.; Asosingh, Kewal; Stephens, Olivia R.; Queisser, Kimberly A.; Xu, Weiling; Willard, Belinda; Hu, Bo; Dermawan, Josephine Kam Tai; Stark, George R.; Naga Prasad, Sathyamangla V.; Erzurum, Serpil C.

    2016-01-01

    Life-sustaining responses to low oxygen, or hypoxia, depend on signal transduction by HIFs, but the underlying mechanisms by which cells sense hypoxia are not completely understood. Based on prior studies suggesting a link between the β-adrenergic receptor (β-AR) and hypoxia responses, we hypothesized that the β-AR mediates hypoxia sensing and is necessary for HIF-1α accumulation. Beta blocker treatment of mice suppressed hypoxia induction of renal HIF-1α accumulation, erythropoietin production, and erythropoiesis in vivo. Likewise, beta blocker treatment of primary human endothelial cells in vitro decreased hypoxia-mediated HIF-1α accumulation and binding to target genes and the downstream hypoxia-inducible gene expression. In mechanistic studies, cAMP-activated PKA and/or GPCR kinases (GRK), which both participate in β-AR signal transduction, were investigated. Direct activation of cAMP/PKA pathways did not induce HIF-1α accumulation, and inhibition of PKA did not blunt HIF-1α induction by hypoxia. In contrast, pharmacological inhibition of GRK, or expression of a GRK phosphorylation–deficient β-AR mutant in cells, blocked hypoxia-mediated HIF-1α accumulation. Mass spectrometry–based quantitative analyses revealed a hypoxia-mediated β-AR phosphorylation barcode that was different from the classical agonist phosphorylation barcode. These findings indicate that the β-AR is fundamental to the molecular and physiological responses to hypoxia. PMID:28018974

  2. Norepinephrine-sensitive, phenoxybenzamine-resistant receptor sites associated with contraction in rabbit arterial but not venous smooth muscle: possible role in adrenergic neurotransmission.

    PubMed

    Laher, I; Khayal, M A; Bevan, J A

    1986-05-01

    The possibility that not all contractions of rabbit blood vessels to norepinephrine (NE) are mediated through alpha adrenoceptors sensitive to phenoxybenzamine (PBZ) was investigated. Dose-response curves (DRCs) to NE were made in the absence and presence of PBZ pretreatment which minimized the contribution of alpha adrenoceptors. In all arteries studied (saphenous, renal, femoral and central ear arteries), after PBZ-treatment, NE produced biphasic DRCs. The initial component of these DRCs corresponded to doses of NE which in the absence of PBZ were supramaximal. Under conditions of our experimentation the plateau-phase usually occurred at between 5 and 40% of the pre-PBZ maximal response to NE. The second phase occurred with further additions of NE, and achieved a mean of 72 (+/- 4)% of the pre-PBZ maximal contraction to NE. The latter component presumably represented contractions mediated through low-affinity sites for NE which were insensitive to doses of PBZ sufficient to alkylate alpha adrenoceptors. In veins (saphenous and inferior vena cava), we found no evidence for such sites. Our results are discussed in light of current ideas of adrenergic neurotransmission in vascular smooth muscle as proposed by Hirst and Neild (1980a) and others who suggest that response to high concentrations of neuronally released NE occur through PBZ-resistant receptors termed gamma adrenoceptors located exclusively at the postsynaptic membrane. We were able to demonstrate PBZ-resistant, low-affinity sites for NE contractions in the femoral artery, a vessel with very sparse adrenergic innervation, and conclude that such sites for NE are present in a number of arteries (and not veins) irrespective of their innervation.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Vanilloid receptors mediate adrenergic nerve- and CGRP-containing nerve-dependent vasodilation induced by nicotine in rat mesenteric resistance arteries

    PubMed Central

    Eguchi, Shinji; Tezuka, Satoko; Hobara, Narumi; Akiyama, Shinji; Kurosaki, Yuji; Kawasaki, Hiromu

    2004-01-01

    Previous studies showed that nicotine induces adrenergic nerve-dependent vasodilation that is mediated by endogenous calcitonin gene-related peptide (CGRP) released from CGRP-containing (CGRPergic) nerves. The mechanisms underlying the nicotine-induced vasodilation were further studied. Rat mesenteric vascular beds without endothelium were contracted by perfusion with Krebs solution containing methoxamine, and the perfusion pressure was measured with a pressure transducer. Perfusion of nicotine (1–100 μM) for 1 min caused concentration-dependent vasodilation. Capsazepine (vanilloid receptor-1 antagonist; 1–10 μM) and ruthenium red (inhibitor of vanilloid response; 1–30 μM) concentration-dependently inhibited the nicotine-induced vasodilation without affecting the vasodilator response to exogenous CGRP. Nicotine-induced vasodilation was not inhibited by treatment with 3,4-dihydroxyphenylalanine (DOPA) receptor antagonist (L-DOPA cyclohexyl ester; 0.001–10 μM), dopamine D1 receptor-selective antagonist (SCH23390; 1–10 μM), dopamine D2 receptor antagonist (haloperidol; 0.1–0.5 μM), ATP P2x receptor-desensitizing agonist (α,β-methylene ATP; 1–10 μM), adenosine A2 receptor antagonist (8(p-sulfophenyl)theophylline; 10–50 μM) or neuropeptide Y (NPY)-Y1 receptor antagonist (BIBP3226; 0.1–0.5 μM). Immunohistochemical staining of the mesenteric artery showed dense innervation of CGRP- and vanilloid receptor-1-positive nerves, with both immunostainings appearing in the same neuron. The mesenteric artery was also densely innervated by NPY-positive nerves. Double immunostainings showed that both NPY and CGRP immunoreactivities appeared in the same neuron of the artery. These results suggest that nicotine acts on presynaptic nicotinic receptors to release adrenergic neurotransmitter(s) or related substance(s), which then stimulate vanilloid receptor-1 on CGRPergic nerves, resulting in CGRP release and vasodilation. PMID:15249421

