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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. 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

  3. Innervation of the rabbit cardiac ventricles.

    PubMed

    Pauziene, Neringa; Alaburda, Paulius; Rysevaite-Kyguoliene, Kristina; Pauza, Audrys G; Inokaitis, Hermanas; Masaityte, Aiste; Rudokaite, Gabriele; Saburkina, Inga; Plisiene, Jurgita; Pauza, Dainius H

    2016-01-01

    approximately eight times denser than the myocardial meshwork. Adrenergic NFs predominate considerably in all layers of the ventricular walls and septum, whereas NFs of other neurochemical phenotypes were in the minority and their amount differed between the epicardium, myocardium and endocardium. The densities of NFs positive for nNOS and ChAT were similar in the epicardium and endocardium, but NFs positive for nNOS in the myocardium were eight times more abundant than NFs positive for ChAT. Potentially sensory NFs positive for both calcitonin gene-related peptide and substance P were sparse in the myocardial layer, but numerous in epicardial nerves and particularly abundant within the endocardium. Electron microscopic observations demonstrate that intrinsic ventricular nerves have a distinctive morphology, which may be attributed to remodelling of the peripheral nerves after their access into the ventricular wall. In conclusion, the rabbit ventricles display complex structural organization of intrinsic ventricular nerves, NFs and ganglionic cells. The results provide a basic anatomical background for further functional analysis of the intrinsic nervous system in the cardiac ventricles. PMID:26510903

  4. Impaired cardiac energy metabolism in embryos lacking adrenergic stimulation.

    PubMed

    Baker, Candice N; Gidus, Sarah A; Price, George F; Peoples, Jessica N R; Ebert, Steven N

    2015-03-01

    As development proceeds from the embryonic to fetal stages, cardiac energy demands increase substantially, and oxidative phosphorylation of ADP to ATP in mitochondria becomes vital. Relatively little, however, is known about the signaling mechanisms regulating the transition from anaerobic to aerobic metabolism that occurs during the embryonic period. The main objective of this study was to test the hypothesis that adrenergic hormones provide critical stimulation of energy metabolism during embryonic/fetal development. We examined ATP and ADP concentrations in mouse embryos lacking adrenergic hormones due to targeted disruption of the essential dopamine β-hydroxylase (Dbh) gene. Embryonic ATP concentrations decreased dramatically, whereas ADP concentrations rose such that the ATP/ADP ratio in the adrenergic-deficient group was nearly 50-fold less than that found in littermate controls by embryonic day 11.5. We also found that cardiac extracellular acidification and oxygen consumption rates were significantly decreased, and mitochondria were significantly larger and more branched in adrenergic-deficient hearts. Notably, however, the mitochondria were intact with well-formed cristae, and there was no significant difference observed in mitochondrial membrane potential. Maternal administration of the adrenergic receptor agonists isoproterenol or l-phenylephrine significantly ameliorated the decreases in ATP observed in Dbh-/- embryos, suggesting that α- and β-adrenergic receptors were effective modulators of ATP concentrations in mouse embryos in vivo. These data demonstrate that adrenergic hormones stimulate cardiac energy metabolism during a critical period of embryonic development. PMID:25516547

  5. 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.

  6. 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.

  7. Cardiac and neuroprotection regulated by α1-adrenergic receptor subtypes

    PubMed Central

    Perez, Dianne M.; Doze, Van A.

    2013-01-01

    Sympathetic nervous system regulation by the α1-adrenergic receptor (AR) subtypes (α1A, α1B, α1D) is complex, whereby chronic activity can be either detrimental or protective for both heart and brain function. This review will summarize the evidence that this dual regulation can be mediated through the different α1-AR subtypes in the context of cardiac hypertrophy, heart failure, apoptosis, ischemic preconditioning, neurogenesis, locomotion, neurodegeneration, cognition, neuroplasticity, depression, anxiety, epilepsy, and mental illness. PMID:21338248

  8. Cardiac salvage by tweaking with beta-3-adrenergic receptors.

    PubMed

    Balligand, Jean-Luc

    2016-07-15

    Overstimulation of the orthosympathetic system leads to cardiovascular cell and tissue damage through prolonged activation of β-1-2 adrenergic receptors (BARs). The more recent identification of the third isotype of BAR (B3AR) in cardiac myocytes and endothelial cells with a distinctive coupling and effect on cardiac function and remodelling introduced a new facet to this paradigm. In particular, B3AR is up-regulated in cardiac disease and less prone to homologous desensitization, which may reinforce its influence on the diseased myocardium. Mice with transgenic cardiac-specific expression of the human B3AR are protected from cardiac hypertrophy and fibrosis in response to neurohormonal stimulation. B3AR has also been implicated in cardiac protection after ischaemia-reperfusion and the benefits of exercise on the heart. Many of these salvage mechanisms are mediated by B3AR coupling to nitric oxide synthase (eNOS and nNOS) and downstream cGMP/protein kinase G signalling. Notably, B3AR exerts antioxidant protective effects on these and other signalling elements, which may subserve its protective properties in the setting of chronic heart failure. Additional vasorelaxing properties and paracrine NO-mediated signalling by B3AR in endothelium, together with systemic metabolic effects on beige/brown fat complete the pleiotropic protective properties of this new therapeutic target. PMID:27001422

  9. Natriuretic peptides in relation to the cardiac innervation and conduction system.

    PubMed

    Hansson, Magnus

    2002-09-01

    During the past two decades, the heart has been known to undergo endocrine action, harbouring peptides with hormonal activities. These, termed "atrial natriuretic peptide (ANP)," "brain natriuretic peptide (BNP)," and "C-type natriuretic peptide (CNP)," are polypeptides mainly produced in the cardiac myocardium, where they are released into the circulation, producing profound hypotensive effects due to their diuretic, natriuretic, and vascular dilatory properties. It is, furthermore, well established that cardiac disorders such as congestive heart failure and different forms of cardiomyopathy are combined with increased expression of ANP and BNP, leading to elevated levels of these peptides in the plasma. Besides the occurrence of natriuretic peptides (NPs) in the ordinary myocardium, the presence of ANP in the cardiac conduction system has been described. There is also evidence of ANP gene expression in nervous tissue such as the nodose ganglion and the superior cervical ganglion of the rat, ganglia known to be involved in the neuronal regulation of the heart. Furthermore, in the mammalian heart, ANP appears to affect the cardiac autonomic nervous system by sympathoinhibitory and vagoexcitatory actions. This article provides an overview of the relationship between the cardiac conduction system, the cardiac innervation and NPs in the mammalian heart and provides data for the concept that ANP is also involved in neuronal cardiac regulation. PMID:12226807

  10. Beta(2)-adrenergic receptor regulates cardiac fibroblast autophagy and collagen degradation.

    PubMed

    Aránguiz-Urroz, Pablo; Canales, Jimena; Copaja, Miguel; Troncoso, Rodrigo; Vicencio, Jose Miguel; Carrillo, Constanza; Lara, Hernán; Lavandero, Sergio; Díaz-Araya, Guillermo

    2011-01-01

    Autophagy is a physiological degradative process key to cell survival during nutrient deprivation, cell differentiation and development. It plays a major role in the turnover of damaged macromolecules and organelles, and it has been involved in the pathogenesis of different cardiovascular diseases. Activation of the adrenergic system is commonly associated with cardiac fibrosis and remodeling, and cardiac fibroblasts are key players in these processes. Whether adrenergic stimulation modulates cardiac fibroblast autophagy remains unexplored. In the present study, we aimed at this question and evaluated the effects of b(2)-adrenergic stimulation upon autophagy. Cultured adult rat cardiac fibroblasts were treated with agonists or antagonists of beta-adrenergic receptors (b-AR), and autophagy was assessed by electron microscopy, GFP-LC3 subcellular distribution, and immunowesternblot of endogenous LC3. The predominant expression of b(2)-ARs was determined and characterized by radioligand binding assays using [(3)H]dihydroalprenolol. Both, isoproterenol and norepinephrine (non-selective b-AR agonists), as well as salbutamol (selective b(2)-AR agonist) increased autophagic flux, and these effects were blocked by propanolol (b-AR antagonist), ICI-118,551 (selective b(2)-AR antagonist), 3-methyladenine but not by atenolol (selective b(1)-AR antagonist). The increase in autophagy was correlated with an enhanced degradation of collagen, and this effect was abrogated by the inhibition of autophagic flux. Overall, our data suggest that b(2)-adrenergic stimulation triggers autophagy in cardiac fibroblasts, and that this response could contribute to reduce the deleterious effects of high adrenergic stimulation upon cardiac fibrosis. PMID:20637865

  11. 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

  12. A nuclear pathway for alpha 1-adrenergic receptor signaling in cardiac cells.

    PubMed Central

    Ardati, A; Nemer, M

    1993-01-01

    alpha 1-Adrenergic agonists and antagonists constitute an important class of therapeutic agents commonly used for the treatment of various cardiovascular diseases like hypertension, congestive heart failure and supraventricular tachycardia. At the heart level, activation of alpha 1-adrenergic receptors is associated with marked morphological and genetic changes. These include enhancement of contractility, myocardial growth (hypertrophy) and release of the heart major secretory product, atrial natriuretic factor (ANF). However, the signal transduction pathways which link extracellular activation of the receptors to cellular and genetic changes are not well understood. Using primary cardiocyte cultures from neonate rat hearts, an alpha 1-adrenergic regulatory sequence has been identified in the 5' flanking region of the ANF gene. This sequence, which is necessary and sufficient for transcriptional activation in response to the alpha 1-specific agonist phenylephrine, interacts with novel zinc-dependent proteins which are induced by alpha 1-adrenergic stimulation. Consistent with a conserved regulatory mechanism, the alpha 1 response element is highly conserved between rodent, bovine and human ANF genes, and is also present in the promoter region of other alpha 1-responsive cardiac genes. The identification of a nuclear pathway for alpha 1-receptor signaling will be useful for elucidating the intracellular effectors of alpha 1-adrenergic receptors. Images PMID:8262057

  13. Effect of alpha1-adrenergic receptors in cardiac pathophysiology.

    PubMed

    Shannon, Richard; Chaudhry, Mohammad

    2006-11-01

    Compelling evidence now exists that proves adrenergic blockade is at the center of neurohormonal antagonism in heart failure (HF). Catecholamines are well known to act through both beta- and alpha-adrenergic receptors (ARs), which mediate their effects through distinct receptor pathways. Beta-AR blockers are commonly used in the treatment of HF and have distinct receptor affinity profiles. The recent COMET trial comparing 2 important beta-blocking drugs showed a distinct advantage for carvedilol in decreasing the risk of mortality from HF. The mechanism of action for carvedilol differs from metoprolol tartrate in its ability to block both alpha- and beta-ARs, leading to renewed interest in the potential role of alpha-ARs in the progression of HF. In contrast, however, the ALLHAT study discontinued use of doxazosin, an alpha1-receptor blocker because of an increase in cardiovascular events among patients using this drug. The results of these studies appear to be in contrast with respect to the role of alpha-ARs in regards to cardiovascular pathophysiology. Further study of the alpha-receptor and understanding the role of alpha-ARs in HF is necessary to understand the therapeutic effect of alpha-blockade. This article reviews our understanding of the alpha-AR in HF. PMID:17070143

  14. 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.

  15. 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

  16. Blunted cardiac beta-adrenergic response as an early indication of cardiac dysfunction in Duchenne muscular dystrophy

    PubMed Central

    Li, Ying; Zhang, Shuai; Zhang, Xiaoying; Li, Jing; Ai, Xiaojie; Zhang, Li; Yu, Daohai; Ge, Shuping; Peng, Yizhi; Chen, Xiongwen

    2014-01-01

    Aims To determine whether altered beta-adrenergic responses contribute to early cardiac dysfunction in mdx (X-linked muscular dystrophy) mice, an animal model for human Duchenne muscular dystrophy. Methods and results Replacement fibrosis in mdx hearts gradually increased with age, suggesting a gradual loss of cardiomyocytes. Echocardiography and intra-left ventricular haemodynamic measurements detected baseline cardiac dysfunction in mdx mice at ≥8 months. However, a reduction of cardiac beta-adrenergic response to isoproterenol (ISO) was already present in mdx mice at 4 months. Ventricular myocytes (VMs) isolated from 4- and 8-month-old mdx mice had greater baseline contractile function {fractional shortening, [Ca2+]i, and sarcoplasmic reticulum (SR) Ca2+ content} and ICa-L than age-matched control VMs and than myocytes isolated from 2-month-old mdx mice. ISO increased myocyte function in the VMs of 4- and 8-month-old mdx mice to the same level as in age-matched control VMs. In the VMs of 12-month-old mdx mice, ISO failed to increase myocyte function to the level in VMs of 12-month-old control mice and could not further increaseICa-L. No differences were observed in the expression of Cav1.2α1c, Cav1.2β1, Cav1.2β2, sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), and the Na+/Ca2+ exchanger. In contrast, total ryanodine receptor 2 (RyR2) and basal phosphorylation of RyR2, phospholamban, and Cav1.2α1c were found to be increased in hearts of 4-month-old mdx mice; baseline protein kinase A activity was also increased. After ISO treatment, phosphorylation levels were the same in mdx and control hearts. VMs of 4-month-old mdx mice had reduced beta1-adrenergic receptor (β1-AR) density and beta-adrenergic sensitivity. Conclusion In young mdx mice, the myocyte increases its contractile function to compensate for myocyte loss. However, these myocytes with enhanced baseline function have reduced potential for stimulation, decreased β1-AR density/sensitivity, leading

  17. 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.

  18. 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

  19. Mismatch Between Cardiac Perfusion, Sympathetic Innervation, and Left Ventricular Electroanatomical Map in a Patient with Recurrent Ventricular Tachycardia

    PubMed Central

    Jungen, Christiane; von Gogh, Gwendolyn; Schmitt, Christiane; Kuklik, Pawel; Hoffmann, Boris; Nakajima, Kenichi; Willems, Stephan; Mester, Janos; Meyer, Christian

    2016-01-01

    Patient: Male, 69 Final Diagnosis: Recurrent ventricular tachycardia Symptoms: Multiple ICD shocks Medication: — Clinical Procedure: Ventricular tachycardia ablation Specialty: Cardiology Objective: Rare co-existance of disease or pathology Background: Regional cardiac sympathetic denervation causes electrophysiological heterogeneity and has been found to be a predictor of potentially lethal VT. Case Report: We present the case of 69-year-old patient admitted with recurrent ventricular tachycardia and a history of anterior myocardial infarction. In line with Tc-99m-MIBI-SPECT perfusion imaging, electroanatomical mapping revealed extensive LV anterior scarring as detected by low-voltage areas. Surprisingly, I-123-MIBG-SPECT showed an extensive deficit of sympathetic innervation inferior (mismatch) and anterolateral (match). Conclusions: Combination of electroanatomical mapping with tomographic imaging of innervation and perfusion might improve our understanding of the neural trigger of VT after myocardial infarction or substrate-based catheter ablation. PMID:27109542

  20. 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.

  1. Insulin inhibits cardiac contractility by inducing a Gi-biased β2-adrenergic signaling in hearts.

    PubMed

    Fu, Qin; Xu, Bing; Liu, Yongming; Parikh, Dippal; Li, Jing; Li, Ying; Zhang, Yuan; Riehle, Christian; Zhu, Yi; Rawlings, Tenley; Shi, Qian; Clark, Richard B; Chen, Xiongwen; Abel, E Dale; Xiang, Yang K

    2014-08-01

    Insulin and adrenergic stimulation are two divergent regulatory systems that may interact under certain pathophysiological circumstances. Here, we characterized a complex consisting of insulin receptor (IR) and β2-adrenergic receptor (β2AR) in the heart. The IR/β2AR complex undergoes dynamic dissociation under diverse conditions such as Langendorff perfusions of hearts with insulin or after euglycemic-hyperinsulinemic clamps in vivo. Activation of IR with insulin induces protein kinase A (PKA) and G-protein receptor kinase 2 (GRK2) phosphorylation of the β2AR, which promotes β2AR coupling to the inhibitory G-protein, Gi. The insulin-induced phosphorylation of β2AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated β2AR-Gi signaling effectively attenuates cAMP/PKA activity after β-adrenergic stimulation in cardiomyocytes and consequently inhibits PKA phosphorylation of phospholamban and contractile responses in myocytes in vitro and in Langendorff perfused hearts. These data indicate that increased IR signaling, as occurs in hyperinsulinemic states, may directly impair βAR-regulated cardiac contractility. This β2AR-dependent IR and βAR signaling cross-talk offers a molecular basis for the broad interaction between these signaling cascades in the heart and other tissues or organs that may contribute to the pathophysiology of metabolic and cardiovascular dysfunction in insulin-resistant states. PMID:24677713

  2. 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.

  3. Effect of intramyocardial bone marrow-derived mononuclear cell injection on cardiac sympathetic innervation in patients with chronic myocardial ischemia.

    PubMed

    van Ramshorst, Jan; Beeres, Saskia L M A; Rodrigo, Sander F; Dibbets-Schneider, Petra; Scholte, Arthur J; Fibbe, Willem E; Zwaginga, Jaap J; Schalij, Martin J; Bax, Jeroen J; Atsma, Douwe E

    2014-03-01

    Intramyocardial bone marrow cell injection has been associated with improvements in myocardial perfusion and left ventricular function. The current substudy of a randomized, placebo-controlled, double-blinded study, investigated the effect of intramyocardial bone marrow cell injection on myocardial sympathetic innervation in patients with chronic myocardial ischemia. In a total of 16 patients (64 ± 8 years, 13 men), early and late iodine-123 metaiodobenzylguanidine (MIBG) imaging was performed before and 3 months after intramyocardial bone marrow cell injection. No improvements were observed in global early H/M ratio (P = 0.40), late H/M ratio (P = 0.43) and cardiac washout rate (P = 0.98). However, late 123-I MIBG SPECT defect score showed a trend to improvement in the bone marrow cell group (from 31.0 ± 7.1 to 28.1 ± 14.9) as compared to the placebo group (from 33.6 ± 8.5 to 34.5 ± 9.8, P = 0.055 between groups). This trend was mainly driven by a substantial improvement in three bone marrow cell-treated patients, which all had diabetes and severe MIBG defects. In these patients, the extent and severity of MIBG defects improved substantially independent of myocardial perfusion and cell injection sites. The present study does not demonstrate improvements in global cardiac sympathetic nerve innervation after intramyocardial bone marrow cell injection in patients with chronic myocardial ischemia. However, regional analysis of sympathetic nerve innervation reveals improvements in three diabetic patients independent of myocardial perfusion, suggestive of a therapeutic effect on diabetic cardiac sympathetic dysinnervation. PMID:24481723

  4. Age-associated changes in beta-adrenergic modulation on rat cardiac excitation-contraction coupling.

    PubMed Central

    Xiao, R P; Spurgeon, H A; O'Connor, F; Lakatta, E G

    1994-01-01

    Previous studies have demonstrated that the ability of beta-adrenergic receptor (beta AR) stimulation to increase cardiac contractility declines with aging. In the present study, the control mechanisms of excitation-contraction (EC) coupling, including calcium current (ICa), cytosolic Ca2+ (Cai2+) transient and contraction in response to beta AR stimulation were investigated in ventricular myocytes isolated from rat hearts of a broad age range (2, 6-8, and 24 mo). While the baseline contractile performance and the Cai2+ transient did not differ markedly among cells from hearts of all age groups, the responses of the Cai2+ transient and contraction to beta-adrenergic stimulation by norepinephrine (NE) diminished with aging: the threshold concentration and the ED50 increased in rank order with aging; the maximum responses of contraction and Cai2+ transient decreased with aging. Furthermore, the efficacy of beta AR stimulation to increase ICa was significantly reduced with aging, and the diminished responses of the contraction and Cai2+ transient amplitudes to NE were proportional to the reductions in the ICa response. These findings suggest that the observed age-associated reduction in beta AR modulation of the cardiac contraction is, in part at least, due to a deficit in modulation of Cai2+, particularly the activity of L-type calcium channels. PMID:7962551

  5. Modeling the Effects of β1-Adrenergic Receptor Blockers and Polymorphisms on Cardiac Myocyte Ca2+ Handling

    PubMed Central

    Amanfu, Robert K.