  4. The Alpha-1A Adrenergic Receptor in the Rabbit Heart

    PubMed Central

    Myagmar, Bat-Erdene; Swigart, Philip M.; Baker, Anthony J.; Simpson, Paul C.

    2016-01-01

    The alpha-1A-adrenergic receptor (AR) subtype is associated with cardioprotective signaling in the mouse and human heart. The rabbit is useful for cardiac disease modeling, but data on the alpha-1A in the rabbit heart are limited. Our objective was to test for expression and function of the alpha-1A in rabbit heart. By quantitative real-time reverse transcription PCR (qPCR) on mRNA from ventricular myocardium of adult male New Zealand White rabbits, the alpha-1B was 99% of total alpha-1-AR mRNA, with <1% alpha-1A and alpha-1D, whereas alpha-1A mRNA was over 50% of total in brain and liver. Saturation radioligand binding identified ~4 fmol total alpha-1-ARs per mg myocardial protein, with 17% alpha-1A by competition with the selective antagonist 5-methylurapidil. The alpha-1D was not detected by competition with BMY-7378, indicating that 83% of alpha-1-ARs were alpha-1B. In isolated left ventricle and right ventricle, the selective alpha-1A agonist A61603 stimulated a negative inotropic effect, versus a positive inotropic effect with the nonselective alpha-1-agonist phenylephrine and the beta-agonist isoproterenol. Blood pressure assay in conscious rabbits using an indwelling aortic telemeter showed that A61603 by bolus intravenous dosing increased mean arterial pressure by 20 mm Hg at 0.14 μg/kg, 10-fold lower than norepinephrine, and chronic A61603 infusion by iPRECIO programmable micro Infusion pump did not increase BP at 22 μg/kg/d. A myocardial slice model useful in human myocardium and an anthracycline cardiotoxicity model useful in mouse were both problematic in rabbit. We conclude that alpha-1A mRNA is very low in rabbit heart, but the receptor is present by binding and mediates a negative inotropic response. Expression and function of the alpha-1A in rabbit heart differ from mouse and human, but the vasopressor response is similar to mouse. PMID:27258143

  5. Patterns of innervation of the lacrimal gland with clinical application.

    PubMed

    Scott, Gabriel; Balsiger, Heather; Kluckman, Matthew; Fan, Jerry; Gest, Thomas

    2014-11-01

    Parasympathetic stimulation of the lacrimal gland is responsible for tear production, and this innervation originates from fibers conveyed in the facial nerve. After synapse in the pterygopalatine ganglion, postsynaptic parasympathetic fibers travel within the zygomatic and zygomaticotemporal nerves (ZTN) into the orbit. As described in most anatomy texts, ZTN communicates with the lacrimal nerve (LN) posterior to the gland and then secretomotor fibers enter the gland. This study was performed to gain a better understanding of the innervation of the lacrimal gland. Seventeen cadaver heads were bisected for a total of 34 sides, which then underwent dissection of the superolateral orbital region to observe the course for the LN and ZTN. Three variations of the course of the LN and ZTN were found. In 20 (60.6%) dissections it was documented that the ZTN entered directly into the lacrimal gland with no communication with the LN. In 12 (36.4%) of the bisected heads, ZTN had both a direct connection into the gland and a communicating branch with the LN. In only one (3.0%) bisected head, ZTN communicated with the LN before entering the gland as it is commonly described in anatomy texts. Our study reveals that the ZTN usually takes a different course than is classically described in most anatomy textbooks. A greater understanding of the typical course these nerves take may help surgeons identify them more easily and avoid damaging them.

  6. Innervation regulates synaptic ribbons in lateral line mechanosensory hair cells.

    PubMed

    Suli, Arminda; Pujol, Remy; Cunningham, Dale E; Hailey, Dale W; Prendergast, Andrew; Rubel, Edwin W; Raible, David W

    2016-06-01

    Failure to form proper synapses in mechanosensory hair cells, the sensory cells responsible for hearing and balance, leads to deafness and balance disorders. Ribbons are electron-dense structures that tether synaptic vesicles to the presynaptic zone of mechanosensory hair cells where they are juxtaposed with the post-synaptic endings of afferent fibers. They are initially formed throughout the cytoplasm, and, as cells mature, ribbons translocate to the basolateral membrane of hair cells to form functional synapses. We have examined the effect of post-synaptic elements on ribbon formation and maintenance in the zebrafish lateral line system by observing mutants that lack hair cell innervation, wild-type larvae whose nerves have been transected and ribbons in regenerating hair cells. Our results demonstrate that innervation is not required for initial ribbon formation but suggest that it is crucial for regulating the number, size and localization of ribbons in maturing hair cells, and for ribbon maintenance at the mature synapse. © 2016. Published by The Company of Biologists Ltd.

  7. Innervation regulates synaptic ribbons in lateral line mechanosensory hair cells

    PubMed Central

    Pujol, Remy; Cunningham, Dale E.; Hailey, Dale W.; Prendergast, Andrew; Rubel, Edwin W.; Raible, David W.

    2016-01-01

    ABSTRACT Failure to form proper synapses in mechanosensory hair cells, the sensory cells responsible for hearing and balance, leads to deafness and balance disorders. Ribbons are electron-dense structures that tether synaptic vesicles to the presynaptic zone of mechanosensory hair cells where they are juxtaposed with the post-synaptic endings of afferent fibers. They are initially formed throughout the cytoplasm, and, as cells mature, ribbons translocate to the basolateral membrane of hair cells to form functional synapses. We have examined the effect of post-synaptic elements on ribbon formation and maintenance in the zebrafish lateral line system by observing mutants that lack hair cell innervation, wild-type larvae whose nerves have been transected and ribbons in regenerating hair cells. Our results demonstrate that innervation is not required for initial ribbon formation but suggest that it is crucial for regulating the number, size and localization of ribbons in maturing hair cells, and for ribbon maintenance at the mature synapse. PMID:27103160

  8. Microfluidics co-culture systems for studying tooth innervation

    PubMed Central

    Pagella, Pierfrancesco; Neto, Estrela; Jiménez-Rojo, Lucia; Lamghari, Meriem; Mitsiadis, Thimios A.

    2014-01-01

    Innervation plays a key role in the development and homeostasis of organs and tissues of the orofacial complex. Among these structures, teeth are peculiar organs as they are not innervated until later stages of development. Furthermore, the implication of neurons in tooth initiation, morphogenesis and differentiation is still controversial. Co-cultures constitute a valuable method to investigate and manipulate the interactions of nerve fibers with their target organs in a controlled and isolated environment. Conventional co-cultures between neurons and their target tissues have already been performed, but these cultures do not offer optimal conditions that are closely mimicking the in vivo situation. Indeed, specific cell populations require different culture media in order to preserve their physiological properties. In this study we evaluate the usefulness of a microfluidics system for co-culturing mouse trigeminal ganglia and developing teeth. This device allows the application of specific media for the appropriate development of both neuronal and dental tissues. The results show that mouse trigeminal ganglia and teeth survive for long culture periods in this microfluidics system, and that teeth maintain the attractive or repulsive effect on trigeminal neurites that has been observed in vivo. Neurites are repealed when co-cultured with embryonic tooth germs, while postnatal teeth exert an attractive effect to trigeminal ganglia-derived neurons. In conclusion, microfluidics system devices provide a valuable tool for studying the behavior of neurons during the development of orofacial tissues and organs, faithfully imitating the in vivo situation. PMID:25202282

  9. Differential serotonergic innervation of the amygdala in bonobos and chimpanzees.

    PubMed

    Stimpson, Cheryl D; Barger, Nicole; Taglialatela, Jared P; Gendron-Fitzpatrick, Annette; Hof, Patrick R; Hopkins, William D; Sherwood, Chet C

    2016-03-01

    Humans' closest living relatives are bonobos (Pan paniscus) and chimpanzees (Pan troglodytes), yet these great ape species differ considerably from each other in terms of social behavior. Bonobos are more tolerant of conspecifics in competitive contexts and often use sexual behavior to mediate social interactions. Chimpanzees more frequently employ aggression during conflicts and actively patrol territories between communities. Regulation of emotional responses is facilitated by the amygdala, which also modulates social decision-making, memory and attention. Amygdala responsiveness is further regulated by the neurotransmitter serotonin. We hypothesized that the amygdala of bonobos and chimpanzees would differ in its neuroanatomical organization and serotonergic innervation. We measured volumes of regions and the length density of serotonin transporter-containing axons in the whole amygdala and its lateral, basal, accessory basal and central nuclei. Results showed that accessory basal nucleus volume was larger in chimpanzees than in bonobos. Of particular note, the amygdala of bonobos had more than twice the density of serotonergic axons than chimpanzees, with the most pronounced differences in the basal and central nuclei. These findings suggest that variation in serotonergic innervation of the amygdala may contribute to mediating the remarkable differences in social behavior exhibited by bonobos and chimpanzees. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  10. Extensive somatosensory innervation in infants with obstetric brachial palsy.