    2014-01-01

    β-Adrenergic receptor blockers (β-blockers) are commonly used to treat heart failure, but the biologic mechanisms governing their efficacy are still poorly understood. The complexity of β-adrenergic signaling coupled with the influence of receptor polymorphisms makes it difficult to intuit the effect of β-blockers on cardiac physiology. While some studies indicate that β-blockers are efficacious by inhibiting β-adrenergic signaling, other studies suggest that they work by maintaining β-adrenergic responsiveness. Here, we use a systems pharmacology approach to test the hypothesis that in ventricular myocytes, these two apparently conflicting mechanisms for β-blocker efficacy can occur concurrently. We extended a computational model of the β1-adrenergic pathway and excitation-contraction coupling to include detailed receptor interactions for 19 ligands. Model predictions, validated with Ca2+ and Förster resonance energy transfer imaging of adult rat ventricular myocytes, surprisingly suggest that β-blockers can both inhibit and maintain signaling depending on the magnitude of receptor stimulation. The balance of inhibition and maintenance of β1-adrenergic signaling is predicted to depend on the specific β-blocker (with greater responsiveness for metoprolol than carvedilol) and β1-adrenergic receptor Arg389Gly polymorphisms. PMID:24867460

  6. MIBG scintigraphic assessment of cardiac adrenergic activity in response to altitude hypoxia

    SciTech Connect

    Richalet, J.P.; Merlet, P.; Bourguignon, M.; Le-Trong, J.L.; Keromes, A.; Rathat, C.; Jouve, B.; Hot, M.A.; Castaigne, A.; Syrota, A. )

    1990-01-01

    High altitude hypoxia induces a decrease in the cardiac chronotropic function at maximal exercise or in response to isoproterenol infusion, suggesting an alteration in the cardiac sympathetic activation. Iodine-123 metaiodobenzylguanidine (({sup 123}I)MIBG) was used to map scintigraphically the cardiac sympathetic neuronal function in six male subjects (aged 32 {plus minus} 7 yr) after an exposure to high altitude that created hypoxic conditions. Results obtained just after return to sea level (RSL) were compared with the normal values obtained after 2 or 3 mo of normoxia (N). A static image was created as the sum of the 16-EKG gated images recorded for 10 min in the anterior view of the chest at 20, 60, 120, and 240 min after injection. Regions of interest were located over the heart (H), lungs (L), and mediastinum (M) regions. There was a significant decrease in the H/M and the L/M ratios in RSL compared to N condition. Plasma norepinephrine concentration was elevated during the stay at altitude but not significantly different in RSL compared to N. In conclusion, cardiac ({sup 123}I)MIBG uptake is reduced after an exposure to altitude hypoxia, supporting the hypothesis of an hypoxia-induced reduction of adrenergic neurotransmitter reserve in the myocardium. Furthermore, the observed significant decrease in pulmonary MIBG uptake suggests an alteration of endothelial cell function after exposure to chronic hypoxia.

  7. 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

  8. PHD2/3-dependent hydroxylation tunes cardiac response to β-adrenergic stress via phospholamban

    PubMed Central

    Xie, Liang; Pi, Xinchun; Townley-Tilson, W.H. Davin; Li, Na; Wehrens, Xander H.T.; Entman, Mark L.; Taffet, George E.; Mishra, Ashutosh; Peng, Junmin; Schisler, Jonathan C.; Meissner, Gerhard; Patterson, Cam

    2015-01-01

    Ischemic heart disease is the leading cause of heart failure. Both clinical trials and experimental animal studies demonstrate that chronic hypoxia can induce contractile dysfunction even before substantial ventricular damage, implicating a direct role of oxygen in the regulation of cardiac contractile function. Prolyl hydroxylase domain (PHD) proteins are well recognized as oxygen sensors and mediate a wide variety of cellular events by hydroxylating a growing list of protein substrates. Both PHD2 and PHD3 are highly expressed in the heart, yet their functional roles in modulating contractile function remain incompletely understood. Here, we report that combined deletion of Phd2 and Phd3 dramatically decreased expression of phospholamban (PLN), resulted in sustained activation of calcium/calmodulin-activated kinase II (CaMKII), and sensitized mice to chronic β-adrenergic stress–induced myocardial injury. We have provided evidence that thyroid hormone receptor-α (TR-α), a transcriptional regulator of PLN, interacts with PHD2 and PHD3 and is hydroxylated at 2 proline residues. Inhibition of PHDs increased the interaction between TR-α and nuclear receptor corepressor 2 (NCOR2) and suppressed Pln transcription. Together, these observations provide mechanistic insight into how oxygen directly modulates cardiac contractility and suggest that cardiac function could be modulated therapeutically by tuning PHD enzymatic activity. PMID:26075818

  9. Automated microscopy of cardiac myocyte hypertrophy: a case study on the role of intracellular α-adrenergic receptors.

    PubMed

    Ryall, Karen A; Saucerman, Jeffrey J

    2015-01-01

    Traditional approaches for measuring cardiac myocyte hypertrophy have been of low throughput and subjective, limiting the scope of experimental studies designed to understand it. Here, we describe an automated image acquisition and analysis platform for studying the dynamics of cardiac myocyte hypertrophy in vitro. Image acquisition scripts record 5 × 5 mosaic images of fluorescent protein-labeled neonatal rat ventricular myocytes from each well of a 96-well plate using the microscope's automated stage and focus. Image analysis algorithms automatically segment myocyte boundaries, track myocytes, and quantify changes in shape. We describe each step of the image acquisition and analysis algorithms and provide specific examples of how to implement them using Metamorph and CellProfiler software. With this system, shape dynamics of thousands of individual cardiac myocytes can be tracked for up to a week. This imaging platform was recently applied to study reversal of cardiac myocyte hypertrophy following withdrawal of the α-adrenergic agonist phenylephrine. Hypertrophy readily reversed at low but not high levels of α-adrenergic signaling, leading to identification of an intracellular population of α-adrenergic receptors responsible for this reversibility delay. PMID:25304353

  10. 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.

  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. Regulation of cardiac nitric oxide signaling by nuclear β-adrenergic and endothelin receptors*

    PubMed Central

    Vaniotis, George; Glazkova, Irina; Merlen, Clémence; Smith, Carter; Villeneuve, Louis R.; Chatenet, David; Therien, Michel; Fournier, Alain; Tadevosyan, Artavazd; Trieu, Phan; Nattel, Stanley; Hébert, Terence E.; Allen, Bruce G.

    2013-01-01

    At the cell surface, βARs and endothelin receptors can regulate nitric oxide (NO) production. β-adrenergic receptors (βARs) and type B endothelin receptors (ETB) are present in cardiac nuclear membranes and regulate transcription. The present study investigated the role of the NO pathway in the regulation of gene transcription by these nuclear G protein-coupled receptors. Nitric oxide production and transcription initiation were measured in nuclei isolated from adult rat heart. The cell-permeable fluorescent dye 4,5-diaminofluorescein diacetate (DAF2 DA) was used to provide a direct assessment of nitric oxide release. Both isoproterenol and endothelin increased NO production in isolated nuclei. Furthermore, a β3AR-selective agonist, BRL 37344, increased NO synthesis whereas the β1AR-selective agonist xamoterol did not. Isoproterenol increased, whereas ET-1 reduced, de novo transcription. The NO synthase inhibitor L-NAME prevented isoproterenol from increasing either NO production or de novo transcription. L-NAME also blocked ET-1-induced NO-production but did not alter the suppression of transcription initiation by ET-1. Inhibition of the cGMP-dependent protein kinase (PKG) using KT5823 also blocked the ability of isoproterenol to increase transcription initiation. Furthermore, immunoblotting revealed eNOS, but not nNOS, in isolated nuclei. Finally, caged, cell-permeable isoproterenol and endothelin-1 analogs were used to selectively activate intracellular β-adrenergic and endothelin receptors in intact adult cardiomyocytes. Intracellular release of caged ET-1 or isoproterenol analogs increased NO production in intact adult cardiomyocytes. Hence, activation of the NO synthase/guanylyl cyclase/PKG pathway is necessary for nuclear β3ARs to increase de novo transcription. Furthermore, we have demonstrated the potential utility of caged receptor ligands in selectively modulating signaling via endogenous intracellular G protein-coupled receptors. PMID:23684854

  14. Regulation of cardiac sodium-calcium exchanger by beta-adrenergic agonists.

    PubMed Central

    Fan, J; Shuba, Y M; Morad, M

    1996-01-01

    Na+-Ca2+ exchanger and Ca2+ channel are two major sarcolemmal Ca2+-transporting proteins of cardiac myocytes. Although the Ca2+ channel is effectively regulated by protein kinase A-dependent phosphorylation, no enzymatic regulation of the exchanger protein has been identified as yet. Here we report that in frog ventricular myocytes, isoproterenol down-regulates the Na+-Ca2+ exchanger, independent of intracellular Ca2+ and membrane potential, by activation of the beta-receptor/adenylate-cyclase/cAMP-dependent cascade, resulting in suppression of transmembrane Ca2+ transport via the exchanger and providing for the well-documented contracture-suppressant effect of the hormone on frog heart. The beta-blocker propranolol blocks the isoproterenol effect, whereas forskolin, cAMP, and theophylline mimic it. In the frog heart where contractile Ca2+ is transported primarily by the Na+-Ca2+ exchanger, the beta-agonists' simultaneous enhancement of Ca2+ current, ICa, and suppression of Na+-Ca2+ exchanger current, INa-Ca would enable the myocyte to develop force rapidly at the onset of depolarization (enhancement of ICa) and to decrease Ca2+ influx (suppression of INa-Ca) later in the action potential. This unique adrenergically induced shift in the Ca2+ influx pathways may have evolved in response to paucity of the sarcoplasmic reticulum Ca2+-ATPase/phospholamban complex and absence of significant intracellular Ca2+ release pools in the frog heart. PMID:8643609

  15. In vivo phosphoproteomics analysis reveals the cardiac targets of β-adrenergic receptor signaling.

    PubMed

    Lundby, Alicia; Andersen, Martin N; Steffensen, Annette B; Horn, Heiko; Kelstrup, Christian D; Francavilla, Chiara; Jensen, Lars J; Schmitt, Nicole; Thomsen, Morten B; Olsen, Jesper V

    2013-06-01

    β-Blockers are widely used to prevent cardiac arrhythmias and to treat hypertension by inhibiting β-adrenergic receptors (βARs) and thus decreasing contractility and heart rate. βARs initiate phosphorylation-dependent signaling cascades, but only a small number of the target proteins are known. We used quantitative in vivo phosphoproteomics to identify 670 site-specific phosphorylation changes in murine hearts in response to acute treatment with specific βAR agonists. The residues adjacent to the regulated phosphorylation sites exhibited a sequence-specific preference (R-X-X-pS/T), and integrative analysis of sequence motifs and interaction networks suggested that the kinases AMPK (adenosine 5'-monophosphate-activated protein kinase), Akt, and mTOR (mammalian target of rapamycin) mediate βAR signaling, in addition to the well-established pathways mediated by PKA (cyclic adenosine monophosphate-dependent protein kinase) and CaMKII (calcium/calmodulin-dependent protein kinase type II). We found specific regulation of phosphorylation sites on six ion channels and transporters that mediate increased ion fluxes at higher heart rates, and we showed that phosphorylation of one of these, Ser(92) of the potassium channel KV7.1, increased current amplitude. Our data set represents a quantitative analysis of phosphorylated proteins regulated in vivo upon stimulation of seven-transmembrane receptors, and our findings reveal previously unknown phosphorylation sites that regulate myocardial contractility, suggesting new potential targets for the treatment of heart disease and hypertension. PMID:23737553

  16. 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.

  17. 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

  18. 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

  19. Gender comparison of contractile performance and beta-adrenergic response in isolated rat cardiac trabeculae.

    PubMed

    Monasky, Michelle M; Varian, Kenneth D; Janssen, Paul M L

    2008-03-01

    It is known that gender can affect susceptibility to development of various cardiomyopathies. However, it is unclear whether basic mechanical contractile function of the myocardium differs between genders, whether they respond differently to stressors, or both. To test for a possible gender factor, contractile parameters of healthy, isolated myocardium were investigated under near physiological conditions. Right ventricular ultra-thin trabeculae from young adult LBN-f1 rats were electrically stimulated to isometrically contract at 37 degrees C. No differences were found in developed force or kinetic parameters. In each muscle, the force-frequency relationship was measured at 4, 6, and 8 Hz, encompassing most of the in vivo range. Again, no differences were observed in force-frequency behavior; developed force rose from 21.6 +/- 4.0 at 4 Hz to 30.3 +/- 5.8 mN/mm(2) at 8 Hz in females and from 23.4 +/- 3.4 to 29.8 +/- 3.4 mN/mm(2 )in males. The response to beta-adrenergic stimulation was similar; at 1 microM isoproterenol, developed force increased to 34.5 +/- 6.2 mN/mm(2) in females and 32.3 +/- 3.2 mN/mm(2) in males (female vs. male, not significant). We conclude that basic mechanical performance of healthy isolated myocardium under physiological conditions is not different between males and females, and a different response to stress must underlie gender-based differences in cardiac performance. PMID:18030479

  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. 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

  2. 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.

  3. β-Adrenergic Receptor-Dependent Alterations in Murine Cardiac Transcript Expression Are Differentially Regulated by Gefitinib In Vivo

    PubMed Central

    Talarico, Jennifer A.; Carter, Rhonda L.; Grisanti, Laurel A.; Yu, Justine E.; Repas, Ashley A.; Tilley, Douglas G.

    2014-01-01

    β-adrenergic receptor (βAR)-mediated transactivation of epidermal growth factor receptor (EGFR) has been shown to promote cardioprotection in a mouse model of heart failure and we recently showed that this mechanism leads to enhanced cell survival in part via regulation of apoptotic transcript expression in isolated primary rat neonatal cardiomyocytes. Thus, we hypothesized that this process could regulate cardiac transcript expression in vivo. To comprehensively assess cardiac transcript alterations in response to acute βAR-dependent EGFR transactivation, we performed whole transcriptome analysis of hearts from C57BL/6 mice given i.p. injections of the βAR agonist isoproterenol in the presence or absence of the EGFR antagonist gefitinib for 1 hour. Total cardiac RNA from each treatment group underwent transcriptome analysis, revealing a substantial number of transcripts regulated by each treatment. Gefitinib alone significantly altered the expression of 405 transcripts, while isoproterenol either alone or in conjunction with gefitinib significantly altered 493 and 698 distinct transcripts, respectively. Further statistical analysis was performed, confirming 473 transcripts whose regulation by isoproterenol were significantly altered by gefitinib (isoproterenol-induced up/downregulation antagonized/promoted by gefinitib), including several known to be involved in the regulation of numerous processes including cell death and survival. Thus, βAR-dependent regulation of cardiac transcript expression in vivo can be modulated by the EGFR antagonist gefitinib. PMID:24901703

  4. A Long Lasting β1 Adrenergic Receptor Stimulation of cAMP/Protein Kinase A (PKA) Signal in Cardiac Myocytes*

    PubMed Central

    Fu, Qin; Kim, Sungjin; Soto, Dagoberto; De Arcangelis, Vania; DiPilato, Lisa; Liu, Shubai; Xu, Bing; Shi, Qian; Zhang, Jin; Xiang, Yang K.

    2014-01-01

    Small-molecule, ligand-activated G protein-coupled receptors are generally thought to be rapidly desensitized within a period of minutes through receptor phosphorylation and internalization after repeated or prolonged stimulation. This transient G protein-coupled receptor activation remains at odds with many observed long-lasting cellular and physiological responses. Here, using live cell imaging of cAMP with a FRET-based biosensor and myocyte contraction assay, we show that the catecholamine-activated β1 adrenergic receptor (β1AR) continuously stimulates second messenger cAMP synthesis in primary cardiac myocytes and neurons, which lasts for more than 8 h (a decay t½ of 3.9 h) in cardiac myocytes. However, the β1AR-induced cAMP signal is counterbalanced and masked by the receptor-bound phosphodiesterase (PDE) 4D8-dependent cAMP hydrolysis. Inhibition of PDE4 activity recovers the receptor-induced cAMP signal and promotes contractile response in mouse hearts during extended periods of agonist stimulation. β1AR associates with PDE4D8 through the receptor C-terminal PDZ motif-dependent binding to synaptic-associated protein 97 (SAP97). Knockdown of SAP97 or mutation of the β1AR PDZ motif disrupts the complex and promotes sustained agonist-induced cAMP activity, PKA phosphorylation, and cardiac myocyte contraction response. Together, these findings unveil a long lasting adrenergic signal in neurons and myocytes under prolonged stimulation and an underappreciated role of PDE that is essential in classic receptor signaling desensitization and in maintaining a long lasting cAMP equilibrium for ligand-induced physiological response. PMID:24713698

  5. Characterization of a beta-adrenergically inhibited K+ current in rat cardiac ventricular cells.

    PubMed Central

    Scamps, F

    1996-01-01

    1. The electrophysiological properties and beta-adrenergic regulation of a non-inactivating K+ current were studied using the whole-cell patch-clamp technique (22 +/- 2 degrees C) in adult rat ventricular cells. 2. In the presence of 4-aminopyridine, an inhibitor of the rapidly inactivating current, the depolarization-activated current consisted only of a slowly decaying outward current (IK). The presence of a non-inactivating current (ISS) was revealed when analysing inactivation curves. 3. IK and ISS were both sensitive to 50 mM tetraethylammonium and 10 mM 4-aminopyridine inhibition. IK was totally blocked by 100 microM clofilium, while ISS was not inhibited but rather enhanced by this class III anti-arrhythmic agent. 4. Unlike IK, ISS was only slightly decreased by depolarizing prepulses and it did not show time-dependent inactivation when measured during 500 ms depolarizations. 5. ISS was decreased by the beta-adrenergic agonist isoprenaline (1 microM). Forskolin (10 microM) mimicked the effects of isoprenaline. The non-specific beta-adrenergic antagonist, propranolol (3 microM), and a specific beta 1-adrenergic antagonist, CGP 20712A (0.3 microM), both prevented the effects of isoprenaline. Cell perfusion with 100 microM PKI6-22, a peptide inhibitor of the cyclic AMP-dependent protein kinase, reduced or abolished the effects of isoprenaline. 6. The dose-response curve for the inhibition of ISS by isoprenaline was positioned to the left of that for the calcium current. The threshold dose and the dose giving 50% of the maximal effect were, respectively, 0.1 and 0.21 nM for ISS and 1 and 4.3 nM for ICa. 7. In view of the high sensitivity of ISS to isoprenaline, its possible physiological effect was evaluated on action potential duration during beta-adrenergic stimulation. At 1 nM, a concentration that did not increase ICa, isoprenaline induced a significant prolongation of action potential duration as a consequence of ISS inhibition. With 1 microM isoprenaline

  6. Assessment of anti-arrhythmic activity of antipsychotic drugs in an animal model: influence of non-cardiac α₁-adrenergic receptors.

    PubMed

    Mow, Tomas; Frederiksen, Kristen; Thomsen, Morten B

    2015-02-01

    Torsades de Pointes (TdP) is a potentially lethal cardiac arrhythmia and a known adverse effect of many drugs secondary to block of the rapidly activating delayed rectifier potassium current (IKr). In animal models antipsychotic drugs have shown reduced pro-arrhythmic potential compared to drugs with comparable IKr-blocking characteristics. The reduced pro-arrhythmic properties of antipsychotic drugs has been attributed to a variety of different causes e.g., effects on α₁-adrenergic receptors, β-adrenergic receptors, muscarinic receptors or cardiac ion channels like Ca(2+)- and Na(+)-channels. Since only limited experimental information exists about the effects of α₁-adrenergic receptor activity of antipsychotic drugs in pro-arrhythmic models, we have decided to investigate this. In this study we show that four antipsychotic drugs all have high affinity for α₁-adrenergic receptor (sertindole>risperidone>haloperidol>olanzapine) and all block IKr (sertindole>haloperidol>risperidone>olanzapine). In canine Purkinje fibres, α₁-adrenergic stimulation prolonged action potential duration; however, the stimulation does not cause afterdepolarizations, even in the presence of dofetilide-induced delayed repolarization. We showed for the first time in an in vivo pro-arrhythmic rabbit model that several antipsychotic drugs in accordance with their known α₁-adrenergic receptor blocking properties reduced the incidence of drug-induced TdP and that the overall ability of the antipsychotic drugs to prevent TdP was associated with prevention of methoxamine induced increase in blood pressure. Further investigations are required to clarify the relative importance of α₁-adrenergic receptor antagonism in conjunction with the additional effects of antipsychotic drugs on various receptors and ion channels. PMID:25530269

  7. Cardiac Myocyte Alternans in Intact Heart: Influence of Cell-Cell Coupling and β-Adrenergic Stimulation

    PubMed Central

    Hammer, Karin P.; Ljubojevic, Senka; Ripplinger, Crystal M.; Pieske, Burkert M.; Bers, Donald M.

    2015-01-01

    Background Cardiac alternans are proarrhythmic and mechanistically link cardiac mechanical dysfunction and sudden cardiac death. Beat-to-beat alternans occur when beats with large Ca2+ transients and long action potential duration (APD) alternate with the converse. APD alternans are typically driven by Ca2+ alternans and sarcoplasmic reticulum (SR) Ca2+ release alternans. But the effect of intercellular communication via gap junctions (GJ) on alternans in intact heart remains unknown. Objective We assessed the effects of cell-to-cell coupling on local alternans in intact Langen-dorff-perfused mouse hearts, measuring single myocyte [Ca2+] alternans synchronization among neighboring cells, and effects of β-adrenergic receptor (β-AR) activation and reduced GJ coupling. Methods and Results Mouse hearts (C57BL/6) were retrogradely perfused and loaded with Fluo-8 AM to record cardiac myocyte [Ca2+] in situ with confocal microscopy. Single cell resolution allowed analysis of alternans within the intact organ during alternans induction. Carbenoxolone (25 μM), a GJ inhibitor, significantly increased the occurrence and amplitude of alternans in single cells within the intact heart. Alternans were concordant between neighboring cells throughout the field of view, except transiently during onset. β-AR stimulation only reduced Ca2+ alternans in tissue that had reduced GJ coupling, matching effects seen in isolated myocytes. Conclusions Ca2+ alternans among neighboring myocytes is predominantly concordant, likely because of electrical coupling between cells. Consistent with this, partial GJ uncoupling increased propensity and amplitude of Ca2+ alternans, and made them more sensitive to reversal by β-AR activation, as in isolated myocytes. Electrical coupling between myocytes may thus limit the alternans initiation, but also allow alternans to be more stable once established. PMID:25828762

  8. 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

  9. 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

  10. 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. PMID:24145181

  11. Cardiac-specific ablation of G-protein receptor kinase 2 redefines its roles in heart development and beta-adrenergic signaling.