    PubMed

    Colon, A J; Vredeveld, J W; Blaauw, G; Slooff, A C J; Richards, R

    2003-01-01

    In the pre-operative screening of infants with obstetric brachial palsy (OBP), the results of routine electromyography are often overly optimistic when compared to the peri-operative findings. This prompted us to include investigation of the sensory innervation of these infants using the N20 (the first cortical response to a peripheral stimulation) of the somatosensory evoked potentials (SSEP). Three to seven months after birth, SSEP were recorded at the skull after stimulation of the thumb and middle finger in infants with obstetric rupture of the upper trunk or avulsion of roots C5, C6, or C7, and in whom no clinical improvement of motor function was observed in the biceps brachii and deltoid muscles. In most infants, a normal N20 could be evoked, indicating the existence of peripheral sensory pathways. From the thumb, these sensory pathways would necessarily bypass the upper trunk and dorsal roots of spinal nerves C5 and C6, and from the middle finger bypass the middle trunk and dorsal root C7, before extending into the dorsal column and projecting toward the thalamus and cerebral cortex. These data suggest that in infancy the segmental sensory innervation of the hand is more diverse than is described in most textbooks. Copyright 2002 Wiley-Liss, Inc.

  11. Differential serotonergic innervation of the amygdala in bonobos and chimpanzees

    PubMed Central

    Barger, Nicole; Taglialatela, Jared P.; Gendron-Fitzpatrick, Annette; Hof, Patrick R.; Hopkins, William D.; Sherwood, Chet C.

    2016-01-01

    Humans’ closest living relatives are bonobos (Pan paniscus) and chimpanzees (Pan troglodytes), yet these great ape species differ considerably from each other in terms of social behavior. Bonobos are more tolerant of conspecifics in competitive contexts and often use sexual behavior to mediate social interactions. Chimpanzees more frequently employ aggression during conflicts and actively patrol territories between communities. Regulation of emotional responses is facilitated by the amygdala, which also modulates social decision-making, memory and attention. Amygdala responsiveness is further regulated by the neurotransmitter serotonin. We hypothesized that the amygdala of bonobos and chimpanzees would differ in its neuroanatomical organization and serotonergic innervation. We measured volumes of regions and the length density of serotonin transporter-containing axons in the whole amygdala and its lateral, basal, accessory basal and central nuclei. Results showed that accessory basal nucleus volume was larger in chimpanzees than in bonobos. Of particular note, the amygdala of bonobos had more than twice the density of serotonergic axons than chimpanzees, with the most pronounced differences in the basal and central nuclei. These findings suggest that variation in serotonergic innervation of the amygdala may contribute to mediating the remarkable differences in social behavior exhibited by bonobos and chimpanzees. PMID:26475872

  12. Ancestry of motor innervation to pectoral fin and forelimb

    PubMed Central

    Ma, Leung-Hang; Gilland, Edwin; Bass, Andrew H.; Baker, Robert

    2010-01-01

    Motor innervation to the tetrapod forelimb and fish pectoral fin is assumed to share a conserved spinal cord origin, despite major structural and functional innovations of the appendage during the vertebrate water-to-land transition. In this paper, we present anatomical and embryological evidence showing that pectoral motoneurons also originate in the hindbrain among ray-finned fish. New and previous data for lobe-finned fish, a group that includes tetrapods, and more basal cartilaginous fish showed pectoral innervation that was consistent with a hindbrain-spinal origin of motoneurons. Together, these findings support a hindbrain–spinal phenotype as the ancestral vertebrate condition that originated as a postural adaptation for pectoral control of head orientation. A phylogenetic analysis indicated that Hox gene modules were shared in fish and tetrapod pectoral systems. We propose that evolutionary shifts in Hox gene expression along the body axis provided a transcriptional mechanism allowing eventual decoupling of pectoral motoneurons from the hindbrain much like their target appendage gained independence from the head. PMID:20975699

  13. [Microscopic innervation and vascularization of the tongue. General study].

    PubMed

    Fuentes, A; Sanchiz, O

    1992-01-01

    Our study deals with 23 prenatal human tongues, and a comparative study was carried out on one neonatal tongue and a few human and animal postnatal tongues. Sagittal and coronal sections were stained with various techniques. After the 7th week, the development of the nerves and their relationships with the neighboring structures can be observed. There are very few capillaries making up the superficial vascular network under the epithelium. The vessels whose walls are beginning to develop include the future red blood cells with their basophilic nuclei. During the whole process of evolution, there is a tight correlation between the collagen fibers and the neighboring structures. The innervation and vascularization--the latter with changes in the vascular walls--progressively increase. A short time before birth, the nerve fibers include their characteristic components, except for the Schmidt-Lantermann fissures. A considerable innervation advances towards the papillae, and anterior and posterior nerve networks enter the papillae, whose connective tissue includes groups of corpuscles on serial sections.