    PubMed

    Matkovich, Scot J; Diwan, Abhinav; Klanke, Justin L; Hammer, Daniel J; Marreez, Yehia; Odley, Amy M; Brunskill, Eric W; Koch, Walter J; Schwartz, Robert J; Dorn, Gerald W

    2006-10-27

    G-protein receptor kinase 2 (GRK2) is 1 of 7 mammalian GRKs that phosphorylate ligand-bound 7-transmembrane receptors, causing receptor uncoupling from G proteins and potentially activating non-G-protein signaling pathways. GRK2 is unique among members of the GRK family in that its genetic ablation causes embryonic lethality. Cardiac abnormalities in GRK2 null embryos implicated GRK2 in cardiac development but prevented studies of the knockout phenotype in adult hearts. Here, we created GRK2-loxP-targeted mice and used Cre recombination to generate germline and cardiac-specific GRK2 knockouts. GRK2 deletion in the preimplantation embryo with EIIa-Cre (germline null) resulted in developmental retardation and embryonic lethality between embryonic day 10.5 (E10.5) and E11.5. At E9.5, cardiac myocyte specification and cardiac looping were normal, but ventricular development was delayed. Cardiomyocyte-specific ablation of GRK2 in the embryo with Nkx2.5-driven Cre (cardiac-specific GRK2 knockout) produced viable mice with normal heart structure, function, and cardiac gene expression. Cardiac-specific GRK2 knockout mice exhibited enhanced inotropic sensitivity to the beta-adrenergic receptor agonist isoproterenol, with impairment of normal inotropic and lusitropic tachyphylaxis, and exhibited accelerated development of catecholamine toxicity with chronic isoproterenol treatment. These findings show that cardiomyocyte autonomous GRK2 is not essential for myocardial development after cardiac specification, suggesting that embryonic developmental abnormalities may be attributable to extracardiac effects of GRK2 ablation. In the adult heart, cardiac GRK2 is a major factor regulating inotropic and lusitropic tachyphylaxis to beta-adrenergic agonist, which likely contributes to its protective effects in catecholamine cardiomyopathy. PMID:17008600

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

    PubMed

    Ferron, Artur Junio Togneri; Jacobsen, Bruno Barcellos; 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

  13. 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

  14. Genetic variation in the β1-adrenergic receptor is associated with the risk of atrial fibrillation after cardiac surgery

    PubMed Central

    Jeff, Janina M.; Donahue, Brian S.; Brown-Gentry, Kristin; Roden, Dan M.; Crawford, Dana C.; Stein, C. Michael; Kurnik, Daniel

    2013-01-01

    Background: Postoperative atrial fibrillation (PoAF) after cardiac surgery is common and associated with increased morbidity and mortality. Increased sympathetic activation after surgery contributes to PoAF, and beta-blockers are the first-line recommendation for its prevention. We examined the hypothesis that common functional genetic variants in the β1-adrenoreceptor, the mediator of cardiac sympathetic activation and drug target of beta-blockers, are associated with the risk for PoAF and with the protective effect of beta-blockers. Methods: In a prospective cohort study, we studied 947 adult European Americans who underwent cardiac surgery at Vanderbilt University between 1999-2005. We genotyped two variants in the β1-adrenoreceptor, rs1801253 (Arg389Gly) and rs1801252 (Ser49Gly), and used logistic regression to examine the association between genotypes and PoAF occurring within 14 days after surgery, before and after adjustment for demographic and clinical covariates. Results: PoAF occurred in 239 patients (25.2%) and was associated with rs1801253 genotype (adjusted P=0.008), with Gly389Gly having an odds ratio of 2.63 (95% confidence interval, 1.42 to 4.89) for PoAF compared to the common Arg389Arg (P=0.002). In a predefined subgroup analysis, this association appeared to be stronger among patients without beta-blocker prophylaxis (adjusted OR=7.00; 95% CI, 1.82 to 26.96; P=0.005) compared to patients with beta-blocker prophylaxis, among whom the association between rs1801253 genotype and PoAF was not statistically significant (adjusted P=0.11). Conclusion: The Gly389 variant in the β1-adrenoreceptor is associated with PoAF, and this association appears to be modulated by beta-blocker therapy. Future studies of the association of other adrenergic pathway genes with PoAF will be of interest. PMID:24332148

  15. Loss of the transcription factor Meis1 prevents sympathetic neurons target-field innervation and increases susceptibility to sudden cardiac death

    PubMed Central

    Bouilloux, Fabrice; Thireau, Jérôme; Ventéo, Stéphanie; Farah, Charlotte; Karam, Sarah; Dauvilliers, Yves; Valmier, Jean; Copeland, Neal G; Jenkins, Nancy A; Richard, Sylvain; Marmigère, Frédéric

    2016-01-01

    Although cardio-vascular incidents and sudden cardiac death (SCD) are among the leading causes of premature death in the general population, the origins remain unidentified in many cases. Genome-wide association studies have identified Meis1 as a risk factor for SCD. We report that Meis1 inactivation in the mouse neural crest leads to an altered sympatho-vagal regulation of cardiac rhythmicity in adults characterized by a chronotropic incompetence and cardiac conduction defects, thus increasing the susceptibility to SCD. We demonstrated that Meis1 is a major regulator of sympathetic target-field innervation and that Meis1 deficient sympathetic neurons die by apoptosis from early embryonic stages to perinatal stages. In addition, we showed that Meis1 regulates the transcription of key molecules necessary for the endosomal machinery. Accordingly, the traffic of Rab5+ endosomes is severely altered in Meis1-inactivated sympathetic neurons. These results suggest that Meis1 interacts with various trophic factors signaling pathways during postmitotic neurons differentiation. DOI: http://dx.doi.org/10.7554/eLife.11627.001 PMID:26857994

  16. Milrinone enhances cytosolic calcium transient and contraction in rat cardiac myocytes during beta-adrenergic stimulation.

    PubMed

    Raffaeli, S; Ferroni, C; Spurgeon, H A; Capogrossi, M C

    1989-01-01

    We have investigated the mechanism that underlies the absence of a positive inotropic effect of milrinone on rat myocardium. The twitch characteristics of enzymatically dissociated left ventricular myocytes from the adult rat and guinea pig were assessed by edge tracking during field stimulation. In some rat myocytes loaded with the ester derivative of the Ca2+ probe Indo-1 we simultaneously measured changes in cell length and in the associated cytosolic Ca2+ (Cai) transient. Our results show that in guinea pig myocytes bathed in 0.5 mM [Ca2+] and field stimulated at 1 Hz, milrinone (10 microM) had a positive inotropic effect. In contrast milrinone had no effect on the contractile properties of rat myocytes studied under similar conditions and field stimulated at 0.2 Hz. In rat myocytes bathed in 0.5 mM [Ca2+] and stimulated at 0.2 Hz isoproterenol (1 nM) increased the amplitude and shortened the duration of the contraction and of the associated Cai transient; these effects of beta-adrenergic stimulation were further enhanced by the addition of milrinone (10 microM) in the presence of isoproterenol. Under conditions of higher cell Ca2+ loading achieved by raising bathing [Ca2+] to 1 mM and isoproterenol to 3 nM the positive inotropic effect of milrinone (10 microM) in rat myocytes saturated when spontaneous oscillatory Ca2+ release appeared in the diastolic intervals between electrically stimulated twitches. Our results suggest that an enhancement in the baseline beta-adrenergic stimulation is required for milrinone to exercise a positive inotropic action on rat myocardial tissue. PMID:2576017

  17. 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

  18. Tendon Innervation.

    PubMed

    Ackermann, Paul W; Salo, Paul; Hart, David A

    2016-01-01

    The regulation of tendon metabolism including the responses to loading is far from being well understood. During the last decade, however, accumulating data show that tendon innervation in addition to afferent functions, via efferent pathways has a regulatory role in tendon homeostasis via a wide range of neuromediators, which coordinate metabolic and neuro-inflammatory pathways.Innervation of intact healthy tendons is localized in the surrounding structures, i.e paratenon, endotenon and epitenon, whereas the tendon proper is practically devoid of neuronal supply. This anatomical finding reflects that the tendon metabolism is regulated from the tendon envelope, i.e. interfascicular matrix (see Chap. 1 ).Tendon innervation after injury and during repair, however, is found as extensive nerve ingrowth into the tendon proper, followed by a time-dependent emergence of different neuronal mediators, which amplify and fine-tune inflammatory and metabolic pathways in tendon regeneration. After healing nerve fibers retract to the tendon envelope.In tendinopathy innervation has been identified to consist of excessive and protracted nerve ingrowth in the tendon proper, suggesting pro-inflammatory, nociceptive and hypertrophic (degenerative) tissue responses.In metabolic disorders such as eg. diabetes impaired tendon healing has been established to be related to dysregulation of neuronal growth factors.Targeted approaches to the peripheral nervous system including neuronal mediators and their receptors may prove to be effective therapies for painful, degenerative and traumatic tendon disorders. PMID:27535247

  19. 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.

  20. 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. PMID:26420487

  1. 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

  2. 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

  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. 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

  5. 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. PMID:27582064

  6. AAV6-βARKct gene delivery mediated by molecular cardiac surgery with recirculating delivery (MCARD) in sheep results in robust gene expression and increased adrenergic reserve

    PubMed Central

    Katz, Michael G.; Fargnoli, Anthony S.; Swain, JaBaris D.; Tomasulo, Catherine E.; Ciccarelli, Michele; Huang, Z. Maggie; Rabinowitz, Joseph E.; Bridges, Charles R.

    2013-01-01

    Objective Genetic modulation of heart function is a novel therapeutic strategy. We investigated the effect of molecular cardiac surgery with recirculating delivery (MCARD)–mediated carboxyl-terminus of the β-adrenergic receptor kinase (βARKct) gene transfer on cardiac mechanoenergetics and β-adrenoreceptor (βAR) signaling. Methods After baseline measurements, sheep underwent MCARD-mediated delivery of 1014 genome copies of self-complimentary adeno-associated virus (scAAV6)-βARKct. Four and 8 weeks after MCARD, mechanoenergetic studies using magnetic resonance imaging were performed. Tissues were analyzed with real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting. βAR density, cyclic adenosine monophosphate levels, and physiologic parameters were evaluated. Results There was a significant increase in dP/dtmax at 4 weeks: 1384 ± 76 versus 1772 ± 182 mm Hg/s; and the increase persisted at 8 weeks in response to isoproterenol (P <.05). Similarly, the magnitude of dP/dtmin increased at both 4 weeks and 8 weeks with isoproterenol stimulation (P <.05). At 8 weeks, potential energy was conserved, whereas in controls there was a decrease in potential energy (P <.05) in response to isoproterenol. RT-qPCR confirmed robustness of βARKct expression throughout the left ventricle and undetectable expression in extracardiac tissues. Quantitative Western blot data confirmed higher expression of βARKct in the left ventricle: 0.46 ± 0.05 versus 0.00 in lung and liver (P <.05). Survival was 100%and laboratory parameters of major organ function were within normal limits. Conclusions MCARD-mediated βARKct delivery is safe, results in robust cardiac-specific gene expression, enhances cardiac contractility and lusitropy, increases adrenergic reserve, and improves energy utilization efficiency in a preclinical large animal model. PMID:22143102

  7. Innervation of the cerebral vasculature.

    PubMed

    Duckles, S P

    1983-01-01

    With the development of specific antibodies to vasoactive peptides and application of immunohistochemistry and radioimmunoassay methods, knowledge of vascular innervation has grown rapidly. In the cerebral circulation, four possible neurotransmitters are present: norepinephrine, acetylcholine, vasoactive intestinal peptide (VIP), and substance P. There is a dense adrenergic innervation of cerebral arteries, but contractile responses to nerve stimulation or circulating catecholamines are relatively small both in vitro and in vivo. Recent studies using radioligand binding techniques indicate a lack of specific 3H-prazosin binding in cerebral arteries, in contrast to other vascular beds. Thus a lack of alpha1-adrenergic receptors in cerebral arteries may account for weak responsiveness to sympathetic stimulation. Both VIP and acetylcholine may be vasodilator neurotransmitters, but blockade of cholinergic responses does not alter neurogenic vasodilation. The lack of specific VIP antagonists hampers efforts to explore this system more fully. Substance P-containing nerves are affected by capsaicin, supporting the hypothesis that these are primary sensory afferents, perhaps mediating pain. Future work in this area may focus on defining the pathways of these nerves and exploring the role of co-transmitters and possible interactions between nerves. With this basic information, experiments can be designed to elucidate more clearly the functional roles these nerves play. PMID:6210001

  8. Temperature and species-specific effects on ß3-adrenergic receptor cardiac regulation in two freshwater teleosts: Channel catfish (Ictalurus punctatus) and common carp (Cyprinus carpio).

    PubMed

    Petersen, L H; Burleson, M L; Huggett, D B

    2015-07-01

    β₃-adrenergic receptors (AR) are important in teleost cardiovascular regulation. To date, it is unknown whether temperature acclimation changes ß₃-AR functionality and consequently the involvement of this AR subtype in teleost cardiac regulation. Common carp (Cyprinus carpio) were acclimated at 12 °C or 23 °C (minimum 3 weeks) after which cardiovascular variables (cardiac output (Q), stroke volume (Sv) and heart rate (fH)) were measured upon injection of the ß₃-AR agonist, BRL(37344), and antagonist, SR(59230A). In both 12 °C and 23 °C acclimated carp, BRL(37344) induced significant increases in fH and Q whereas Sv was significantly decreased. While temperature did not affect the change (increase vs. decrease) in cardiac variables, the magnitude and on-set of responses differed. For instance, fH, Sv and Q responded significantly faster to ß₃-AR stimulation in 23 °C carp. In contrast, maximum responses of fH and Q were significantly higher in 23 °C carp whereas the maximum response of Sv was significantly greater in 12 °C carp. These findings suggest that temperature acclimation induced changes in β₃-AR receptor functionality (e.g. density and/or affinity). Stimulation of β₃-ARs in 23 °C acclimated channel catfish (Ictalurus punctatus) caused significant increases in fH, Sv and Q. The increase in Sv was opposite to the decrease observed in 23 °C acclimated common carp. SR(59230A) induced significant decreases in Sv and Q but had no effect in carp (23 °C). Results suggest species diversity in the density and affinity or structure of ß₃-ARs which may explain the different cardiac responses to ß₃-AR ligands. PMID:25882086

  9. Beta-adrenergic modulation of the release of atrial natriuretic factor from rat cardiac atria in vitro

    SciTech Connect

    Brown, A.; Imada, T.; Takayanagi, B.; Inagami, T.

    1986-03-01

    Several stimulatory factors for the release of atrial natriuretic factor, such as atrial stretch, atrial pacing and vasopressin, have been reported. We studied the effects of the adrenergic nervous system on the release of ANF using an in vitro perfusion system. Right and left atria from Sprague-Dawley rats were quartered and perfused with Krebs-Ringer bicarbonate solution gassed with 95% CO/sub 2//5% O/sub 2/ at 37/sup 0/C. Perfusate factions were collected every 2 minutes. Fractions were collected 20 minutes before and for 2 hours during the administration of test agents. ANF was measured by radioimmunoassay. Within 10 minutes of exposure to 10/sup -6/M isoproterenol, ANF secretion fell to less than 50% of its baseline level. However, beta agonists showed a stimulatory effect of 4-5 fold. Carbachol, in a concentration of 10/sup -2/M was used to demonstrate the viability of the atria exposed to isoproterenol, and produced a stimulation of ANF release of 4-6 times the basal level. The adrenergic nervous system can modulate ANF release in vitro. Further studies are being performed with selective beta agonists and antagonists to elucidate these results.

  10. Arg16Gly and Gln27Glu β2 adrenergic polymorphisms influence cardiac autonomic modulation and baroreflex sensitivity in healthy young Brazilians.

    PubMed

    Atala, Magda M; Goulart, Alessandra; Guerra, Grazia M; Mostarda, Cristiano; Rodrigues, Bruno; Mello, Priscila R; Casarine, Dulce E; Irigoyen, Maria-Claudia; Pereira, Alexandre C; Consolim-Colombo, Fernanda M

    2015-01-01

    The association between functional β2 adrenergic receptor (β2-AR) polymorphisms and cardiac autonomic modulation is still unclear. Thus, two common polymorphisms in the β2-AR gene (Gln27Glu β2 and Arg16Gly β2) were studied to determine whether they might affect tonic and reflex cardiac sympathetic activity in healthy young subjects. A total of 213 healthy young white subjects of both genders (53% female), aged 18-30 years (23.5±3.4 y), had their continuous blood pressure curves noninvasively recorded by Finometer at baseline, and other hemodynamic parameters, as cardiac autonomic modulation, baroreflex sensitivity, and allele, genotype, and diplotype frequencies calculated. Associations were made between Arg16Gly β2 and Gln27Glu β2 polymorphisms and between β2-AR diplotypes and all variables. The heart rate was significantly lower (P<0.001) in the presence of homozygous Arg/Arg alleles (60.9±1.5 bpm) than in that of Arg/Gly heterozygotes (65.9±1.0 bpm) or Gly/Gly homozygotes (66.3±1.2 bpm). Homozygous carriers of Arg16 allele had an alpha index (19.2±1.3) significantly higher (P<0.001) than that of the subjects with the Gly allele Gly/Gly (14.5±0.7) or Arg/Gly (14.6±0.7). Furthermore, the recessive Glu27Glu and the heterozygous Gln27Glu genotypes had a higher percentage of low-frequency components (LF%) than the homozygous Gln27Gln (15.1% vs. 16.0% vs. 8.2%, P=0.03, respectively). In healthy young subjects, the presence of β2-AR Arg16 allele in a recessive model was associated with higher baroreflex sensitivity, and increased parasympathetic modulation in studied individuals. PMID:25755837

  11. Arg16Gly and Gln27Glu β2 adrenergic polymorphisms influence cardiac autonomic modulation and baroreflex sensitivity in healthy young Brazilians

    PubMed Central

    Atala, Magda M; Goulart, Alessandra; Guerra, Grazia M; Mostarda, Cristiano; Rodrigues, Bruno; Mello, Priscila R; Casarine, Dulce E; Irigoyen, Maria-Claudia; Pereira, Alexandre C; Consolim-Colombo, Fernanda M

    2015-01-01

    The association between functional β2 adrenergic receptor (β2-AR) polymorphisms and cardiac autonomic modulation is still unclear. Thus, two common polymorphisms in the β2-AR gene (Gln27Glu β2 and Arg16Gly β2) were studied to determine whether they might affect tonic and reflex cardiac sympathetic activity in healthy young subjects. A total of 213 healthy young white subjects of both genders (53% female), aged 18-30 years (23.5±3.4 y), had their continuous blood pressure curves noninvasively recorded by Finometer at baseline, and other hemodynamic parameters, as cardiac autonomic modulation, baroreflex sensitivity, and allele, genotype, and diplotype frequencies calculated. Associations were made between Arg16Gly β2 and Gln27Glu β2 polymorphisms and between β2-AR diplotypes and all variables. The heart rate was significantly lower (P<0.001) in the presence of homozygous Arg/Arg alleles (60.9±1.5 bpm) than in that of Arg/Gly heterozygotes (65.9±1.0 bpm) or Gly/Gly homozygotes (66.3±1.2 bpm). Homozygous carriers of Arg16 allele had an alpha index (19.2±1.3) significantly higher (P<0.001) than that of the subjects with the Gly allele Gly/Gly (14.5±0.7) or Arg/Gly (14.6±0.7). Furthermore, the recessive Glu27Glu and the heterozygous Gln27Glu genotypes had a higher percentage of low-frequency components (LF%) than the homozygous Gln27Gln (15.1% vs. 16.0% vs. 8.2%, P=0.03, respectively). In healthy young subjects, the presence of β2-AR Arg16 allele in a recessive model was associated with higher baroreflex sensitivity, and increased parasympathetic modulation in studied individuals. PMID:25755837

  12. Adipose stem cell sheets improved cardiac function in the rat myocardial infarction, but did not alter cardiac contractile responses to β-adrenergic stimulation.