  14. Evidence that the extraocular motor nuclei innervate monkey palisade endings

    PubMed Central

    Zimmermann, Lars; May, Paul J.; Pastor, Ángel M.; Streicher, Johannes; Blumer, Roland

    2011-01-01

    Palisade endings are found in the extraocular muscles (EOMs) of almost every mammalian species, including primates. These nerve specializations surrounding the muscle fiber insertion have been postulated to be the proprioceptors of the EOMs. However, it was recently demonstrated that palisade endings have a cholinergic nature, which reopened the question of whether palisade endings are motor or sensory structures. In this work, we examined whether the cell bodies of palisade endings lie in EOM motor nuclei by injecting an anterograde tracer, biotinylated dextran amine, into the abducens nucleus of a macaque monkey. Tracer visualization in the lateral rectus muscle was combined with choline acetyltransferase (ChAT) and α-bungarotoxin staining. Analysis of the samples was performed by conventional light microscopy and confocal laser scanning microscopy. About 30% of the nerve fibers innervating the muscle were tracer positive. These were ChAT positive as well. Tracer positive nerve fibers established motor contacts on singly and multiply innervated muscle fibers, which were confirmed by α-bungarotoxin staining. At the transition between muscle and distal tendon, we found palisade endings that contained tracer. Palisade endings exhibited the classic morphology: axons arising from the muscle extend onto the tendon, then turn back 180° and terminate in a cuff of terminals around an individual muscle fiber tip. This finding suggests that the cell bodies of palisade endings lie in the EOM motor nuclei, which complements prior studies demonstrating a cholinergic, and possibly motor, phenotype for palisade endings. PMID:21138754

  15. Regulation of cardiac C-protein phosphorylation

    SciTech Connect

    Titus, F.L.

    1985-01-01

    Molecular mechanisms of cardiac sympathetic and parasympathetic responses were addressed by studying subcellular changes in protein phosphorylation, cAMP-dependent protein kinase activity and protein phosphatase activity in frog hearts. B-adrenergic agonists increased and muscarinic cholinergic agonists decreased (/sup 32/P)phosphate incorporation into C-protein, a thick filament component. Regulation of protein phosphatase activity by Iso and methacholine (MCh) was assayed using extracts of drug treated frog hearts and (/sup 32/P)phospho-C-protein as substrate. Total phosphatase activity decreased 21% in extracts from hearts perfused with 0.1 ..mu..M Iso and 17% in hearts exposed to Iso plus 1 ..mu..M methacholine. This decrease reflected decreased phosphatase-2A activity. No changes in total phosphatase activity were measurable in broken cells treated with Iso or MCh. The results suggest adrenergic stimulation changes contractile activity in frog hearts by activating cAMP-dependent protein kinase associated with particulate cellular elements and inactivating soluble protein phosphatase-2A. This is the first demonstration of coordinated regulation of these enzymes by B-adrenergic agonists favoring phosphorylation of effector proteins. Coordinated regulation by methacholine in the presence of Iso was not observed.

  16. VEGF-A and Semaphorin3A: Modulators of vascular sympathetic innervation

    PubMed Central

    Long, Jennifer B.; Jay, Steven M.; Segal, Steven S.; Madri, Joseph A.

    2010-01-01

    Sympathetic nerve activity regulates blood pressure by altering peripheral vascular resistance. Variations in vascular sympathetic innervation suggest that vascular-derived cues promote selective innervation of particular vessels during development. As axons extend towards peripheral targets, they migrate along arterial networks following gradients of guidance cues. Collective ratios of these gradients may determine whether axons grow towards and innervate vessels or continue past non-innervated vessels towards peripheral targets. Utilizing directed neurite outgrowth in a three-dimensional (3D) co-culture, we observed increased axon growth from superior cervical ganglion explants (SCG) towards innervated compared to non-innervated vessels, mediated in part by vascular endothelial growth factor (VEGF-A) and Semaphorin3A (Sema3A) which both signal via neuropilin-1 (Nrp1). Exogenous VEGF-A, delivered by high-expressing VEGF-A–LacZ vessels or by rhVEGF-A/alginate spheres, increased sympathetic neurite outgrowth while exogenous rhSema3A/Fc decreased neurite outgrowth. VEGF-A expression is similar between the innervated and non-innervated vessels examined. Sema3A expression is higher in non-innervated vessels. Spatial gradients of Sema3A and VEGF-A may promote differential Nrp1 binding. Vessels expressing high levels of Sema3A favor Nrp1-PlexinA1 signaling, producing chemorepulsive cues limiting sympathetic neurite outgrowth and vascular innervation; while low Sema3A expressing vessels favor Nrp1-VEGFR2 signaling providing chemoattractive cues for sympathetic neurite outgrowth and vascular innervation. PMID:19631637

  17. Heart as a target organ in 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity: decreased. beta. -adrenergic responsiveness and evidence of increased intracellular calcium

    SciTech Connect

    Canga, L.; Levi, R.; Rifkind, A.B.

    1988-02-01

    The heart has not been regarded as a major target organ of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity notwithstanding that lethal cardiac dysfunction can occur in the absence of histopathological changes. To assess possible TCDD cardiotoxicity, the authors studied the effect of TCDD five days after treatment on the contractility of guinea pig right ventricular papillary muscle. TCDD treatment significantly decreased ..beta..-adrenergic responsiveness. In papillary muscles from TCDD-treated guinea pigs, the positive inotropic effect on isoproterenol was decreased by a mean of 65%, and the enhancement in the velocity of relaxation was 60% less than in the controls. On the other hand, TCDD treatment did not alter the positive inotropic effect of lower concentrations of isoproterenol. After TCDD, responsiveness to low-frequency stimulation was enhanced, responsiveness to increases in extracellular Ca/sup 2 +/ concentration was attenuated, and isoproterenol-elicited aftercontractions in K/sup +/-depolarized preparations were increased in magnitude. Collectively, the latter findings suggest that in addition to decreasing ..beta..-adrenergic responsiveness, TCDD increases the intracellular Ca/sup 2 +/ concentration in papillary muscle. The findings indicate that TCDD causes a specific pattern of cardiac dysfunction in a mammalian species, selectively augmenting or decreasing different cardiac responses. The cardiac changes are consistent with reported membrane effects of TCDD; further, they suggest that the heart may be a major target organ for TCDD toxicity.