    PubMed

    Otsuki, Yuki; Nakamura, Yoshinobu; Harada, Shingo; Yamamoto, Yasutaka; Ogino, Kazuhide; Morikawa, Kumi; Ninomiya, Haruaki; Miyagawa, Shigeru; Sawa, Yoshiki; Hisatome, Ichiro; Nishimura, Motonobu

    2015-01-01

    Adipose stem cells (ASCs) are a source of regenerative cells available for autologous transplantation to hearts. We compared protective actions of ASC sheets on rat myocardial infarction (MI) in comparison with those of skeletal myoblast cell sheets. Their effects on infarcted hearts were evaluated by biological, histochemical as well as physiological analyses. ASC sheets secreted higher concentrations of angiogenic factors (HGF, VEGF, and bFGF; P < 0.05) under normoxic and hypoxic conditions than those of myoblast cell sheets, associated with reduction of cell apoptosis (P < 0.05). Like myoblast cell sheets, ASC sheets improved cardiac function (P < 0.05) and decreased the plasma level of ANP (P < 0.05) in MI hearts. ASC sheets restored cardiac remodeling characterized by fibrosis, cardiac hypertrophy and impaired angiogenesis (P < 0.05), which was associated with increases in angiogenic factors (P < 0.05). In isolated perfused rat hearts, ASC sheets improved both systolic and diastolic functions, which was comparable to cardiac functions of myoblast cell sheets, while both cell sheets failed to restore cardiac contractile response to either isoproterenol, pimobendan or dibutyryl cAMP. These results indicated that ASC sheets improved cardiac function and remodeling of MI hearts mediated by their paracrine action and this improvement was comparable to those by myoblast cell sheets. PMID:25749147

  13. [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. PMID:17768375

  14. Prognostic Significance of Imaging Myocardial Sympathetic Innervation.

    PubMed

    Malhotra, Saurabh; Fernandez, Stanley F; Fallavollita, James A; Canty, John M

    2015-08-01

    There has been a longstanding interest in understanding whether the presence of inhomogeneity in myocardial sympathetic innervation can predict patients at risk of sudden cardiac arrest from lethal ventricular arrhythmias. The advent of radiolabeled norepinephrine analogs has allowed this to be imaged in patients with ischemic and non-ischemic cardiomyopathy using single, photon emission computed tomography (SPECT) and positron emission tomography (PET). Several observational studies have demonstrated that globally elevated myocardial sympathetic tone (as reflected by reduced myocardial norepinephrine analog uptake) can predict composite cardiac end-points including total cardiovascular mortality. More recent studies have indicated that quantifying the extent of regional denervation can predict the risk of lethal ventricular arrhythmias and sudden cardiac death. This review will summarize our current understanding of the prognostic significance of altered myocardial sympathetic innervation. PMID:26087899

  15. 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

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

    PubMed Central

    Zhao, Ru; Zheng, Qingqing; Li, Lan; Yang, Wenbing; Ding, Lu; Xue, Feng; Fan, Junming; Gong, Yongsheng

    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

  17. β2 adrenergic receptor activation governs cardiac repolarization and arrhythmogenesis in a guinea pig model of heart failure

    PubMed Central

    Wang, Yao; Yuan, Jiamin; Qian, Zhiyong; Zhang, Xiwen; Chen, Yanhong; Hou, Xiaofeng; Zou, Jiangang

    2015-01-01

    β2-AR activation increases the risk of sudden cardiac death (SCD) in heart failure (HF) patients. Non-selective β-AR blockers have greater benefits on survival than selective β1-AR blockers in chronic HF patients, indicating that β2-AR activation contributes to SCD in HF. This study investigated the role of β2-AR activation on repolarization and ventricular arrhythmia (VA) in the experimental HF model. The guinea pig HF was induced by descending aortic banding. The effective refractoriness period (ERP), corrected QT (QTc) and the incidence of VA were examined using Langendorff and programmed electrical stimulation. Ikr and APD were recorded by the whole cell patch clamp. Selective β2-AR agonist salbutamol significantly increased the incidence of VA, prolonged QTc and shortened ERP. These effects could be prevented by the selective β2-AR antagonist, ICI118551. Salbutamol prolonged APD90 and reduced Ikr in guinea pig HF myocytes. The antagonists of cAMP (Rp-cAMP) and PKA (KT5720) attenuated Ikr inhibition and APD prolongation induced by salbutamol. However, the antagonists of Gi protein (PTX) and PDE III (amrinone) showed opposite effects. This study indicates that β2-AR activation increases the incidence of VA in the experimental HF model via activation of Gs/cAMP/PKA and/or inhibition of Gi/PDE pathways. PMID:25567365

  18. 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

  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. The coordinated increased expression of biliverdin reductase and heme oxygenase-2 promotes cardiomyocyte survival: a reductase-based peptide counters β-adrenergic receptor ligand-mediated cardiac dysfunction

    PubMed Central

    Ding, Bo; Gibbs, Peter E. M.; Brookes, Paul S.; Maines, Mahin D.

    2011-01-01

    HO-2 oxidizes heme to CO and biliverdin; the latter is reduced to bilirubin by biliverdin reductase (BVR). In addition, HO-2 is a redox-sensitive K/Ca2-associated protein, and BVR is an S/T/Y kinase. The two enzymes are components of cellular defense mechanisms. This is the first reporting of regulation of HO-2 by BVR and that their coordinated increase in isolated myocytes and intact heart protects against cardiotoxicity of β-adrenergic receptor activation by isoproterenol (ISO). The induction of BVR mRNA, protein, and activity and HO-2 protein was maintained for ≥96 h; increase in HO-1 was modest and transient. In isolated cardiomyocytes, experiments with cycloheximide, proteasome inhibitor MG-132, and siBVR suggested BVR-mediated stabilization of HO-2. In both models, activation of BVR offered protection against the ligand's stimulation of apoptosis. Two human BVR-based peptides known to inhibit and activate the reductase, KKRILHC281 and KYCCSRK296, respectively, were tested in the intact heart. Perfusion of the heart with the inhibitory peptide blocked ISO-mediated BVR activation and augmented apoptosis; conversely, perfusion with the activating peptide inhibited apoptosis. At the functional level, peptide-mediated inhibition of BVR was accompanied by dysfunction of the left ventricle and decrease in HO-2 protein levels. Perfusion of the organ with the activating peptide preserved the left ventricular contractile function and was accompanied by increased levels of HO-2 protein. Finding that BVR and HO-2 levels, myocyte apoptosis, and contractile function of the heart can be modulated by small human BVR-based peptides offers a promising therapeutic approach for treatment of cardiac dysfunctions.—Ding, B., Gibbs, P. E. M., Brookes, P. S., Maines, M. D. The coordinated increased expression of biliverdin reductase and heme oxygenase-2 promotes cardiomyocyte survival; a reductase-based peptide counters β-adrenergic receptor ligand-mediated cardiac dysfunction

  1. 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

  2. Cardiac Function, Perfusion, Metabolism, and Innervation following Autologous Stem Cell Therapy for Acute ST-Elevation Myocardial Infarction. A FINCELL-INSIGHT Sub-Study with PET and MRI

    PubMed Central

    Mäki, Maija T.; Koskenvuo, Juha W.; Ukkonen, Heikki; Saraste, Antti; Tuunanen, Helena; Pietilä, Mikko; Nesterov, Sergey V.; Aalto, Ville; Airaksinen, K. E. Juhani; Pärkkä, Jussi P.; Lautamäki, Riikka; Kervinen, Kari; Miettinen, Johanna A.; Mäkikallio, Timo H.; Niemelä, Matti; Säily, Marjaana; Koistinen, Pirjo; Savolainen, Eeva-Riitta; Ylitalo, Kari; Huikuri, Heikki V.; Knuuti, Juhani

    2012-01-01

    Purpose: Beneficial mechanisms of bone marrow cell (BMC) therapy for acute ST-segment elevation myocardial infarct (STEMI) are largely unknown in humans. Therefore, we evaluated the feasibility of serial positron emission tomography (PET) and MRI studies to provide insight into the effects of BMCs on the healing process of ischemic myocardial damage. Methods: Nineteen patients with successful primary reteplase thrombolysis (mean 2.4 h after symptoms) for STEMI were randomized for BMC therapy (2.9 × 106 CD34+ cells) or placebo after bone marrow aspiration in a double-blind, multi-center study. Three days post-MI, coronary angioplasty, and paclitaxel eluting stent implantation preceded either BMC or placebo therapy. Cardiac PET and MRI studies were performed 7–12 days after therapies and repeated after 6 months, and images were analyzed at a central core laboratory. Results: In BMC-treated patients, there was a decrease in [11C]-HED defect size (−4.9 ± 4.0 vs. −1.6 ± 2.2%, p = 0.08) and an increase in [18F]-FDG uptake in the infarct area at risk (0.06 ± 0.09 vs. −0.05 ± 0.16, p = 0.07) compared to controls, as well as less left ventricular dilatation (−4.4 ± 13.3 vs. 8.0 ± 16.7 mL/m2, p = 0.12) at 6 months follow-up. However, BMC treatment was inferior to placebo in terms of changes in rest perfusion in the area at risk (−0.09 ± 0.17 vs. 0.10 ± 0.17, p = 0.03) and infarct size (0.4 ± 4.2 vs. −5.1 ± 5.9 g, p = 0.047), and no effect was observed on ejection fraction (p = 0.37). Conclusion: After the acute phase of STEMI, BMC therapy showed only minor trends of long-term benefit in patients with rapid successful thrombolysis. There was a trend of more decrease in innervation defect size and enhanced glucose metabolism in the infarct-related myocardium and also a trend of less ventricular dilatation in the BMC-treated group compared to placebo. However, no

  3. 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. PMID:26820641

  4. Incidence of sudden cardiac death associated with coronary artery occlusion in dogs with hypertension and left ventricular hypertrophy is reduced by chronic beta-adrenergic blockade.

    PubMed

    Dellsperger, K C; Martins, J B; Clothier, J L; Marcus, M L

    1990-09-01

    Because beta-adrenergic blockade has as one of its many effects altered electrophysiological abnormalities after dogs with left ventricular hypertrophy have been subjected to coronary occlusion, we tested the hypothesis that metoprolol (200-400 mg/day) would reduce mortality rates in dogs with one-kidney, one clip left ventricular hypertrophy while a similar reduction in arterial pressure with enalapril (20-40 mg/day) would not. Dogs with left ventricular hypertrophy were given metoprolol or enalapril for 5-7 days before a 3-hour coronary occlusion. Infarct size and risk area were measured with triphenyltetrazolium chloride stain and barium angiography, respectively. For control (n = 15), left ventricular hypertrophy (n = 17), left ventricular hypertrophy plus metoprolol (n = 12), and left ventricular hypertrophy plus enalapril (n = 15) groups, mean arterial pressure, ratio of infarct size to risk area, and dogs experiencing sudden death were 110 +/- 4, 142 +/- 4, 121 +/- 7, and 120 +/- 3 mm Hg; 44 +/- 5%, 65 +/- 5%, 44 +/- 7%, and 30 +/- 4%; and 27%, 65%, 17%, and 53%, respectively. Thus, the excessive increase in early mortality occurring when dogs with hypertension and left ventricular hypertrophy undergo coronary occlusion is interrupted with beta-blockade, possibly via electrophysiological effects rather than by changes in arterial pressure or infarct size. PMID:1975521

  5. The effects of α- and β-adrenergic blocking agents on postresuscitation myocardial dysfunction and myocardial tissue injury in a rat model of cardiac arrest.

    PubMed

    Yang, Min; Hu, Xianwen; Lu, Xiaoye; Wu, Xiaobo; Xu, Jiefeng; Yang, Zhengfei; Qian, Jie; Sun, Shijie; Cahoon, Jena; Tang, Wanchun

    2015-05-01

    We investigated the relationship between the severity of postresuscitation (PR) myocardial tissue injury and myocardial dysfunction after the administration of epinephrine as well as the protective effects of α- and β-adrenergic blocking agents. Forty male Sprague-Dawley rats were randomized into 6 groups: (1) placebo; (2) epinephrine; (3) epinephrine pretreated with α1-blocker (prazosin); (4) epinephrine pretreated with α2-blocker (yohimbine); (5) epinephrine pretreated with β-blocker (propranolol); and (6) epinephrine pretreated with β- plus α1-blocker (propranolol and prazosin). Cardiopulmonary resuscitation was initiated after 8 minutes of untreated ventricular fibrillation and continued for an additional 8 minutes. The myocardial function and the serum concentrations of troponin I (Tn I) and N-terminal probrain natriuretic peptide (NT-proBNP) were measured at baseline and after resuscitation. After resuscitation, both Tn I and NT-proBNP were significantly increased in all groups, especially in the epinephrine and epinephrine pretreated with α2-blocker groups. Significantly better PR myocardial function and neurologic deficit score were observed in epinephrine pretreated with the α1- or β-blocker with decreased releases of Tn I and NT-proBNP. However, the most significant improvements were observed in the animals pretreated with β- plus α1-blocker. The present study demonstrated that myocardial stunning may not be the only mechanism of PR myocardial dysfunction. Administration of epinephrine increased the severity of PR myocardial tissue injury and dysfunction. The β- and β- plus α1-blocker pretreatment significantly reduced the severity of PR myocardial tissue injury and myocardial dysfunction with better neurologic function and prolonged duration of survival. PMID:25468485

  6. [Innervation of the intervertebral disc].

    PubMed

    García-Cosamalón, José; Fernández-Fernández, Javier; González-Martínez, Emilio; Ibáñez-Plágaro, Javier; Robla Costales, Javier; Martínez-Madrigal, Milton; López Muñíz, Alfonso; del Valle, Miguel Enrique; Vega, José Antonio

    2013-01-01

    Until very recently, intervertebral disc innervation was a subject of considerable debate. Nowadays, the introduction of inmunohistochemical techniques associated to specific antibodies and studies with retrograde tracers in nerves have allowed greater understanding of disc innervation in physiological and pathological conditions and also endings characteristics and their patterns of distribution in both situations. The existing controversies regarding structural basis of discogenic pain, have raised the interest of knowing the influence of innervation in back pain from discal origin and its characteristics. Today, we know that pathologic neoinnervation accompanying radial fissures is an important factor in the genesis of discogenic pain; within a complex mechanism in which other neurobiomechemical, inflammatory and biomechanical factors are involved. PMID:23582224

  7. Reductions in the Cardiac Transient Outward K+ Current Ito Caused by Chronic β-Adrenergic Receptor Stimulation Are Partly Rescued by Inhibition of Nuclear Factor κB.

    PubMed

    Panama, Brian K; Korogyi, Adam S; Aschar-Sobbi, Roozbeh; Oh, Yena; Gray, Charles B B; Gang, Hongying; Brown, Joan Heller; Kirshenbaum, Lorrie A; Backx, Peter H

    2016-02-19

    The fast transient outward potassium current (Ito,f) plays a critical role in the electrical and contractile properties of the myocardium. Ito,f channels are formed by the co-assembly of the pore-forming α-subunits, Kv4.2 and Kv4.3, together with the accessory β-subunit KChIP2. Reductions of Ito,f are common in the diseased heart, which is also associated with enhanced stimulation of β-adrenergic receptors (β-ARs). We used cultured neonatal rat ventricular myocytes to examine how chronic β-AR stimulation decreases Ito,f. To determine which downstream pathways mediate these Ito,f changes, adenoviral infections were used to inhibit CaMKIIδc, CaMKIIδb, calcineurin, or nuclear factor κB (NF-κB). We observed that chronic β-AR stimulation with isoproterenol (ISO) for 48 h reduced Ito,f along with mRNA expression of all three of its subunits (Kv4.2, Kv4.3, and KChIP2). Inhibiting either CaMKIIδc nor CaMKIIδb did not prevent the ISO-mediated Ito,f reductions, even though CaMKIIδc and CaMKIIδb clearly regulated Ito,f and the mRNA expression of its subunits. Likewise, calcineurin inhibition did not prevent the Ito,f reductions induced by β-AR stimulation despite strongly modulating Ito,f and subunit mRNA expression. In contrast, NF-κB inhibition partly rescued the ISO-mediated Ito,f reductions in association with restoration of KChIP2 mRNA expression. Consistent with these observations, KChIP2 promoter activity was reduced by p65 as well as β-AR stimulation. In conclusion, NF-κB, and not CaMKIIδ or calcineurin, partly mediates the Ito,f reductions induced by chronic β-AR stimulation. Both mRNA and KChIP2 promoter data suggest that the ISO-induced Ito,f reductions are, in part, mediated through reduced KChIP2 transcription caused by NF-κB activation. PMID:26742842

  8. 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

  9. Evidence for central innervation of intracerebral blood vessels: local cerebral blood flow measurements and histofluorescence analysis by the sucrose-phosphate-glyoxylic acid (SPG) method.

    PubMed

    de la Torre, J C

    1976-12-01

    Local cerebral blood flow using a hydrogen clearance technique and a histofluorescent modification of the glyoxylic acid method (SPG method) were used in rats to study the influence of brain stem centers on intracerebral flood flow. Recording of local cerebral blood flow following stimulation of the locus coeruleus but not of the ventrocaudal nucleus of the lateral lemniscus showed a significant blood flow decrease in anterior brain regions where innervation of ascending adrenergic pathways are known to occur. Adrenergic innervation using the SPG method (sucrose-potassium phosphate-glyoxylic acid) histofluorescence could not be verified in the rat but was evident in the dog and rhesus monkey brain sections examined. The results provide additional evidence suggestive of a role for the locus coeruleus in modulating or controlling intracerebral blood flow in these animals. In addition, histofluorescent visualization of intracerebral vessels in dog and monkey show an association between adrenergic varicosities and arterioles in bilaterally ganglion-ectomized animals. This adrenergic-vascular association was not seen in the rat. The results provide further evidence that central adrenergic innervation from the brain stem may control intracerebral blood flow independent of sympathetic influence. PMID:11370237

  10. Innervation of sinoatrial nodal cells in the rabbit.

    PubMed

    Inokaitis, Hermanas; Pauziene, Neringa; Rysevaite-Kyguoliene, Kristina; Pauza, Dainius H

    2016-05-01

    In spite of the fact that the rabbit is being widely used as a laboratory animal in experimental neurocardiology, neural control of SAN cells in the rabbit heart has been insufficiently examined thus far. This study analyzes the distribution of SAN cells and their innervation pattern employing fluorescent immunohistochemistry on rabbit whole mount atrial preparations. A dense network of adrenergic (positive for TH), cholinergic (positive for ChAT), nitrergic (positive for nNOS) and possibly sensory (positive for SP) NFs together with numerous neuronal somata were identified on the RRCV where the main mass of SAN cells positive for HCN4 were distributed as well. In general, the area occupied by SAN cells comprised nearly the entire RRCV and possessed a three to four times denser network of NFs compared with adjacent atrial walls. Adrenergic NFs predominated noticeably in-between SAN cells. Solitary neuronal somata or somata gathered into small clusters were positive solely for ChAT or nNOS, respectively or simultaneously for both neuronal markers (ChAT and nNOS). Neuronal somata positive for nNOS were more frequent than those positive for ChAT. In conclusion, findings of the present study demonstrate a dense and complex ganglionated neural network of both autonomic and sensory NFs, closely related to SAN cells which spread widely on the RRCV and extend as sleeves of these cells toward the walls of the rabbit RA. PMID:27045595

  11. Murine Hematopoietic Stem cells and Progenitors Express Adrenergic Receptors

    PubMed Central

    Muthu, Kuzhali; Iyer, Sivaraman; He, L-K.; Szilagyi, Andrea; Gamelli, Richard L; Shankar, Ravi; Jones, Stephen B

    2007-01-01

    Association between the nervous and immune system is well documented. Immune cells originate within the bone marrow that is innervated. Thermal injury induces adrenergic stimulation, augments monocytopoiesis and alters the β-adrenergic receptor (AR) profile of bone marrow monocyte committed progenitors. This provides an impetus to study AR expression in hematopoietic progenitors along myeloid lineage. Using FACS analysis and confocal microscopy, we report the expression of α1-, α2- and β2- AR in enriched populations of ER-MP20+ and ER-MP12+ myeloid progenitors, CD117+ and CD34+ multi-potential progenitors and more importantly pluripotent stem cells suggesting a plausible role for catecholamine in hematopoietic development. PMID:17428548

  12. Functions of adrenergic and cholinergic nerves in canine effectors of seminal emission.

    PubMed

    Arver, S; Sjöstrand, N O

    1982-05-01

    Spontaneous activity responses to acetylcholine (ACh), adrenaline (A), noradrenaline (NA) and barium chloride as well as the effects of various autonomic drugs on effects of field stimulation of nerves and muscle cells of isolated pieces or strips of cauda epididymidis, vas deferens, ampulla ductus deferentis and prostate of dog were studied. The main results and conclusions are: the muscles show little spontaneous activity but rhythmicity can easily be produced by e.g. stimulating agonists. The muscles are contracted by alpha-adrenoceptor stimulants. ACh has usually no or a very weak contractile effect in high concentrations. Muscles of young dogs are more sensitive to ACh. The excitatory innervation of the muscles is adrenergic and completely blocked by adrenergic neuron blockers as well as alpha-adrenoceptor blocking drugs. Stimulation of adrenergic nerves leads to maximum response already at low frequencies (4-6 Hz). This response is very similar to that provoked by a supramaximal dose of NA. Scopolamine enhances neurogenic contractile effects while physostigmine suppresses them. Hence cholinergic nerves may act by muscarinic prejunctional inhibition of the excitatory adrenergic neurotransmission rather than act directly upon the smooth muscle cells. Since secretory cells receive cholinergic innervation prejunctional inhibition of the adrenergic myomotor nerves may be of functional significance in at least the long copulatory events of the dog. PMID:6127870

  13. Quantification of sweat gland innervation

    PubMed Central

    Gibbons, Christopher H.; Illigens, Ben M. W.; Wang, Ningshan; Freeman, Roy

    2009-01-01

    Objective: To evaluate a novel method to quantify the density of nerve fibers innervating sweat glands in healthy control and diabetic subjects, to compare the results to an unbiased stereologic technique, and to identify the relationship to standardized physical examination and patient-reported symptom scores. Methods: Thirty diabetic and 64 healthy subjects had skin biopsies performed at the distal leg and distal and proximal thigh. Nerve fibers innervating sweat glands, stained with PGP 9.5, were imaged by light microscopy. Sweat gland nerve fiber density (SGNFD) was quantified by manual morphometry. As a gold standard, three additional subjects had biopsies analyzed by confocal microscopy using unbiased stereologic quantification. Severity of neuropathy was measured by standardized instruments including the Neuropathy Impairment Score in the Lower Limb (NIS-LL) while symptoms were measured by the Michigan Neuropathy Screening Instrument. Results: Manual morphometry increased with unbiased stereology (r = 0.93, p < 0.01). Diabetic subjects had reduced SGNFD compared to controls at the distal leg (p < 0.001), distal thigh (p < 0.01), and proximal thigh (p < 0.05). The SGNFD at the distal leg of diabetic subjects decreased as the NIS-LL worsened (r = −0.89, p < 0.001) and was concordant with symptoms of reduced sweat production (p < 0.01). Conclusions: We describe a novel method to quantify the density of nerve fibers innervating sweat glands. The technique differentiates groups of patients with mild diabetic neuropathy from healthy control subjects and correlates with both physical examination scores and symptoms relevant to sudomotor dysfunction. This method provides a reliable structural measure of sweat gland innervation that complements the investigation of small fiber neuropathies. GLOSSARY AOI = area of interest; CI = confidence interval; ICC = intraclass correlation coefficient; IENFD = intraepidermal nerve fiber density; IgG = immunoglobulin G; NIS

  14. 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. PMID:22277162

  15. 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.