  18. Cardiac Sarcoidosis.

    PubMed

    Birnie, David; Ha, Andrew C T; Gula, Lorne J; Chakrabarti, Santabhanu; Beanlands, Rob S B; Nery, Pablo

    2015-12-01

    Studies suggest clinically manifest cardiac involvement occurs in 5% of patients with pulmonary/systemic sarcoidosis. The principal manifestations of cardiac sarcoidosis (CS) are conduction abnormalities, ventricular arrhythmias, and heart failure. Data indicate that an 20% to 25% of patients with pulmonary/systemic sarcoidosis have asymptomatic (clinically silent) cardiac involvement. An international guideline for the diagnosis and management of CS recommends that patients be screened for cardiac involvement. Most studies suggest a benign prognosis for patients with clinically silent CS. Immunosuppression therapy is advocated for clinically manifest CS. Device therapy, with implantable cardioverter defibrillators, is recommended for some patients.

  19. Adrenal medullary regulation of rat renal cortical adrenergic receptors

    SciTech Connect

    Sundaresan, P.R.; Guarnaccia, M.M.; Izzo, J.L. Jr. )

    1987-11-01

    The role of the adrenal medulla in the regulation of renal cortical adrenergic receptors was investigated in renal cortical particular fractions from control rats and rats 6 wk after adrenal demedullation. The specific binding of ({sup 3}H)prazosin, ({sup 3}H)rauwolscine, and ({sup 125}I)iodocyanopindolol were used to quantitate {alpha}{sub 1}-, {alpha}{sub 2}-, and {beta}-adrenergic receptors, respectively. Adrenal demedullation increased the concentration of all three groups of renal adrenergic receptors; maximal number of binding sites (B{sub max}, per milligram membrane protein) for {alpha}{sub 1}-, and {alpha}{sub 2}-, and {beta}-adrenergic receptors were increased by 22, 18.5, and 25%, respectively. No differences were found in the equilibrium dissociation constants (K{sub D}) for any of the radioligands. Plasma corticosterone and plasma and renal norepinephrine levels were unchanged, whereas plasma epinephrine was decreased 72% by adrenal demedullation, renal cortical epinephrine was not detectable in control or demedullated animals. The results suggest that, in the physiological state, the adrenal medulla modulates the number of renal cortical adrenergic receptors, presumably through the actions of a circulating factor such as epinephrine.

  20. Effects of cholinergic and beta-adrenergic blockade on orthostatic tolerance in healthy subjects

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Sather, T. M.

    2000-01-01

    Cardiovascular responses during a graded lower body negative pressure (LBNP) protocol were compared before and after atropine and propranolol administration to test the hypothesis that both sympathetic and parasympathetic control of cardio-acceleration are associated with syncopal predisposition to orthostatic stress in healthy subjects. Eleven men were categorized into two groups having high (HT, N = 6) or low (LT, N = 5) tolerance based on their total time before the onset of presyncopal symptoms. HT and LT groups were similar in physical characteristics, fitness, and baseline cardiovascular measurements. Atropine treatment had no effect on LBNP tolerance or mean arterial pressure at presyncope, despite an atropine-induced increase in heart rate. Propranolol treatment reduced (p<0.05) LBNP tolerance in both groups. Diminished LBNP tolerance after propranolol administration was associated with reductions in cardiac output, whereas increase in systemic peripheral resistance from baseline to presyncope was unaffected by propranolol. Reduction in cardiac output and LBNP tolerance after beta blockade reflected a chronotropic effect because lower LBNP tolerance for the HT (-50%) and LT (-39%) groups was associated with dramatic reductions (p <0.05) in the magnitude of LBNP-induced tachycardia without significant effects on stroke volume at presyncope. Absence of an atropine-induced difference in cardiac output and systemic peripheral resistance between HT and LT groups failed to support the notion that cardiac vagal withdrawal represents a predominant mechanism that could account for differences in orthostatic tolerance. Because a reduction in LBNP tolerance in both HT and LT groups after propranolol treatment was most closely associated with reduced tachycardia, the data suggest that a primary autonomically mediated mechanism for maintenance of mean arterial pressure and orthostatic tolerance in healthy subjects is beta adrenergic-induced tachycardia.

  1. Effects of cholinergic and beta-adrenergic blockade on orthostatic tolerance in healthy subjects

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Sather, T. M.

    2000-01-01

    Cardiovascular responses during a graded lower body negative pressure (LBNP) protocol were compared before and after atropine and propranolol administration to test the hypothesis that both sympathetic and parasympathetic control of cardio-acceleration are associated with syncopal predisposition to orthostatic stress in healthy subjects. Eleven men were categorized into two groups having high (HT, N = 6) or low (LT, N = 5) tolerance based on their total time before the onset of presyncopal symptoms. HT and LT groups were similar in physical characteristics, fitness, and baseline cardiovascular measurements. Atropine treatment had no effect on LBNP tolerance or mean arterial pressure at presyncope, despite an atropine-induced increase in heart rate. Propranolol treatment reduced (p<0.05) LBNP tolerance in both groups. Diminished LBNP tolerance after propranolol administration was associated with reductions in cardiac output, whereas increase in systemic peripheral resistance from baseline to presyncope was unaffected by propranolol. Reduction in cardiac output and LBNP tolerance after beta blockade reflected a chronotropic effect because lower LBNP tolerance for the HT (-50%) and LT (-39%) groups was associated with dramatic reductions (p <0.05) in the magnitude of LBNP-induced tachycardia without significant effects on stroke volume at presyncope. Absence of an atropine-induced difference in cardiac output and systemic peripheral resistance between HT and LT groups failed to support the notion that cardiac vagal withdrawal represents a predominant mechanism that could account for differences in orthostatic tolerance. Because a reduction in LBNP tolerance in both HT and LT groups after propranolol treatment was most closely associated with reduced tachycardia, the data suggest that a primary autonomically mediated mechanism for maintenance of mean arterial pressure and orthostatic tolerance in healthy subjects is beta adrenergic-induced tachycardia.

  2. The surdo-cardiac syndrome and therapeutic observations

    PubMed Central

    Olley, P. M.; Fowler, R. S.

    1970-01-01

    First recognized in 1957, the surdo-cardiac syndrome includes congenital deafness, prolonged QT interval, and a high incidence of syncope and sudden death. Haemodynamic studies in two patients were normal except for an abnormal wave during left ventricular diastole probably related to abnormal left ventricular relaxation. The syncopal attacks are based on cardiac arrhythmias: both ventricular fibrillation and asystole may occur. Abnormal adrenergic stimulation of the heart is probably responsible. Propranolol appears to be effective in preventing the syncopal attacks. Artificial pacemaking provoked ventricular fibrillation in one patient and seems contraindicated. Images PMID:5433307

  3. Carbamazepine alone and in combination with doxycycline attenuates isoproterenol-induced cardiac hypertrophy.

    PubMed

    Errami, Mounir; Tassa, Amina T; Galindo, Cristi L; Skinner, Michael A; Hill, Joseph A; Garner, Harold R

    2010-06-23

    β-adrenergic signaling is involved in the development of cardiac hypertrophy (CH), justifying the use of β-blockers as a therapy to minimize and postpone the consequences of this disease. Evidence suggests that adenylate cyclase, a downstream effector of the β-adrenergic pathway, might be a therapeutic target. We examined the effects of the anti-epileptic drug carbamazepine (CBZ), an inhibitor of adenylate cyclase. In a murine cardiac hypertrophy model, carbamazepine significantly attenuates isoproteronol (ISO)-induced cardiac hypertrophy. Carbamazepine also has an effect in transverse aortic banding induced cardiac hypertrophy (TAB) (P=0.07). When carbamazepine was given in combination with the antibiotic doxycycline (DOX), which inhibits matrix metalloproteinases (MMPs), therapeutic outcome measured by heart weight-to-body weight and heart weight-to-tibia length ratios was improved compared to either drug alone. Additionally, the combination therapy resulted in an increase in the survival rate over a 56-day period compared to that of untreated mice with cardiac hypertrophy or either drug used alone. Moreover, in support of a role for carbamaze -pine as a β-adrenergic antagonist via cAMP inhibition, a lower heart rate and a lower level of the activated phosphorylated form of the cAMP Response Element-Binding (CREB) were observed in heart extracts from mice treated with carbamazepine. Gene expression analysis identified 19 genes whose expression is significantly altered in treated animals and might be responsible for the added benefit provided by the combination therapy. These results suggest that carbamazepine acts as a β-adrenergic antagonist. Carbamazepine and doxycycline are approved by the US Food and Drug Administration (FDA) as drugs that might complement medications for cardiac hypertrophy or serve as an alternative therapy to traditional β-blockers. Furthermore, these agents reproducibly impact the expression of genes that may serve as additional

  4. Carbamazepine alone and in combination with doxycycline attenuates isoproterenol-induced cardiac hypertrophy

    PubMed Central

    Errami, Mounir; Tassa, Amina T; Galindo, Cristi L; Skinner, Michael A.; Hill, Joseph A; Garner, Harold R