  16. Altered β-adrenergic response in mice lacking myotonic dystrophy protein kinase.

    PubMed

    Llagostera, Esther; Álvarez López, María Jesús; Scimia, Cecilia; Catalucci, Daniele; Párrizas, Marcelina; Ruiz-Lozano, Pilar; Kaliman, Perla

    2012-01-01

    The protein kinase product of the gene mutated in myotonic dystrophy 1 (DMPK) is reported to play a role in cardiac pathophysiology. To gain insight into the molecular mechanisms modulated by DMPK, we characterize the impact of DMPK ablation in the context of cardiac β-adrenergic function. Our data demonstrate that DMPK knockout mice present altered β-agonist-induced responses and suggest that this is due, at least in part, to a reduced density of β(1)-adrenergic receptors in cardiac plasma membranes. PMID:22190319

  17. Altered β-adrenergic response in mice lacking myotonic dystrophy protein kinase (DMPK)

    PubMed Central

    Llagostera, Esther; López, María Jesús Álvarez; Scimia, Cecilia; Catalucci, Daniele; Párrizas, Marcelina; Ruiz-Lozano, Pilar; Kaliman, Perla

    2011-01-01

    The protein kinase product of the gene mutated in myotonic dystrophy 1 (DMPK) is reported to play a role in cardiac pathophysiology. To gain insight into the molecular mechanisms modulated by DMPK, we characterize the impact of DMPK ablation in the context of cardiac β-adrenergic function. Our data demonstrate that DMPK knock-out mice present altered β-agonist-induced responses and suggest that this is due, at least in part, to a reduced density of β1-adrenergic receptors in cardiac plasma membranes. PMID:22190319

  18. The innervation of the mammalian adrenal gland.

    PubMed Central

    Parker, T L; Kesse, W K; Mohamed, A A; Afework, M

    1993-01-01

    Early conflicting reports and the lack of sensitive anatomical methods have led to an oversimplified view of adrenal gland innervation. It was not until the introduction of nerve fibre tracing techniques in the mid-1970s that the true complexity of adrenal innervation began to emerge. The first part of this article comprises a brief review of these and other relevant reports dealing with both medullary and cortical innervation. In the second part a detailed account is given of the work undertaken in Rex Coupland's Department relating to the innervation of the rodent and primate adrenal medulla using a retrograde fluorescent tracer technique. It was concluded that, in all 3 species studied, the adrenal medulla receives a sympathetic and parasympathetic efferent and an afferent innervation. The possible interrelationship between neural control of cortical and medullar secretions is discussed briefly. Images Fig. 1 Fig. 2 Fig. 5 PMID:8300416

  19. On the adrenergic system of ganoid fish: the beluga, Huso huso (chondrostei).

    PubMed

    Balashov, N V; Fänge, R; Govyrin, V A; Leont'eva, G R; Nilsson, S; Prozorovskaya, M P

    1981-04-01

    The adrenergic system of the beluga, Huso huso, was studied by glyoxylic acid fluorescence histochemistry, analyses of catecholamine content in various organs and studies of the effects of acetylcholine and adrenaline on isolated strip preparations from blood vessels, spleen, atrium and ventricle. Chromaffin cells were found mainly in the walls of the posterior cardinal veins, and to some extent also in the wall of the celiaco-mesenteric artery. The plasma concentration of adrenaline was high enough to affect the contraction force of the isolated atrial and ventricular strips, thus adding an adrenergic component to a possible cholinergic inhibitory vagal control of the heart. Fluorescence histochemistry revealed no direct adrenergic innervation of the heart, but blood vessels in the heart and elsewhere received a rich supply of adrenergic nerve terminals. Adrenaline contracted the celiaco-mesenteric artery and the spleen, and produced positive inotropic effects on the paced atrial and ventricular strip preparations. Acetylcholine contracted the ventral aorta and the celiaco-mesenteric artery, and reduced the contraction force of paced ventricular and, especially, atrial preparations. It is concluded that the beluga has a well developed adrenergic system consisting of both chromaffin cells and adrenergic neurons with varicose nerve terminals of the type found in the higher vertebrates. PMID:7304205

  20. Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non-adrenergic inhibitory nerves in the gut

    PubMed Central

    Burnstock, G; Campbell, G; Satchell, D; Smythe, ANNE

    1997-01-01

    Stimulation of the vagal non-adrenergic inhibitory innervation caused the release of adenosine and inosine into vascular perfusates from the stomachs of guinea-pigs and toads. Stimulation of portions of Auerbach's plexus isolated from turkey gizzard caused the release of adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP). ATP, added to solutions perfused through the toad stomach vasculature, was broken down to adenosine, inosine and adenine. Of a series of purine and pyrimidine derivatives tested for inhibitory activity on the guinea-pig isolated taenia coli, ATP and ADP were the most potent. ATP caused inhibition of twelve other gut preparations previously shown to contain non-adrenergic inhibitory nerves. The inhibitory action of ATP was not prevented by tetrodotoxin. Quinidine antagonized relaxations of the guinea-pig taenia coli caused by catecholamines or adrenergic nerve stimulation. Higher concentrations of quinidine antagonized relaxations caused by ATP or non-adrenergic inhibitory nerve stimulation. When tachyphylaxis to ATP had been produced in the rabbit ileum, there was a consistent depression of the responses to non-adrenergic inhibitory nerve stimulation but not of responses to adrenergic nerve stimulation. It is suggested that ATP or a related nucleotide is the transmitter substance released by the non-adrenergic inhibitory innervation of the gut. PMID:9142414

  1. Circadian 5-HT production regulated by adrenergic signaling

    PubMed Central

    Sun, Xing; Deng, Jie; Liu, Tiecheng; Borjigin, Jimo

    2002-01-01

    Using on-line microdialysis, we have characterized in vivo dynamics of pineal 5-hydroxytryptamine (5-HT; serotonin) release. Daily pineal 5-HT output is triphasic: (i) 5-HT levels are constant and high during the day; (ii) early in the night, there is a novel sharp rise in 5-HT synthesis and release, which precedes the nocturnal rise in melatonin synthesis; and (iii) late in the night, levels are low. This triphasic 5-HT production persists in constant darkness and is influenced strongly by intrusion of light at night. We demonstrate that both diurnal 5-HT synthesis and 5-HT release are activated by sympathetic innervation from the superior cervical ganglion and show that these processes are controlled by distinct receptors. The increase in 5-HT synthesis is controlled by β-adrenergic receptors, whereas the increase in 5-HT release is mediated by α-adrenergic signaling. On the other hand, the marked decrease in 5-HT content and release late at night is a passive process, influenced by the extent of melatonin synthesis. In the absence of melatonin synthesis, the late-night decline in 5-HT release is prevented, reaching levels roughly twice as high as that of the day value. In summary, our results demonstrate that 5-HT levels display marked circadian rhythms that depend on adrenergic signaling. PMID:11917109

  2. Scintigraphic detection of regional disruption of adrenergic neurons in the heart

    SciTech Connect

    Sisson, J.C.; Lynch, J.J.; Johnson, J.; Jaques, S. Jr.; Wu, D.; Bolgos, G.; Lucchesi, B.R.; Wieland, D.M.

    1988-07-01

    Experiments were designed to detect regional disruptions of adrenergic neurons in the hearts of living dogs. The neuron disruption was achieved by the application of phenol to the epicardium of the left ventricle. Evidence for denervation was the reduction in endogenous norepinephrine (NE) concentrations in the myocardium beneath the region of phenol treatment and toward the apex. Radiolabeled meta-iodobenzylguanidine (MIBG) acts as an analog of NE and as such is concentrated in adrenergic nerve terminals. Following phenol application, MIBG labeled with /sup 125/I was found, 20 hours after injection, to be distributed within myocardium in patterns comparable to those of NE. However, left stellectomy did not alter the distributions of NE or /sup 125/I-MIBG in the myocardium and apparently did not disrupt adrenergic innervation. MIBG labeled with /sup 123/I enabled scintigraphic images of heart neurons in the living dog 3 and 20 hours after injection; these images portrayed the regions of adrenergic neuron disruption caused by phenol treatment. Concentrations of thallium-201 depicted on scintigraphic image and of triphenyltetrazolium observed on in vitro staining demonstrated no myocardial injury. Thus, scintigraphy with /sup 123/I-MIBG will display regional adrenergic denervations in the heart.

  3. 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.

  4. 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. PMID:21896144

  5. 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…

  6. 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. PMID:25467222

  7. 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. PMID:27173955

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

    PubMed Central

    O'Dell, Thomas J.; Connor, Steven A.; Guglietta, Ryan

    2015-01-01

    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. PMID:26286656

  9. The functional role of the alpha-1 adrenergic receptors in cerebral blood flow regulation

    PubMed Central

    Purkayastha, Sushmita; Raven, Peter B.

    2011-01-01

    Cerebral vasculature is richly innervated by the α-1 adrenergic receptors similar to that of the peripheral vasculature. However, the functional role of the α-1adrenergic receptors in cerebral blood flow (CBF) regulation is yet to be established. The traditional thinking being that during normotension and normocapnia sympathetic neural activity does not play a significant role in CBF regulation. Reports in the past have stated that catecholamines do not penetrate the blood brain barrier (BBB) and therefore only influence cerebral vessels from outside the BBB and hence, have a limited role in CBF regulation. However, with the advent of dynamic measurement techniques, beat-to-beat CBF assessment can be done during dynamic changes in arterial blood pressure. Several studies in the recent years have reported a functional role of the α-1adrenergic receptors in CBF regulation. This review focuses on the recent developments on the role of the sympathetic nervous system, specifically that of the α-1 adrenergic receptors in CBF regulation. PMID:22021989

  10. Organization of medullary adrenergic and noradrenergic projections to the periaqueductal gray matter in the rat.

    PubMed

    Herbert, H; Saper, C B

    1992-01-01

    The periaqueductal or midbrain central gray matter (CG) in the rat contains a dense network of adrenergic and noradrenergic fibers. We examined the origin of this innervation by using retrograde and anterograde axonal tracers combined with immunohistochemistry for the catecholamine biosynthetic enzymes tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT). Following injections of the fluorescent tracers Fast Blue or Fluorogold into the CG, double-labeled neurons in the medulla were identified mainly in the noradrenergic A1 group in the caudal ventrolateral medulla (VLM) and A2 group in the medial part of the nucleus of the solitary tract (NTS); and in the adrenergic C1 group in the rostral ventrolateral medulla and C3 group in the rostral dorsomedial medulla. Injections of Phaseolus vulgaris-leucoagglutinin (PHA-L) into these cell groups resulted in a distinct pattern of axonal labeling in various subdivisions of the CG. Anterogradely labeled fibers originating in the medial NTS were predominantly found in the lateral portion of the dorsal raphe nucleus and in the adjacent part of the lateroventral CG (CGlv). Following PHA-L injections into the C3 region the anterogradely labeled fibers were diffusely distributed in the CGlv and the dorsal raphe nucleus at caudal levels, but rostrally tended to be located laterally in the CGlv. In contrast, ascending fibers from the caudal and rostral VLM terminated in the rostral dorsal part of the CGlv and in the dorsal nucleus of the CG, whereas ventral parts of the CG, including the dorsal raphe nucleus, contained few afferent fibers. Double-label studies with antisera against DBH and PNMT confirmed that noradrenergic neurons in the A1 and A2 groups and adrenergic neurons in the C1 and C3 groups contributed to these innervation patterns in the CGlv. Noradrenergic and adrenergic projections from the medulla to the CG may play an important role in a variety of autonomic

  11. Influence of adrenergic drugs upon vital organ perfusion during CPR.

    PubMed

    Holmes, H R; Babbs, C F; Voorhees, W D; Tacker, W A; de Garavilla, B

    1980-03-01

    To determine whether adrenergic drugs administered during CPR alter the distribution of artificial cardiac output, the authors measured regional blood flow and cardiac output using radioactive microspheres in 12 dogs. Ventricular fibrillation was induced electrically and CPR was immediately begun with a mechanical chest compressor and ventilator (Thumper) at 60 compressions/min, with a ventilation: compression ratio of 1:5, a compression duration of 0.5 sec, and a ventilation pressure of 20 cm H2O. Compression force was sufficient to develop 40--50 mm Hg peak intraesophageal pressure. After 30 sec of CPR, either 0.9% saline vehicle or 50 micrograms/kg of epinephrine, phenylephrine, or isoproterenol was administered through a central venous catheter. One min later, microspheres were injected into the left ventricle. After 250 sec of CPR, the ventricles were defibrillated electrically. Between each drug injection, 20-min recovery periods were interposed. Each dog received all three drugs and saline according to a predetermined sequence. After saline, epinephrine, phenylephrine, and isoproterenol treatment, respective, cardiac output averaged 392, 319, 255, and 475 ml/min; brain blood flow averaged 37, 54, 29, and 28 ml/min; coronary blood flow averaged 25, 79, 26, and 15 ml/min; and kidney blood flow averaged 44, 4, 16, and 29 ml/min. Epinephrine improved blood flow to the brain, probably because of its alpha-adrenergic activity. Epinephrine improved blood flow to the heart during CPR much more than the other agents, probably because of its combined alpha- and beta-adrenergic activity. This effect may explain its superiority in restoring circulation after prolonged arrest and resuscitation. Isoproterenol should not be used in CPR because it shunts blood away from vital organs. PMID:7363628

  12. 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.

  13. 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

  14. Modification by Beta-Adrenergic Blockade of the Circulatory Responses to Acute Hypoxia in Man*

    PubMed Central

    Richardson, David W.; Kontos, Hermes A.; Raper, A. Jarrell; Patterson, John L.

    1967-01-01

    In 17 healthy men, beta-adrenergic blockade reduced significantly the tachycardia and the elevation of cardiac output associated with inhalation of 7.5% oxygen for 7 to 10 minutes. Hypoxia did not increase plasma concentrations of epinephrine or norepinephrine in six subjects. Furthermore, blockade of alpha and beta receptors in the forearm did not modify the vasodilation in the forearm induced by hypoxia, providing pharmacologic evidence that hypoxia of the degree and duration used was not associated with an increase in the concentrations of circulating catecholamines in man. Part of the increase in cardiac output and heart rate during acute hypoxia in man is produced by stimulation of beta-adrenergic receptors, probably by cardiac sympathetic nerves. The mechanism of the vasodilation in the forearm during hypoxia remains uncertain. PMID:4381183

  15. Sympathetic innervation and excitability of arterioles originating from the rat middle cerebral artery.

    PubMed Central

    Hill, C E; Hirst, G D; Silverberg, G D; van Helden, D F

    1986-01-01

    The densities of the adrenergic innervation of the internal carotid and middle cerebral arteries and their extracerebral branches have been determined using fluorescence histochemistry. The density of the nerve plexus on the internal carotid artery was greater than that of the middle cerebral artery. The density of the plexus on the middle cerebral artery decreased with increasing distance from its origin. The density and the peripheral extent of the nerve fibre plexus on the arterioles arising from the carotid artery were greater than those arising from the middle cerebral artery. On any arteriole the density of innervation decreased with increasing distance from its origin. The passive electrical properties of proximal and distal middle cerebral arteriolar segments were compared. Both proximal and distal arteriolar segments had similar resistances and time constants in the order of 100 M omega and 250 ms respectively. Small regenerative responses could be elicited in all proximal middle cerebral arteriolar segments but only in a proportion of corresponding distal segments. The addition of external tetraethylammonium ions (TEA) provided much larger regenerative responses. Action potentials in proximal middle cerebral arteriolar segments had larger peak amplitudes and faster rise times than those of corresponding distal segments. Distal carotid arteriolar segments had similar voltage-dependent excitability as proximal segments of middle cerebral arterioles but generated less inward current for a given voltage step. There was a direct correlation between the density of innervation and the voltage-dependent excitability of arteriolar smooth muscle cells. The possibility that the presence of nerves is correlated with the density of calcium channels is discussed. Images PLATE 2 PLATE 1 PMID:3701653

  16. 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. PMID:23445261

  17. 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

  18. [The beta-adrenergic receptor].

    PubMed

    Bicho, M P; Manso, C F

    1992-12-01

    The Authors review the constitution and mechanism of action of the beta adrenergic receptor. It is part of a large family which includes visual pigments, muscarinic, serotonergic, olfactive and substance K receptors. Catecholamines given an electron to the receptor. It goes then successively to the alpha submit of Gs protein ant to adenylyl cyclase. The process of activation consists in a successive transfer of one electron. PMID:1337834

  19. 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. PMID:26676806

  20. Compartmentalized Innervation of Primate Lateral Rectus Muscle

    PubMed Central

    Peng, Michelle; Poukens, Vadims; da Silva Costa, Roberta Martins; Yoo, Lawrence; Tychsen, Lawrence

    2010-01-01

    Purpose. Skeletal and craniofacial muscles are frequently composed of multiple neuromuscular compartments that serve different physiological functions. Evidence of possible regional selectivity in LR intramuscular innervation was sought in a study of the anatomic potential of lateral rectus (LR) muscle compartmentalization. Methods. Whole orbits of two humans and five macaque monkeys were serially sectioned at 10-μm thickness and stained with Masson trichrome. The abducens nerve (CN6) was traced anteriorly from the deep orbit as it branched to enter the LR and arborized among extraocular muscle (EOM) fibers. Three-dimensional reconstruction was performed in human and monkey orbits. Results. Findings were in concordance in the monkey and human orbits. External to the LR global surface, CN6 bifurcated into approximately equal-sized trunks before entering the global layer. Subsequent arborization showed a systematic topography, entering a well-defined inferior zone 0.4 to 2.5 mm more posteriorly than branches entering the largely nonoverlapping superior zone. Zonal innervation remained segregated anteriorly and laterally within the LR. Conclusions. Consistent segregation of intramuscular CN6 arborization in humans and monkeys suggests functionally distinct superior and inferior zones for the LR. Since the LR is shaped as a broad vertical strap, segregated control of the two zones could activate them separately, potentially mediating previously unappreciated but substantial torsional and vertical oculorotary LR actions. PMID:20435590

  1. Anatomical evidence for ileal Peyer's patches innervation by enteric nervous system: a potential route for prion neuroinvasion?

    PubMed

    Chiocchetti, Roberto; Mazzuoli, Gemma; Albanese, Valeria; Mazzoni, Maurizio; Clavenzani, Paolo; Lalatta-Costerbosa, Giovanna; Lucchi, Maria L; Di Guardo, Giovanni; Marruchella, Giuseppe; Furness, John B

    2008-05-01

    We have examined the innervation of the gut-associated lymphoid system of the sheep ileum, with a view to identifying potential sites for neuroinvasion by pathogens, such as prions (PrP(Sc)). Special attention has been paid to the follicles of Peyer's patches (PPs), which are major sites of PrP(Sc) accumulation during infection. Evidence exists that the enteric nervous system, together with the parasympathetic and sympathetic pathways projecting to the intestine, are important for PrP(Sc) entry into the central nervous system. Thus, PrP(Sc) might move from PPs to the neurons and nerve fibres that innervate them. We investigated, by immunohistochemistry and retrograde tracing (DiI) from the follicles, the distribution and phenotype of enteric neurons innervating the follicles. Antibodies against protein gene product 9.5, tyrosine hydroxylase, dopamine beta hydroxylase, choline acetyltransferase, calbindin (CALB), calcitonin gene-related peptide (CGRP), and nitric oxide synthase were used to characterise the neurons. Immunoreactivity for each of these was observed in fibres around and inside PP follicles. CGRP-immunoreactive fibres were mainly seen at the follicular dome. Retrograde tracing revealed submucosal neurons that contributed to the innervation of PPs, including Dogiel type II neurons and neurons immunoreactive for CALB and CGRP. The major source of the adrenergic fibres are the sympathetic ganglia. Our results thus suggest that enteric and sympathetic neurons are involved during the first stage of neuroinvasion, with neurons connecting to them acting as potential carriers of PrP(Sc) to the central nervous system. PMID:18317812

  2. 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.