    2010-01-01

    β-adrenergic signaling is involved in the development of cardiac hypertrophy (CH), justifying the use of β-blockers as a therapy to minimize and postpone the consequences of this disease. Evidence suggests that adenylate cyclase, a downstream effector of the β-adrenergic pathway, might be a therapeutic target. We examined the effects of the anti-epileptic drug carbamazepine (CBZ), an inhibitor of adenylate cyclase. In a murine cardiac hypertrophy model, carbamazepine significantly attenuates isoproteronol (ISO)-induced cardiac hypertrophy. Carbamazepine also has an effect in transverse aortic banding induced cardiac hypertrophy (TAB) (P=0.07). When carbamazepine was given in combination with the antibiotic doxycycline (DOX), which inhibits matrix metalloproteinases (MMPs), therapeutic outcome measured by heart weight-to-body weight and heart weight-to-tibia length ratios was improved compared to either drug alone. Additionally, the combination therapy resulted in an increase in the survival rate over a 56-day period compared to that of untreated mice with cardiac hypertrophy or either drug used alone. Moreover, in support of a role for carbamaze -pine as a β-adrenergic antagonist via cAMP inhibition, a lower heart rate and a lower level of the activated phosphorylated form of the cAMP Response Element-Binding (CREB) were observed in heart extracts from mice treated with carbamazepine. Gene expression analysis identified 19 genes whose expression is significantly altered in treated animals and might be responsible for the added benefit provided by the combination therapy. These results suggest that carbamazepine acts as a β-adrenergic antagonist. Carbamazepine and doxycycline are approved by the US Food and Drug Administration (FDA) as drugs that might complement medications for cardiac hypertrophy or serve as an alternative therapy to traditional β-blockers. Furthermore, these agents reproducibly impact the expression of genes that may serve as additional

  5. Neo-innervation of a bioengineered intestinal smooth muscle construct around chitosan scaffold.

    PubMed

    Zakhem, Elie; Raghavan, Shreya; Bitar, Khalil N

    2014-02-01

    Neuromuscular disorders of the gut result in disturbances in gastrointestinal transit. The objective of this study was to evaluate the neo-innervation of smooth muscle in an attempt to restore lost innervation. We have previously shown the potential use of composite chitosan scaffolds as support for intestinal smooth muscle constructs. However, the constructs lacked neuronal component. Here, we bioengineered innervated colonic smooth muscle constructs using rabbit colon smooth muscle and enteric neural progenitor cells. We also bioengineered smooth muscle only tissue constructs using colonic smooth muscle cells. The constructs were placed next to each other around tubular chitosan scaffolds and left in culture. Real time force generation conducted on the intrinsically innervated smooth muscle constructs showed differentiated functional neurons. The bioengineered smooth muscle only constructs became neo-innervated. The neo-innervation results were confirmed by immunostaining assays. Chitosan supported (1) the differentiation of neural progenitor cells in the constructs and (2) the neo-innervation of non-innervated smooth muscle around the same scaffold.

  6. Marked innervation but also signs of nerve degeneration in between the Achilles and plantaris tendons and presence of innervation within the plantaris tendon in midportion Achilles tendinopathy.

    PubMed

    Spang, C; Harandi, V M; Alfredson, H; Forsgren, S

    2015-06-01

    The plantaris tendon is increasingly recognised as an important factor in midportion Achilles tendinopathy. Its innervation pattern is completely unknown. Plantaris tendons (n=56) and associated peritendinous tissue from 46 patients with midportion Achilles tendinopathy and where the plantaris tendon was closely related to the Achilles tendon were evaluated. Morphological evaluations and stainings for nerve markers [general (PGP9.5), sensory (CGRP), sympathetic (TH)], glutamate NMDA receptor and Schwann cells (S-100β) were made. A marked innervation, as evidenced by evaluation for PGP9.5 reactions, occurred in the peritendinous tissue located between the plantaris and Achilles tendons. It contained sensory and to some extent sympathetic and NMDAR1-positive axons. There was also an innervation in the zones of connective tissue within the plantaris tendons. Interestingly, some of the nerve fascicles showed a partial lack of axonal reactions. New information on the innervation patterns for the plantaris tendon in situations with midportion Achilles tendinopathy has here been obtained. The peritendinous tissue was found to be markedly innervated and there was also innervation within the plantaris tendon. Furthermore, axonal degeneration is likely to occur. Both features should be further taken into account when considering the relationship between the nervous system and tendinopathy.

  7. Marked innervation but also signs of nerve degeneration in between the Achilles and plantaris tendons and presence of innervation within the plantaris tendon in midportion Achilles tendinopathy

    PubMed Central

    Spang, C.; Harandi, V.M.; Alfredson, H.; Forsgren, S.

    2015-01-01

    Objectives: The plantaris tendon is increasingly recognised as an important factor in midportion Achilles tendinopathy. Its innervation pattern is completely unknown. Methods: Plantaris tendons (n=56) and associated peritendinous tissue from 46 patients with midportion Achilles tendinopathy and where the plantaris tendon was closely related to the Achilles tendon were evaluated. Morphological evaluations and stainings for nerve markers [general (PGP9.5), sensory (CGRP), sympathetic (TH)], glutamate NMDA receptor and Schwann cells (S-100β) were made. Results: A marked innervation, as evidenced by evaluation for PGP9.5 reactions, occurred in the peritendinous tissue located between the plantaris and Achilles tendons. It contained sensory and to some extent sympathetic and NMDAR1-positive axons. There was also an innervation in the zones of connective tissue within the plantaris tendons. Interestingly, some of the nerve fascicles showed a partial lack of axonal reactions. Conclusion: New information on the innervation patterns for the plantaris tendon in