  3. 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.

  4. 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

  5. Contribution of the cervical sympathetic ganglia to the innervation of the pharyngeal arch arteries and the heart in the chick embryo.

    PubMed

    Verberne, M E; Gittenberger-De Groot, A C; Van Iperen, L; Poelmann, R E

    1999-08-01

    In the chick heart, sympathetic innervation is derived from the sympathetic neural crest (trunk neural crest arising from somite level 10-20). Since the trunk neural crest gives rise to sympathetic ganglia of their corresponding level, it suggests that the sympathetic neural crest develops into cervical ganglia 4-14. We therefore tested the hypothesis that, in addition to the first thoracic ganglia, the cervical ganglia might contribute to cardiac innervation as well. Putative sympathetic nerve connections between the cervical ganglia and the heart were demonstrated using the differentiation markers tyrosine hydroxylase and HNK-1. In addition, heterospecific transplantation (quail to chick) of the cardiac and trunk neural crest was used to study the relation between the sympathetic neural crest and the cervical ganglia. Quail cells were visualized using the quail nuclear antibody QCPN. The results by immunohistochemical study show that the superior and the middle cervical ganglia and possibly the carotid paraganglia contribute to the carotid nerve. This nerve subsequently joins the nodose ganglion of the vagal nerve via which it contributes to nerve fibers in cardiac vagal branches entering the arterial and venous pole of the heart. In addition, the carotid nerve contributes to nerve fibers connected to putative baro- and chemoreceptors in and near the wall of pharyngeal arch arteries suggesting a role of the superior and middle cervical ganglia and the paraganglia of the carotid plexus in sensory afferent innervation. The lower cervical ganglia 13 and 14 contribute predominantly to nerve branches entering the venous pole via the anterior cardinal veins. We did not observe a thoracic contribution. Heterospecific transplantation shows that the cervical ganglia 4-14 as well as the carotid paraganglia are derived from the sympathetic neural crest. The cardiac neural crest does not contribute to the neurons of the cervical ganglia. We conclude that the cervical ganglia

  6. Propranolol, a beta-adrenergic antagonist, retards response to MSH in skin of Anolis carolinensis.

    PubMed

    Vaughan, G L; Greenberg, N

    1987-01-01

    Lacking sympathetic innervation, the skin of A. carolinensis, an iguanid lizard, darkens within minutes in response to circulating melanocyte stimulating hormone (MSH) or beta adrenergic agonists such as epinephrine (EPI). This change is produced by dispersion of melanin from a perinculear position within dermal melanophores into superficial dendritic processes. These melanophores possess alpha-2 and beta-2 adrenergic as well as MSH receptors except in a patch of skin behind the eye, the eyespot, which lacks alpha receptors. Activation of beta or MSH receptors leads to stimulation of adenyl cyclase whereas alpha stimulation inhibits the enzyme to override the others. In a series of trials, injection of saline or propranolol was followed after 30 minutes by saline, EPI, or MSH. Propranolol inhibited chromatophore response to EPI. It also, unexpectedly, retarded the response to MSH, increasing latency to eyespot formation and body color change as well as the duration of darkening for both. Alteration of MSH response by a beta blocker could be explained by linkage of both adrenergic receptors and the MSH receptor to a common adenyl cyclase molecule to form a functional unit in the membrane of the melanophore. PMID:3671516

  7. Innervation of the renal proximal convoluted tubule of the rat

    SciTech Connect

    Barajas, L.; Powers, K. )

    1989-12-01

    Experimental data suggest the proximal tubule as a major site of neurogenic influence on tubular function. The functional and anatomical axial heterogeneity of the proximal tubule prompted this study of the distribution of innervation sites along the early, mid, and late proximal convoluted tubule (PCT) of the rat. Serial section autoradiograms, with tritiated norepinephrine serving as a marker for monoaminergic nerves, were used in this study. Freehand clay models and graphic reconstructions of proximal tubules permitted a rough estimation of the location of the innervation sites along the PCT. In the subcapsular nephrons, the early PCT (first third) was devoid of innervation sites with most of the innervation occurring in the mid (middle third) and in the late (last third) PCT. Innervation sites were found in the early PCT in nephrons located deeper in the cortex. In juxtamedullary nephrons, innervation sites could be observed on the PCT as it left the glomerulus. This gradient of PCT innervation can be explained by the different tubulovascular relationships of nephrons at different levels of the cortex. The absence of innervation sites in the early PCT of subcapsular nephrons suggests that any influence of the renal nerves on the early PCT might be due to an effect of neurotransmitter released from renal nerves reaching the early PCT via the interstitium and/or capillaries.

  8. Beta Adrenergic Receptors in Keratinocytes

    PubMed Central

    Sivamani, Raja K.; Lam, Susanne T.; Isseroff, R. Rivkah

    2007-01-01

    Synopsis Beta2 adrenergic receptors were identified in keratinocytes more than 30 years ago, but their function in the epidermis continues to be elucidated. Abnormalities in their expression, signaling pathway, or in the generation of endogenous catecholamine agonists by keratinocytes have been implicated in the pathogenesis of cutaneous diseases such as atopic dermatitis, vitiligo and psoriasis. New studies also indicate that the beta2AR also modulates keratinocyte migration, and thus can function to regulate wound re-epithelialization. This review focuses on the function of these receptors in keratinocytes and their contribution to cutaneous physiology and disease. PMID:17903623

  9. Allometry of left ventricular myocardial innervation.

    PubMed

    Schipke, Julia; Mayhew, Terry M; Mühlfeld, Christian

    2014-04-01

    Body mass (BM) of terrestrial mammalian species ranges from a few grams in the case of the Etruscan shrew to a few tonnes for an elephant. The mass-specific metabolic rate, as well as heart rate, decrease with increasing BM, whereas heart mass is proportional to BM. In the present study, we investigated the scaling behaviour of several compartments of the left ventricular myocardium, notably its innervation, capillaries and cardiomyocytes. Myocardial samples were taken from 10 mammalian species with BM between approximately 2 g and 900 kg. Samples were analysed by design-based stereology and electron microscopy and the resulting data were subjected to linear regression and correlation analyses. The total length of nerve fibres (axons) in the left ventricle increased from 0.017 km (0.020 km) in the shrew to 7237 km (13,938 km) in the horse. The innervation density was similar among species but the mean number of axons per nerve fibre profile increased with rising BM. The total length of capillaries increased from 0.119 km (shrew) to 10,897 km (horse). The volume of cardiomyocytes was 0.017 cm(3) in the shrew and 1818 cm(3) in the horse. Scaling of the data against BM indicated a higher degree of complexity of the axon tree in larger animals and an allometric relationship between total length of nerve fibres/axons and BM. In contrast, the density of nerve fibres is independent of BM. It seems that the structural components of the autonomic nervous system in the heart are related to BM and heart mass rather than to functional parameters such as metabolic rate. PMID:24325466

  10. Modulation of β-Adrenergic Receptor Signaling in Heart Failure and Longevity: Targeting Adenylyl Cyclase Type 5

    PubMed Central

    Ho, David; Yan, Lin; Iwatsubo, Kousaku; Vatner, Dorothy E.; Vatner, Stephen F.

    2011-01-01

    Despite remarkable advances in therapy, heart failure remains a leading cause of morbidity and mortality. Although enhanced β-adrenergic receptor stimulation is part of normal physiologic adaptation to either the increase in physiologic demand or decrease in cardiac function, chronic β-adrenergic stimulation has been associated with increased mortality and morbidity in both animal models and humans. For example, overexpression of cardiac Gsα or β-adrenergic receptors in transgenic mice results in enhanced cardiac function in young animals, but with prolonged overstimulation of this pathway, cardiomyopathy develops in these mice as they age. Similarly, chronic sympathomimetic amine therapy increases morbidity and mortality in patients with heart failure. Conversely, the use of β-blockade has proven to be of benefit and is currently part of the standard of care for heart failure. It is conceivable that interrupting distal mechanisms in the β-adrenergic receptor-G protein-adenylyl cyclase pathway may also provide targets for future therapeutic modalities for heart failure. Interestingly, there are two major isoforms of adenylyl cyclase (AC) in the heart (type 5 and type 6), which may exert opposite effects on the heart, i.e., cardiac overexpression of AC6 appears to be protective, whereas disruption of type 5 AC prolongs longevity and protects against cardiac stress. The goal of this review is to summarize the paradigm shift in the treatment of heart failure over the past 50 years from administering sympathomimetic amine agonists to administering β-adrenergic receptor antagonists, and to explore the basis for a novel therapy of inhibiting type 5 AC. PMID:20658186

  11. 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

  12. Adrenergic signaling and oxidative stress: a role for sirtuins?

    PubMed Central

    Corbi, Graziamaria; Conti, Valeria; Russomanno, Giusy; Longobardi, Giancarlo; Furgi, Giuseppe; Filippelli, Amelia; Ferrara, Nicola

    2013-01-01

    The adrenergic system plays a central role in stress signaling and stress is often associated with increased production of ROS. However, ROS overproduction generates oxidative stress, that occurs in response to several stressors. β-adrenergic signaling is markedly attenuated in conditions such as heart failure, with downregulation and desensitization of the receptors and their uncoupling from adenylyl cyclase. Transgenic activation of β2-adrenoceptor leads to elevation of NADPH oxidase activity, with greater ROS production and p38MAPK phosphorylation. Inhibition of NADPH oxidase or ROS significantly reduced the p38MAPK signaling cascade. Chronic β2-adrenoceptor activation is associated with greater cardiac dilatation and dysfunction, augmented pro-inflammatory and profibrotic signaling, while antioxidant treatment protected hearts against these abnormalities, indicating ROS production to be central to the detrimental signaling of β2-adrenoceptors. It has been demonstrated that sirtuins are involved in modulating the cellular stress response directly by deacetylation of some factors. Sirt1 increases cellular stress resistance, by an increased insulin sensitivity, a decreased circulating free fatty acids and insulin-like growth factor (IGF-1), an increased activity of AMPK, increased activity of PGC-1a, and increased mitochondrial number. Sirt1 acts by involving signaling molecules such P-I-3-kinase-Akt, MAPK and p38-MAPK-β. βAR stimulation antagonizes the protective effect of the AKT pathway through inhibiting induction of Hif-1α and Sirt1 genes, key elements in cell survival. More studies are needed to better clarify the involvement of sirtuins in the β-adrenergic response and, overall, to better define the mechanisms by which tools such as exercise training are able to counteract the oxidative stress, by both activation of sirtuins and inhibition of GRK2 in many cardiovascular conditions and can be used to prevent or treat diseases such as heart failure

  13. 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.

  14. 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

  15. Cholinergic innervation and receptors in the cerebellum.

    PubMed

    Jaarsma, D; Ruigrok, T J; Caffé, R; Cozzari, C; Levey, A I; Mugnaini, E; Voogd, J

    1997-01-01

    We have studied the source and ultrastructural characteristics of ChAT-immunoreactive fibers in the cerebellum of the rat, and the distribution of muscarinic and nicotinic receptors in the cerebellum of the rat, rabbit, cat and monkey, in order to define which of the cerebellar afferents may use ACh as a neurotransmitter, what target structures are they, and which cholinergic receptor mediate the actions of these pathways. Our data confirm and extend previous observations that cholinergic markers occur at relatively low density in the cerebellum and show not only interspecies variability, but also heterogeneity between cerebellar lobules in the same species. As previously demonstrated by Barmack et al. (1992a,b), the predominant fiber system in the cerebellum that might use ACh as a transmitter or a co-transmitter is formed by mossy fibers originating in the vestibular nuclei and innervating the nodulus and ventral uvula. Our results show that these fibers innervate both granule cells and unipolar brush cells, and that the presumed cholinergic action of these fibers most likely is mediated by nicotinic receptors. In addition to cholinergic mossy fibers, the rat cerebellum is innervated by beaded ChAT-immunoreactive fibers. We have demonstrated that these fibers originate in the pedunculopontine tegmental nucleus (PPTg), the lateral paragigantocellular nucleus (LPGi), and to a lesser extent in various raphe nuclei. In both the cerebellar cortex and the cerebellar nuclei these fibers make asymmetric synaptic junctions with small and medium-sized dendritic profiles. Both muscarinic and nicotinic receptor could mediate the action of these diffuse beaded fibers. In the cerebellar nuclei the beaded cholinergic fibers form a moderately dense network, and could in principle have a significant effect on neuronal activity. For instance, the cholinergic fibers arising in the PPTg may modulate the excitability of the cerebellonuclear neurons in relation to sleep and arousal (e

  16. 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

  17. Locus coeruleus noradrenergic innervation of the amygdala facilitates alerting-induced constriction of the rat tail artery.

    PubMed

    Mohammed, Mazher; Kulasekara, Keerthi; Ootsuka, Youichirou; Blessing, William W

    2016-06-01

    The amygdala, innervated by the noradrenergic locus coeruleus, processes salient environmental events. α2-adrenoceptor-stimulating drugs (clonidine-like agents) suppress the behavioral and physiological components of the response to salient events. Activation of sympathetic outflow to the cutaneous vascular bed is part of the physiological response to salience-mediated activation of the amygdala. We have determined whether acute systemic and intra-amygdala administration of clonidine, and chronic immunotoxin-mediated destruction of the noradrenergic innervation of the amygdala, impairs salience-related vasoconstrictor episodes in the tail artery of conscious freely moving Sprague-Dawley rats. After acute intraperitoneal injection of clonidine (10, 50, and 100 μg/kg), there was a dose-related decrease in the reduction in tail blood flow elicited by alerting stimuli, an effect prevented by prior administration of the α2-adrenergic blocking drug idazoxan (1 mg/kg ip or 75 nmol bilateral intra-amygdala). A dose-related decrease in alerting-induced tail artery vasoconstriction was also observed after bilateral intra-amygdala injection of clonidine (5, 10, and 20 nmol in 200 nl), an effect substantially prevented by prior bilateral intra-amygdala injection of idazoxan. Intra-amygdala injection of idazoxan by itself did not alter tail artery vasoconstriction elicited by alerting stimuli. Intra-amygdala injection of saporin coupled to antibodies to dopamine-β-hydroxylase (immunotoxin) destroyed the noradrenergic innervation of the amygdala and the parent noradrenergic neurons in the locus coeruleus. The reduction in tail blood flow elicited by standardized alerting stimuli was substantially reduced in immunotoxin-treated rats. Thus, inhibiting the release of noradrenaline within the amygdala reduces activation of the sympathetic outflow to the vascular beds elicited by salient events. PMID:27101292

  18. Correlation of peripheral innervation density and dorsal horn map scale.

    PubMed

    Wang, L; Millecchia, R; Brown, P B

    1997-08-01

    Dorsal horn map scale and peripheral innervation density were compared to test a hypothesized linear relationship. In anesthetized cats, low-threshold mechanoreceptive peripheral nerve innervation fields (IFs) were measured by outlining areas of skin from which action potentials could be elicited in cutaneous nerves. The same nerves were processed histologically and used to count myelinated axons. Innervation density for each nerve was calculated as number of axons divided by IF area. Single units were recorded throughout the hindlimb representation, in laminae III and IV. These data, combined with single-unit data from other animals and with cell counts in laminae III and IV, permitted estimation of numbers of cells whose receptive field centers fell in contiguous 1-cm bands from tips of toes to proximal thigh. A similar estimate was performed with the use of the nerve innervation data, so that peripheral innervation densities and map scales for the different 1-cm bands of skin could be compared. Correlation between the two was quite high (r = 0.8), and highly significant (P = 2.5 x 10(-7)). These results are consistent with a proposed developmental model in which map scale, peripheral innervation density, and reciprocal of dorsal horn cell receptive field size are mutually proportional, as a result of developmental mechanisms that produce constant divergence and convergence between primary afferent axons and dorsal horn cells. PMID:9307105

  19. Innervation of sonic muscles in teleosts: occipital vs. spinal nerves.

    PubMed

    Onuki, Atsushi; Somiya, Hiroaki

    2007-01-01

    The innervation of sonic muscles in teleosts has been categorized into three types: occipital nerve, spinal nerve, and a combination of occipital and spinal nerves. The innervation patterns of sonic muscles were examined (or re-examined) in seven sonic fish species (rockfish, pinecone fish, sweeper, tigerfish, piranha, dory, and pollack) that use the sonic muscles to vibrate the swimbladder. The peripheral nerves (occipital or spinal) were identified based on skeletal preparations. The sonic muscle innervation was of the occipital type in four species (rockfish, pinecone fish, sweeper, and tigerfish) and of the spinal type in three species (piranha, dory, and pollack); none of the seven species examined showed the combination type. Therefore, we hypothesized that innervation patterns could be divided simply into occipital and spinal types. Moreover, the present results revealed that previously reported innervation patterns are inaccurate for three species (tigerfish, piranha, and dory) re-examined in this study. Therefore, it is important to define the peripheral nerves precisely, by using skeletal preparations, in future investigations of sonic muscle innervation. PMID:17230021

  20. Effect of renal sympathetic nerve on adrenergically and angiotensin II-induced renal vasoconstriction in normal Wistar-Kyoto rats

    PubMed Central

    2011-01-01

    Background This study examined the effect of renal sympathetic innervation on adrenergically and angiotensin II (Ang II)-induced renal vasoconstriction in Wistar-Kyoto (WKY) rats. Methods Forty-eight WKY rats were treated with either losartan (10 mg/kg/day p.o.) or carvedilol (5 mg/kg/day p.o.) or a combination of them (10 mg/kg/day + 5 mg/kg/day p.o.) for 7 days. On day 8, the rats were anaesthetized, and renal vasoconstrictor experiments were carried out. A group of rats was subjected to acute unilateral renal denervation during the acute study. Changes in the renal vasoconstrictor responses were determined in terms of reductions in renal blood flow caused by Ang II, noradrenaline (NA), and methoxamine (ME). Results In normal animals, losartan decreased (P < 0.05) the renal vasoconstrictor response to Ang II but not to NA or ME. Carvedilol treatment, however, blunted (P < 0.05) the renal vasoconstrictor responses to Ang II and adrenergic agonists. Combination of losartan and carvedilol blunted (P < 0.05) the renal vasoconstrictor response to Ang II but augmented the responses to NA and ME (all P < 0.05). Interestingly, when denervated rats were treated with the same combination, there was a reduction (P < 0.05) in the renal vasoconstrictor responses to Ang II and adrenergic agonists. Conclusions Data suggest that the renal sympathetic nerve contributes to adrenergic agonist-mediated renal vasoconstrictions in normal rats. The data further indicate an interactive relationship between renin-angiotensin and sympathetic nervous systems in modulating adrenergically and Ang II-induced renal vasoconstriction in WKY rats. PMID:21047287

  1. Depletion of cutaneous peptidergic innervation in HIV-associated xerosis.

    PubMed

    Rowe, A; Mallon, E; Rosenberger, P; Barrett, M; Walsh, J; Bunker, C B

    1999-03-01

    Severe xerosis occurs in approximately 20% of human immunodeficiency virus seropositive patients. Changes in cutaneous innervation have been found in various inflammatory skin diseases and in xerotic skin in familial amyloid. We have therefore carried out a quantitative examination of the cutaneous peptidergic innervation in human immunodeficiency virus-associated xerosis. Immunohistochemistry and image analysis quantitation were used to compare total cutaneous innervation (protein gene product 9.5), calcitonin gene-related peptide, substance P, and vasoactive intestinal peptide peptidergic fibers, at two sites in the skin of human immunodeficiency virus-associated xerosis patients (upper arm, n = 12; upper leg, n = 11) and site-matched seronegative controls (upper arm, n = 10; upper leg, n = 10). Measurement of lengths of fibers of each type was carried out for each subject in the epidermis and papillary dermis, and around the sweat glands. Immunostained mast cells in these areas were counted. Epidermal integrity and maturation were assessed by immunostaining for involucrin. There were significant (Mann-Whitney U test; p < 0.02) decreases in total lengths of protein gene product 9.5 fibers in both epidermis/papillary dermis and sweat gland fields; of calcitonin gene-related peptide innervation in the epidermis/papillary dermis; and of substance P innervation of the sweat glands. There were no differences in the distribution of mast cells, or in the epidermal expression of involucrin. Depletion of the calcitonin gene-related peptide innervation may affect the nutrient blood supply of the upper dermis, and the integrity and function of basal epidermis and Langerhans cells. Diminished substance P innervation of the sweat glands may affect their secretory activity. Both of these changes may be implicated in the development of xerosis. PMID:10084303

  2. 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

  3. Cardiac Rehabilitation

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Cardiac Rehabilitation? Cardiac rehabilitation (rehab) is a medically supervised program ... be designed to meet your needs. The Cardiac Rehabilitation Team Cardiac rehab involves a long-term commitment ...

  4. 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

  5. The innervation of the zebrafish pharyngeal jaws and teeth.

    PubMed

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

    2015-07-01

    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

  6. The innervation of canine hip joint capsule: an anatomic study.

    PubMed

    Huang, C H; Hou, S M; Yeh, L S

    2013-12-01

    To clarify the contributions of the nerves supplying the canine hip joint capsule for clinical application, cadaver study of six healthy mongrel dogs was performed. The pelvises and hindlimbs of cadavers were dissected and fixed in formaldehyde. Innervation of the joint capsule was investigated with the aid of an operative microscope. As a result, the canine hip joint capsule receives multiple innervations from articular branches of four nerves. They are articular nerve fibres of femoral, obturator, cranial gluteal and sciatic nerves from the cranioventral, caudoventral, craniolateral and dorsolateral directions of the joint, respectively. No branch originating from the caudal gluteal nerve was observed innervating the hip joint capsule. Our data provides useful information for research on the canine hip joint, including pain analysis with hip disorders and surgical nerve blockade to relieve pain. PMID:23410229

  7. The ins and outs of adrenergic signaling.

    PubMed

    Lohse, Martin J

    2015-09-01

    Adrenergic signaling, in particular signaling in the sympathetic nervous system, is a prime example of the control of an essential physiological system. It has served as a model system both for the control of mediator release and for receptor signaling and regulation. This review covers the historical development of the field and then addresses issues that represent key fields of ongoing research: the mechanisms and kinetics of receptor activation, temporal patterns of downstream signaling and signal bias, receptor mobility and aggregation, and signal compartmentation and specificity. The available evidence suggests that adrenergic signaling may involve complex spatiotemporal patterns, which give texture to the signaling process and may contain additional biological information. PMID:26199112

  8. 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

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

    PubMed

    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

  10. Regulation of coronary vascular tone via redox modulation in the alpha1-adrenergic-angiotensin-endothelin axis of the myocardium.

    PubMed

    Yamaguchi, Osamu; Kaneshiro, Takashi; Saitoh, Shu-ichi; Ishibashi, Toshiyuki; Maruyama, Yukio; Takeishi, Yasuchika

    2009-01-01

    We hypothesized that alpha(1)-adrenoceptor stimulation of cardiac myocytes results in the production of an endothelin (ET)-releasing factor that stimulates the coronary vasculature to release ET and, by manipulating the redox state of cardiac and vascular cells, may influence the extent of alpha(1)-adrenergic-ET-1 vasoconstriction. Dihydroethidium (DHE) and dichlorodihydrofluorescein (DCF) intensities were increased by phenylephrine stimulation in isolated rat cardiac myocytes, which were enhanced by the mitochondrial electron transport chain complex I inhibitor rotenone (DHE: 20.4 +/- 1.2-fold and DCF: 25.2 +/- 0.9-fold, n = 8, P < 0.01, respectively) but not by the NADPH oxidase inhibitor apocynin. Olmesartan, an angiotensin II type 1 receptor antagonist, and enalaprilate did not change DHE and DCF intensities by phenylephrine. Next, we measured the vasoconstriction of isolated, pressurized rat coronary arterioles (diameter: 74 +/- 8 microm) in response to supernatant collected from isolated cardiac myocytes. The addition of supernatant from phenylephrine-stimulated myocytes to a 2-ml vessel bath (n = 8 each) caused volume-dependent vasoconstriction (500 microl: -14.8 +/- 2.2%). Olmesartan and TA0201, an ET type A receptor antagonist, converted vasoconstriction into vasodilation (8.5 +/- 1.2% and 10.5 +/- 0.5%, P < 0.01, respectively) in response to supernatant from phenylephrine-stimulated myocytes, which was eliminated with catalase. Vasoconstriction was weakened using supernatant from phenylephrine with rotenone-treated myocytes. Treatment of arterioles with apocynin to myocyte supernatant converted vasoconstriction into vasodilation (7.8 +/- 0.8%, P < 0.01). These results suggest that alpha(1)-adrenergic stimulation in cardiac myocytes produces angiotensin I and H(2)O(2) and that angiotensin releases ET-1 through NADPH oxidase in coronary arterioles. Thus, coronary vasoconstriction via the alpha-adrenergic-angiotensin-ET axis appears to require redox

  11. Dysferlin deficiency blunts β-adrenergic-dependent lusitropic function of mouse heart.

    PubMed

    Wei, Bin; Wei, Hongguang; Jin, J-P

    2015-12-01

    Dysferlin is a cell membrane bound protein with a role in the repair of skeletal and cardiac muscle cells. Deficiency of dysferlin leads to limb-girdle muscular dystrophy 2B (LGMD2B) and Miyoshi myopathy. In cardiac muscle, dysferlin is located at the intercalated disc and transverse tubule membranes. Loss of dysferlin causes death of cardiomyocytes, notably in ageing hearts, leading to dilated cardiomyopathy and heart failure in LGM2B patients. To understand the primary pathogenesis and pathophysiology of dysferlin cardiomyopathy, we studied cardiac phenotypes of young adult dysferlin knockout mice and found early myocardial hypertrophy with largely compensated baseline cardiac function. Cardiomyocytes isolated from dysferlin-deficient mice showed normal shortening and re-lengthening velocities in the absence of external load with normal peak systolic Ca(2+) but slower Ca(2+) re-sequestration than wild-type controls. The effects of isoproterenol on relaxation velocity, left ventricular systolic pressure and stroke volume were blunted in dysferlin-deficient mouse hearts compared with that in wild-type hearts. Young dysferlin-deficient mouse hearts expressed normal isoforms of myofilament proteins whereas the phosphorylation of ventricular myosin light chain 2 was significantly increased, implying a molecular response to the impaired lusitropic function. These early phenotypes of diastolic cardiac dysfunction and blunted lusitropic response of cardiac muscle to β-adrenergic stimulation indicate a novel pathogenic mechanism of dysferlin cardiomyopathy. PMID:26415898

  12. 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

  13. Vascular endothelial growth factor coordinates islet innervation via vascular scaffolding

    PubMed Central

    Reinert, Rachel B.; Cai, Qing; Hong, Ji-Young; Plank, Jennifer L.; Aamodt, Kristie; Prasad, Nripesh; Aramandla, Radhika; Dai, Chunhua; Levy, Shawn E.; Pozzi, Ambra; Labosky, Patricia A.; Wright, Christopher V. E.; Brissova, Marcela; Powers, Alvin C.

    2014-01-01

    Neurovascular alignment is a common anatomical feature of organs, but the mechanisms leading to this arrangement are incompletely understood. Here, we show that vascular endothelial growth factor (VEGF) signaling profoundly affects both vascularization and innervation of the pancreatic islet. In mature islets, nerves are closely associated with capillaries, but the islet vascularization process during embryonic organogenesis significantly precedes islet innervation. Although a simple neuronal meshwork interconnects the developing islet clusters as they begin to form at E14.5, the substantial ingrowth of nerve fibers into islets occurs postnatally, when islet vascularization is already complete. Using genetic mouse models, we demonstrate that VEGF regulates islet innervation indirectly through its effects on intra-islet endothelial cells. Our data indicate that formation of a VEGF-directed, intra-islet vascular plexus is required for development of islet innervation, and that VEGF-induced islet hypervascularization leads to increased nerve fiber ingrowth. Transcriptome analysis of hypervascularized islets revealed an increased expression of extracellular matrix components and axon guidance molecules, with these transcripts being enriched in the islet-derived endothelial cell population. We propose a mechanism for coordinated neurovascular development within pancreatic islets, in which endocrine cell-derived VEGF directs the patterning of intra-islet capillaries during embryogenesis, forming a scaffold for the postnatal ingrowth of essential autonomic nerve fibers. PMID:24574008

  14. 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. PMID:24646609

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

    PubMed Central

    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.; Ann Remme, Carol; Baartscheer, Antonius; de Winter, Robbert J.; de Vries, Carlie J. M.; Arkenbout, E. Karin; de Waard, Vivian

    2015-01-01

    Distinct stressors may induce heart failure. As compensation, β-adrenergic stimulation enhances myocardial contractility by elevating cardiomyocyte intracellular Ca2+ ([Ca2+]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 [Ca2+]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 [Ca2+]i, Ca2+-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 Ca2+ homeostasis and distinct remodelling outcome depending on the type of insult. Detailed knowledge on the role of Nur77 in maintaining cardiomyocyte Ca2+ homeostasis and the dual role Nur77 plays in cardiac remodelling will aid in developing personalized therapies against heart failure. PMID:26486271

  16. 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. PMID:24395053

  17. 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

  18. Cardiac Catheterization

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Cardiac Catheterization? Cardiac catheterization (KATH-eh-ter-ih-ZA-shun) is a ... disease. Doctors also can use ultrasound during cardiac catheterization to see blockages in the coronary arteries. Ultrasound ...

  19. 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. PMID:25888515

  20. Non-co-ordinate development of beta-adrenergic receptors and adenylate cyclase in chick heart.

    PubMed Central

    Alexander, R W; Galper, J B; Neer, E J; Smith, T W

    1982-01-01

    We have studied the properties of beta-adrenergic receptors and of their interaction with adenylate cyclase in the chick myocardium during embryogenesis. Between 4.5 and 7.5 days in ovo the number of receptors determined by (-)-[3H]dihydroalprenolol ([3H]DHA) binding is constant at approx. 0.36 pmol of receptor/mg of protein. By day 9 the density decreases significantly to 0.22 pmol of receptor/mg of protein. At day 12.5--13.5 the number was 0.14--0.18 pmol of receptor/mg of protein. This number did not change further up to day 16. The same results were obtained with guanosine 5'-[beta, gamma-imido]triphosphate (p[NH]ppG) added to the assay mixtures. There was no significant change in receptor affinity for the antagonist [3H]DHA between days 5.5 and 13. Despite the decrease in numbers of beta-adrenergic receptors, there was no change in basal, p[NH]ppG-, isoprenaline- or isoprenaline-plus-p[NH]ppG-stimulated adenylate cyclase activity between days 3 and 12 of development. We conclude that beta-adrenergic receptors and adenylate cyclase are not co-ordinately regulated during early embryonic development of the chick heart. Some of the beta-adrenergic receptors present very early in the ontogeny of cardiac tissue appear not to be coupled to adenylate cyclase since their loss is not reflected in decreased activation of the enzyme. PMID:6289805

  1. β-Adrenergic receptor subtype signaling in heart: From bench to bedside

    PubMed Central

    Woo, Anthony Yiu Ho; Xiao, Rui-ping

    2012-01-01

    β-adrenergic receptor (βAR) stimulation by the sympathetic nervous system or circulating catecholamines is broadly involved in peripheral blood circulation, metabolic regulation, muscle contraction, and central neural activities. In the heart, acute βAR stimulation serves as the most powerful means to regulate cardiac output in response to a fight-or-flight situation, whereas chronic βAR stimulation plays an important role in physiological and pathological cardiac remodeling. There are three βAR subtypes, β1AR, β2AR and β3AR, in cardiac myocytes. Over the past two decades, we systematically investigated the molecular and cellular mechanisms underlying the different even opposite functional roles of β1AR and β2AR subtypes in regulating cardiac structure and function, with keen interest in the development of novel therapies based on our discoveries. We have made three major discoveries, including (1) dual coupling of β2AR to Gs and Gi proteins in cardiomyocytes, (2) cardioprotection by β2AR signaling in improving cardiac function and myocyte viability, and (3) PKA-independent, CaMKII-mediated β1AR apoptotic and maladaptive remodeling signaling in the heart. Based on these discoveries and salutary effects of β1AR blockade on patients with heart failure, we envision that activation of β2AR in combination with clinically used β1AR blockade should provide a safer and more effective therapy for the treatment of heart failure. PMID:22286918

  2. Noninvasive monitoring of beta-adrenergic tone during isoproterenol infusions.

    PubMed

    Easley, R B; Rodbard, D

    1977-12-01

    Sphygmo-Recording is a simple, noninvasive technique for analysis of pulse wave contour and timing which has been used to evaluate the change in cardiac dynamics during isoproterenol infusion. The QKd interval, i.e., the time interval between the onset of the QRS complex and the onset of the Korotkoff sound at the brachial artery when the sphygomomanometer cuff is at diastolic pressure, is normally 205 +/- 15 msec. Continuous intravenous infusion of isoproterenol at 0.01, 0.02, and 0.03 microgram/kg/min into 12 euthyroid normotensive adult volunteers for 10-min intervals resulted in decreases of 55, 79, and 89 msec in QKd and increases of heart rate of 14, 27, and 43 beats/min, respectively. The corresponding changes in dP/dt, i.e., slope of the pulse wave upstroke at the brachial artery determined noninvasively from the same records, were 0.65, 1.47, and 2.26 mm Hg/msec. These results confirm previous studies which indicate that the chronotropic response of normal subjects to isoproterenol infusion is comparable to that previously reported in patients with the putative "hyperdynamic beta-adrenergic state." PMID:200395

  3. Pathophysiology of Sepsis-Related Cardiac Dysfunction: Driven by Inflammation, Energy Mismanagement, or Both?

    PubMed Central

    Lymperopoulos, Anastasios; Kennel, Peter Johannes; Pollak, Nina; Schulze, P. Christian; Goldberg, Ira J.

    2015-01-01

    Sepsis is a systemic inflammatory response that follows bacterial infection. Cardiac dysfunction is an important consequence of sepsis that affects mortality and has been attributed to either elevated inflammation or suppression of both fatty acid and glucose oxidation and eventual ATP depletion. Moreover, cardiac adrenergic signaling is compromised in septic patients and this aggravates further heart function. While anti-inflammatory therapies are important for the treatment of the disease, administration of anti-inflammatory drugs did not improve survival in septic patients. This review article summarizes findings on inflammatory and other mechanisms that are triggered in sepsis and affect cardiac function and mortality. Particularly, it focuses on the effects of the disease in metabolic pathways, as well as in adrenergic signaling and the potential interplay of the latter with inflammation. It is suggested that therapeutic approaches should include combination of anti-inflammatory treatments, stimulation of energy production, and restoration of adrenergic signaling in the heart. PMID:25475180

  4. 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. PMID:27103160

  5. Venous endothelin guides sympathetic innervation of the developing mouse heart

    PubMed Central

    Manousiouthakis, Eleana; Mendez, Monica; Garner, Madeline C.; Exertier, Prisca; Makita, Takako

    2014-01-01

    The mechanisms responsible for establishing correct target innervation during organ development are largely unknown. Sympathetic nerves traverse or follow blood vessels to reach their end-organs, suggesting the existence of vascular guidance cues that direct axonal extension. The sinoatrial node and the ventricle of the heart receive sympathetic innervation from the stellate ganglia (STG). Here we show that STG axons follow veins, specifically the superior vena cavae and sinus venosus, to reach these targets. We find that the election of these routes is determined by venous endothelium-derived endothelin-1, acting through its specific receptor Ednra expressed within a subpopulation of STG neurons. Furthermore, we demonstrate that Edn1-Ednra signaling is essential for functional regulation of the heart by sympathetic nerves. Our findings present venous Edn1 as a sympathetic guidance cue, and show how axon guidance mechanisms are coordinated with end-organ morphogenesis. PMID:24875861

  6. 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. PMID:17368123

  7. 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

  8. Compartmental Innervation of the Superior Oblique Muscle in Mammals

    PubMed Central

    Le, Alan; Poukens, Vadims; Ying, Howard; Rootman, Daniel; Goldberg, Robert A.; Demer, Joseph L.

    2015-01-01

    Purpose Intramuscular innervation of mammalian horizontal rectus extraocular muscles (EOMs) is compartmental. We sought evidence of similar compartmental innervation of the superior oblique (SO) muscle. Methods Three fresh bovine orbits and one human orbit were dissected to trace continuity of SO muscle and tendon fibers to the scleral insertions. Whole orbits were also obtained from four humans (two adults, a 17-month-old child, and a 33-week stillborn fetus), two rhesus monkeys, one rabbit, and one cow. Orbits were formalin fixed, embedded whole in paraffin, serially sectioned in the coronal plane at 10-μm thickness, and stained with Masson trichrome. Extraocular muscle fibers and branches of the trochlear nerve (CN4) were traced in serial sections and reconstructed in three dimensions. Results In the human, the lateral SO belly is in continuity with tendon fibers inserting more posteriorly on the sclera for infraducting mechanical advantage, while the medial belly is continuous with anteriorly inserting fibers having mechanical advantage for incycloduction. Fibers in the monkey superior SO insert more posteriorly on the sclera to favor infraduction, while the inferior portion inserts more anteriorly to favor incycloduction. In all species, CN4 bifurcates prior to penetrating the SO belly. Each branch innervates a nonoverlapping compartment of EOM fibers, consisting of medial and lateral compartments in humans and monkeys, and superior and inferior compartments in cows and rabbits. Conclusions The SO muscle of humans and other mammals is compartmentally innervated in a manner that could permit separate CN4 branches to selectively influence vertical versus torsional action. PMID:26426404

  9. Innervation of amphibian reproductive system. Histological and ultrastructural studies.

    PubMed

    Cisint, Susana; Crespo, Claudia A; Medina, Marcela F; Iruzubieta Villagra, Lucrecia; Fernández, Silvia N; Ramos, Inés

    2014-10-01

    In the present study we describe for the first time in anuran amphibians the histological and ultrastructural characteristics of innervation in the female reproductive organs. The observations in Rhinella arenarum revealed the presence of nerve fibers located predominantly in the ovarian hilium and in the oviduct wall. In both organs the nerves fibers are placed near blood vessels and smooth muscles fibers. In the present study the histological observations were confirmed using antibodies against peripherin and neurofilament 200 proteins. Ultrastructural analyses demonstrated that the innervation of the reproductive organs is constituted by unmyelinated nerve fibers surrounded by Schwann cells. Axon terminals contain a population of small, clear, translucent vesicles that coexist with a few dense cored vesicles. The ultrastructural characteristics together with the immunopositive reaction to tyrosine hydroxylase of the nerve fibers and the type of synaptic vesicles present in the axon terminal would indicate that the reproductive organs of R. arenarum females are innervated by the sympathetic division of the autonomic nervous system. PMID:24882461

  10. 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

  11. 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. PMID:22338020

  12. Beta 1- and beta 2-adrenergic /sup 125/I-pindolol binding sites in the interpeduncular nucleus of the rat: Normal distribution and the effects of deafferentation

    SciTech Connect

    Battisti, W.P.; Artymyshyn, R.P.; Murray, M.

    1989-07-01

    The plasticity of the beta 1- and beta 2-adrenergic receptor subtypes was examined in the interpeduncular nucleus (IPN) of the adult rat. The beta-adrenergic receptor antagonist 125I-pindolol (125I-PIN) was used in conjunction with the selective subtype antagonists ICI 118,551 and ICI 89,406 to determine the subnuclear distribution of beta 1- and beta 2-adrenergic receptors in this nucleus and to correlate the receptor distribution with the distribution of both noradrenergic afferents from the locus coeruleus (LC) and non-noradrenergic afferents from the fasiculus retroflexus (FR). The density of these binding sites was examined following lesions that decreased (LC lesions) or increased (FR lesions) the density of the noradrenergic projection in the IPN. Quantitative radioautography indicated that beta 1-labeled binding sites account for the larger percentage of binding sites in the IPN. The beta 1-binding sites are densest in those subnuclei that receive a noradrenergic projection from the LC: the central, rostral, and intermediate subnuclei. beta 1-binding sites are algo homogeneously distributed throughout the lateral subnuclei, where there is no detectable noradrenergic innervation. beta 2-binding sites have a more restricted distribution. They are concentrated in the ventral half of the lateral subnuclei, where they account for 70% of total 125I-PIN binding sites. beta 2-binding sites are also present along the ventral border of the IPN. Some of this labeling extends into the central and intermediate subnuclei. Bilateral lesions of the LC, which selectively remove noradrenergic innervation to the IPN, result in an increase in the beta 1-binding sites. Bilateral lesions of the FR, which remove the major cholinergic and peptidergic input from the IPN, elicit an increase in noradrenergic projections and a decrease in beta 1-binding sites.

  13. Cardiac cAMP: production, hydrolysis, modulation and detection.

    PubMed

    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

  14. 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

  15. 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. PMID:25979090

  16. 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

  17. 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

  18. Adrenergic Modulation of Pancreatic Glucagon Secretion in Man

    PubMed Central

    Gerich, John E.; Langlois, Maurice; Noacco, Claudio; Schneider, Victor; Forsham, Peter H.

    1974-01-01

    In order to characterize the influence of the adrenergic system on pancreatic glucagon secretion in man, changes in basal glucagon secretion during infusions of pure alpha and beta adrenergic agonists and their specific antagonists were studied. During infusion of isoproterenol (3 μg/min), a beta adrenergic agonist, plasma glucagon rose from a mean (±SE) basal level of 104±10 to 171±15 pg/ml, P < 0.0002. Concomitant infusion of propranolol (80 μg/min), a beta adrenergic antagonist, prevented the effects of isoproterenol, although propranolol itself had no effect on basal glucagon secretion. During infusion of methoxamine (0.5 mg/min), an alpha adrenergic agonist, plasma glucagon declined from a mean basal level of 122±15 to 75±17 pg/ml, P < 0.001. Infusion of phentolamine (0.5 mg/min), an alpha adrenergic antagonist, caused a rise in plasma glucagon from a mean basal level of 118±16 to 175±21 pg/ml, P < 0.0001. Concomitant infusion of methoxamine with phentolamine caused a reversal of the effects of phentolamine. The present studies thus confirm that catecholamines affect glucagon secretion in man and demonstrate that the pancreatic alpha cell possesses both alpha and beta adrenergic receptors. Beta adrenergic stimulation augments basal glucagon secretion, while alpha adrenergic stimulation diminishes basal glucagon secretion. Furthermore, since infusion of phentolamine, an alpha adrenergic antagonist, resulted in an elevation of basal plasma glucagon levels, there appears to be an inhibitory alpha adrenergic tone governing basal glucagon secretion. The above findings suggest that catecholamines may influence glucose homeostasis in man through their effects on both pancreatic alpha and beta cell function. Images PMID:4825234

  19. beta(1)-adrenergic antagonists improve sleep and behavioural disturbances in a circadian disorder, Smith-Magenis syndrome.

    PubMed

    De Leersnyder, H; de Blois, M C; Vekemans, M; Sidi, D; Villain, E; Kindermans, C; Munnich, A

    2001-09-01

    Smith-Magenis syndrome (SMS) is a clinically recognisable contiguous gene syndrome ascribed to interstitial deletions of chromosome 17p11.2. Patients have a phase shift of their circadian rhythm of melatonin with a paradoxical diurnal secretion of the hormone. Serum melatonin levels and day-night behaviour were studied in nine SMS children (aged 4 to 17 years) given acebutolol, a selective beta(1)-adrenergic antagonist (10 mg/kg early in the morning). Cardiac examination, serum melatonin, motor activity recordings, and sleep diaries were monitored before and after drug administration. The present study shows that a single morning dose of acebutolol suppressed the inappropriate secretion of melatonin in SMS. A significant improvement of inappropriate behaviour with increased concentration, delayed sleep onset, increased hours of sleep, and delayed waking were also noted. These results suggest that beta(1)-adrenergic antagonists help to manage hyperactivity, enhance cognitive performance, and reduce sleep disorders in SMS. PMID:11546826

  20. 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

  1. 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

  2. Crossed motor innervation of the base of human tongue.

    PubMed

    Kubin, Leszek; Jordan, Amy S; Nicholas, Christian L; Cori, Jennifer M; Semmler, John G; Trinder, John

    2015-06-01

    Muscle fibers of the genioglossus (GG) form the bulk of the muscle mass at the base of the tongue. The motor control of the tongue is critical for vocalization, feeding, and breathing. Our goal was to assess the patterns of motor innervation of GG single motor units (SMUs) in humans. Simultaneous monopolar recordings were obtained from four sites in the base of the tongue bilaterally at two antero-posterior levels from 16 resting, awake, healthy adult males, who wore a face mask with airway pressure and airflow sensors. We analyzed 69 data segments in which at least one lead contained large action potentials generated by an SMU. Such potentials served as triggers for spike-triggered averaging (STA) of signals recorded from the other three sites. Spontaneous activity of the SMUs was classified as inspiratory modulated, expiratory modulated, or tonic. Consistent with the antero-posterior orientation of GG fibers, 44 STAs (77%) recorded ipsilateral to the trigger yielded sharp action potentials with a median amplitude of 52 μV [interquartile range (IQR): 25-190] that were time shifted relative to the trigger by about 1 ms. Notably, 48% of recordings on the side opposite to the trigger also yielded sharp action potentials. Of those, 17 (29%) had a median amplitude of 63 μV (IQR: 39-96), and most were generated by tonic SMUs. Thus a considerable proportion of GG muscle fibers receive a crossed motor innervation. Crossed innervation may help ensure symmetry and stability of tongue position and movements under normal conditions and following injury or degenerative changes affecting the tongue. PMID:25855691

  3. Crossed motor innervation of the base of human tongue

    PubMed Central

    Jordan, Amy S.; Nicholas, Christian L.; Cori, Jennifer M.; Semmler, John G.; Trinder, John

    2015-01-01

    Muscle fibers of the genioglossus (GG) form the bulk of the muscle mass at the base of the tongue. The motor control of the tongue is critical for vocalization, feeding, and breathing. Our goal was to assess the patterns of motor innervation of GG single motor units (SMUs) in humans. Simultaneous monopolar recordings were obtained from four sites in the base of the tongue bilaterally at two antero-posterior levels from 16 resting, awake, healthy adult males, who wore a face mask with airway pressure and airflow sensors. We analyzed 69 data segments in which at least one lead contained large action potentials generated by an SMU. Such potentials served as triggers for spike-triggered averaging (STA) of signals recorded from the other three sites. Spontaneous activity of the SMUs was classified as inspiratory modulated, expiratory modulated, or tonic. Consistent with the antero-posterior orientation of GG fibers, 44 STAs (77%) recorded ipsilateral to the trigger yielded sharp action potentials with a median amplitude of 52 μV [interquartile range (IQR): 25–190] that were time shifted relative to the trigger by about 1 ms. Notably, 48% of recordings on the side opposite to the trigger also yielded sharp action potentials. Of those, 17 (29%) had a median amplitude of 63 μV (IQR: 39–96), and most were generated by tonic SMUs. Thus a considerable proportion of GG muscle fibers receive a crossed motor innervation. Crossed innervation may help ensure symmetry and stability of tongue position and movements under normal conditions and following injury or degenerative changes affecting the tongue. PMID:25855691

  4. Postnatal reduction of BDNF regulates the developmental remodeling of taste bud innervation.

    PubMed

    Huang, Tao; Ma, Liqun; Krimm, Robin F

    2015-09-15

    The refinement of innervation is a common developmental mechanism that serves to increase the specificity of connections following initial innervation. In the peripheral gustatory system, the extent to which innervation is refined and how refinement might be regulated is unclear. The initial innervation of taste buds is controlled by brain-derived neurotrophic factor (BDNF). Following initial innervation, taste receptor cells are added and become newly innervated. The connections between the taste receptor cells and nerve fibers are likely to be specific in order to retain peripheral coding mechanisms. Here, we explored the possibility that the down-regulation of BDNF regulates the refinement of taste bud innervation during postnatal development. An analysis of BDNF expression in Bdnf(lacZ/+) mice and real-time reverse transcription polymerase chain reaction (RT-PCR) revealed that BDNF was down-regulated between postnatal day (P) 5 and P10. This reduction in BDNF expression was due to a loss of precursor/progenitor cells that express BDNF, while the expression of BDNF in the subpopulations of taste receptor cells did not change. Gustatory innervation, which was identified by P2X3 immunohistochemistry, was lost around the perimeter where most progenitor/precursor cells are located. In addition, the density of innervation in the taste bud was reduced between P5 and P10, because taste buds increase in size without increasing innervation. This reduction of innervation density was blocked by the overexpression of BDNF in the precursor/progenitor population of taste bud cells. Together these findings indicate that the process of BDNF restriction to a subpopulation of taste receptor cells between P5 and P10, results in a refinement of gustatory innervation. We speculate that this refinement results in an increased specificity of connections between neurons and taste receptor cells during development. PMID:26164656

  5. 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

  6. 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.

  7. Physiological and Clinical Implications of Adrenergic Pathways at High Altitude.

    PubMed

    Richalet, Jean-Paul

    2016-01-01

    The adrenergic system is part of a full array of mechanisms allowing the human body to adapt to the hypoxic environment. Triggered by the stimulation of peripheral chemoreceptors, the adrenergic centers in the medulla are activated in acute hypoxia and augment the adrenergic drive to the organs, especially to the heart, leading to tachycardia. With prolonged exposure to altitude hypoxia, the adrenergic drive persists, as witnessed by elevated blood concentrations of catecholamines and nerve activity in adrenergic fibers. In response to this persistent stimulation, the pathways leading to the activation of adenylate cyclase are modified. A downregulation of β-adrenergic and adenosinergic receptors is observed, while muscarinic receptors are upregulated. The expression and activity of Gi and Gs proteins are modified, leading to a decreased response of adenylate cyclase activity to adrenergic stimulation. The clinical consequences of these cellular and molecular changes are of importance, especially for exercise performance and protection of heart function. The decrease in maximal exercise heart rate in prolonged hypoxia is fully accounted for the observed changes in adrenergic and muscarinic pathways. The decreased heart rate response to isoproterenol infusion is another marker of the desensitization of adrenergic pathways. These changes can be considered as mechanisms protecting the heart from a too high oxygen consumption in conditions where the oxygen availability is severely reduced. Similarly, intermittent exposure to hypoxia has been shown to protect the heart from an ischemic insult with similar mechanisms involving G proteins and downregulation of β receptors. Other pathways with G proteins are concerned in adaptation to hypoxia, such as lactate release by the muscles and renal handling of calcium. Altogether, the activation of the adrenergic system is useful for the acute physiological response to hypoxia. With prolonged exposure to hypoxia, the autonomous

  8. 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.

  9. 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

  10. 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.

  11. Incidence of cardiac events in burned patients.

    PubMed

    Meyers, David G; Hoestje, Sara M; Korentager, Richard A

    2003-06-01

    Given the increased level of adrenergic stimulation in burn patients, it would be expected that they would experience an increased incidence of cardiac arrhythmias and other cardiac events. We performed a retrospective chart review of 56 acute burn patients matched by age, length of hospital stay, and sex to 56 trauma patients, all of whom had been continuously monitored electrocardiographically. Burn and trauma patients were similar in injury severity, admission laboratory values, and prior history of cardiopulmonary diseases. Arrhythmias were noted in 34% of burn patients and 28% of trauma patients. One myocardial infarction and six deaths occurred in burn patients. No myocardial infarctions or deaths were observed in trauma patients. A past history of cardiopulmonary disease increased the risk of myocardial infarction or death by 6.6 times. Cardiac arrhythmias and other events are relatively infrequent and benign in burn patients and are similar to those experienced by other patients with acute injuries. PMID:12781616

  12. 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

  13. Rat hepatic. beta. /sub 2/-adrenergic receptor: structural similarities to the rat fat cell. beta. /sub 1/-adrenergic receptor

    SciTech Connect

    Graziano, M.P.

    1984-01-01

    The mammalian ..beta../sub 2/-adrenergic receptor from rat liver has been purified by sequential cycles of affinity chromatography followed by steric-exclusion high performance liquid chromatography. Electrophoresis of highly purified receptor preparations on polyacrylamide gels in the presence of sodium dodecyl sulfate under reducing conditions reveals a single peptide M/sub r/ = 67,000, as judged by silver staining. Purified ..beta../sub 2/-adrenergic receptor migrates on steric-exclusion high performance liquid chromatography in two peaks, with M/sub r/ = 140,000 and 67,000. Specific binding of the high affinity, ..beta..-adrenergic receptor antagonists (-)(/sup 3/H)dihydroalprenolol and (-)(/sup 125/I)iodocyanopindolol to purified rat liver ..beta..-adrenergic receptor preparations displays stereoselectivity for (-)isomers of agonists and a rank order of potencies for agonists characteristics of a ..beta../sub 2/-adrenergic receptor. Radioiodinated, ..beta../sub 1/-adrenergic receptors from rat fat cells and ..beta../sub 2/-adrenergic receptors from rat liver purified in the presence of protease inhibitors comigrate in electrophoretic separations on polyacrylamide gels in the presence of sodium dodecyl sulfate as 67,000-M/sub r/ peptides. Autoradiograms of two dimensional partial proteolytic digests of the purified, radioiodinated rat liver ..beta../sub 2/-adrenergic receptor, generated with ..cap alpha..-chymotrypsin, S. aureus V8 protease and elastase reveal a pattern of peptide fragments essentially identical to those generated by partial proteolytic digests of the purified, radioiodinated ..beta../sub 1/-adrenergic receptor from rat fat cells, by these same proteases. These data indicate that a high degree of homology exists between these two pharmacologically distinct mammalian ..beta..-adrenergic receptor proteins.

  14. Skin innervation: important roles during normal and pathological cutaneous repair.

    PubMed

    Laverdet, Betty; Danigo, Aurore; Girard, Dorothée; Magy, Laurent; Demiot, Claire; Desmoulière, Alexis

    2015-08-01

    The skin is a highly sensitive organ. It is densely innervated with different types of sensory nerve endings, which discriminate between pain, temperature and touch. Autonomic nerve fibres which completely derive from sympathetic (cholinergic) neurons are also present. During all the phases of skin wound healing (inflammatory, proliferative and remodelling phases), neuromediators are involved. Several clinical observations indicate that damage to the peripheral nervous system influences wound healing, resulting in chronic wounds within the affected area. Patients with cutaneous sensory defects due to lepromatous leprosy, spinal cord injury and diabetic neuropathy develop ulcers that fail to heal. In addition, numerous experimental observations suggest that neurogenic stimuli profoundly affect wound repair after injury and that delayed wound healing is observed in animal models after surgical resection of cutaneous nerves. All these observations clearly suggest that innervation and neuromediators play a major role in wound healing. Interactions between neuromediators and different skin cells are certainly crucial in the healing process and ultimately the restoration of pain, temperature, and touch perceptions is a major challenge to solve in order to improve patients' quality of life. PMID:25799052

  15. Selective Thalamic Innervation of Rat Frontal Cortical Neurons.

    PubMed

    Shigematsu, Naoki; Ueta, Yoshifumi; Mohamed, Alsayed A; Hatada, Sayuri; Fukuda, Takaichi; Kubota, Yoshiyuki; Kawaguchi, Yasuo

    2016-06-01

    Most glutamatergic inputs in the neocortex originate from the thalamus or neocortical pyramidal cells. To test whether thalamocortical afferents selectively innervate specific cortical cell subtypes and surface domains, we investigated the distribution patterns of thalamocortical and corticocortical excitatory synaptic inputs in identified postsynaptic cortical cell subtypes using intracellular and immunohistochemical staining combined with confocal laser scanning and electron microscopic observations in 2 thalamorecipient sublayers, lower layer 2/3 (L2/3b) and lower layer 5 (L5b) of rat frontal cortex. The dendrites of GABAergic parvalbumin (PV) cells preferentially received corticocortical inputs in both sublayers. The somata of L2/3b PV cells received thalamic inputs in similar proportions to the basal dendritic spines of L2/3b pyramidal cells, whereas L5b PV somata were mostly innervated by cortical inputs. The basal dendrites of L2/3b pyramidal and L5b corticopontine pyramidal cells received cortical and thalamic glutamatergic inputs in proportion to their local abundance, whereas crossed-corticostriatal pyramidal cells in L5b exhibited a preference for thalamic inputs, particularly in their distal dendrites. Our data demonstrate an exquisite selectivity among thalamocortical afferents in which synaptic connectivity is dependent on the postsynaptic neuron subtype, cortical sublayer, and cell surface domain. PMID:26045568

  16. 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

  17. 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. PMID:26475872

  18. Re-evaluating the efficacy of β-adrenergic agonists and antagonists in long QT-3 syndrome through computational modelling

    PubMed Central

    Ahrens-Nicklas, Rebecca C.; Clancy, Colleen E.; Christini, David J.

    2009-01-01

    Aims Long QT syndrome (LQTS) is a heterogeneous collection of inherited cardiac ion channelopathies characterized by a prolonged electrocardiogram QT interval and increased risk of sudden cardiac death. β-Adrenergic blockers are the mainstay of treatment for LQTS. While their efficacy has been demonstrated in LQTS patients harbouring potassium channel mutations, studies of β-blockers in subtype 3 (LQT3), which is caused by sodium channel mutations, have produced ambiguous results. In this modelling study, we explore the effects of β-adrenergic drugs on the LQT3 phenotype. Methods and results In order to investigate the effects of β-adrenergic activity and to identify sources of ambiguity in earlier studies, we developed a computational model incorporating the effects of β-agonists and β-blockers into an LQT3 mutant guinea pig ventricular myocyte model. β-Activation suppressed two arrhythmogenic phenomena, transmural dispersion of repolarization and early after depolarizations, in a dose-dependent manner. However, the ability of β-activation to prevent cardiac conduction block was pacing-rate-dependent. Low-dose β-blockade by propranolol reversed the beneficial effects of β-activation, while high dose (which has off-target sodium channel effects) decreased arrhythmia susceptibility. Conclusion These results demonstrate that β-activation may be protective in LQT3 and help to reconcile seemingly conflicting results from different experimental models. They also highlight the need for well-controlled clinical investigations re-evaluating the use of β-blockers in LQT3 patients. PMID:19264765

  19. Astrocytic beta(2)-adrenergic receptors: from physiology to pathology.

    PubMed

    Laureys, Guy; Clinckers, Ralph; Gerlo, Sarah; Spooren, Anneleen; Wilczak, Nadine; Kooijman, Ron; Smolders, Ilse; Michotte, Yvette; De Keyser, Jacques

    2010-07-01

    Evidence accumulates for a key role of the beta(2)-adrenergic receptors in the many homeostatic and neuroprotective functions of astrocytes, including glycogen metabolism, regulation of immune responses, release of neurotrophic factors, and the astrogliosis that occurs in response to neuronal injury. A dysregulation of the astrocytic beta(2)-adrenergic-pathway is suspected to contribute to the physiopathology of a number of prevalent and devastating neurological conditions such as multiple sclerosis, Alzheimer's disease, human immunodeficiency virus encephalitis, stroke and hepatic encephalopathy. In this review we focus on the physiological functions of astrocytic beta(2)-adrenergic receptors, and their possible impact in disease states. PMID:20138112

  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. 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.

  2. Vagal Afferent Innervation of the Airways in Health and Disease.

    PubMed

    Mazzone, Stuart B; Undem, Bradley J

    2016-07-01

    Vagal sensory neurons constitute the major afferent supply to the airways and lungs. Subsets of afferents are defined by their embryological origin, molecular profile, neurochemistry, functionality, and anatomical organization, and collectively these nerves are essential for the regulation of respiratory physiology and pulmonary defense through local responses and centrally mediated neural pathways. Mechanical and chemical activation of airway afferents depends on a myriad of ionic and receptor-mediated signaling, much of which has yet to be fully explored. Alterations in the sensitivity and neurochemical phenotype of vagal afferent nerves and/or the neural pathways that they innervate occur in a wide variety of pulmonary diseases, and as such, understanding the mechanisms of vagal sensory function and dysfunction may reveal novel therapeutic targets. In this comprehensive review we discuss historical and state-of-the-art concepts in airway sensory neurobiology and explore mechanisms underlying how vagal sensory pathways become dysfunctional in pathological conditions. PMID:27279650

  3. Genetically Induced Cholinergic Hyper-Innervation Enhances Taste Learning

    PubMed Central

    Neseliler, Selin; Narayanan, Darshana; Fortis-Santiago, Yaihara; Katz, Donald B.; Birren, Susan J.

    2011-01-01

    Acute inhibition of acetylcholine (ACh) has been shown to impair many forms of simple learning, and notably conditioned taste aversion (CTA). The most adhered-to theory that has emerged as a result of this work – that ACh increases a taste’s perceived novelty, and thereby its associability – would be further strengthened by evidence showing that enhanced cholinergic function improves learning above normal levels. Experimental testing of this corollary hypothesis has been limited, however, by side-effects of pharmacological ACh agonism and by the absence of a model that achieves long-term increases in cholinergic signaling. Here, we present this further test of the ACh hypothesis, making use of mice lacking the p75 pan-neurotrophin receptor gene, which show a resultant over-abundance of cholinergic neurons in sub-regions of the basal forebrain (BF). We first demonstrate that the p75−/− abnormality directly affects portions of the CTA circuit, locating mouse gustatory cortex (GC) using a functional assay and then using immunohistochemisty to demonstrate cholinergic hyper-innervation of GC in the mutant mice – hyper-innervation that is unaccompanied by changes in cell numbers or compensatory changes in muscarinic receptor densities. We then demonstrate that both p75−/− and wild-type (WT) mice learn robust CTAs, which extinguish more slowly in the mutants. Further testing to distinguish effects on learning from alterations in memory retention demonstrate that p75−/− mice do in fact learn stronger CTAs than WT mice. These data provide novel evidence for the hypothesis linking ACh and taste learning. PMID:22144949

  4. Effects of Polysialic Acid on Sensory Innervation of the Cornea

    PubMed Central

    Mao, Xiuli; Zhang, Yuntao; Schwend, Tyler; Conrad, Gary W.

    2014-01-01

    Sensory trigeminal growth cones innervate the cornea in a coordinated fashion during embryonic development. Polysialic acid (polySia) is known for its important roles during nerve development and regeneration. The purpose of this work is to determine whether polySia, present in developing eyefronts and on the surface of sensory nerves, may provide guidance cues to nerves during corneal innervation. Expression and localization of polySia in embryonic day (E)5-14 chick eyefronts and E9 trigeminal ganglia were identified using Western blotting and immunostaining. Effects of polySia removal on trigeminal nerve growth behavior were determined in vivo, using exogenous endoneuraminidase (endoN) treatments to remove polySia substrates during chick cornea development, and in vitro, using neuronal explant cultures. PolySia substrates, made by the physical adsorption of colominic acid to a surface coated with poly-D-lysine (PDL), were used as a model to investigate functions of the polySia expressed in axonal environments. PolySia was localized within developing eyefronts and on trigeminal sensory nerves. Distributions of PolySia in corneas and pericorneal regions are developmentally regulated. PolySia removal caused defasciculation of the limbal nerve trunk in vivo from E7 to E10. Removal of polySia on trigeminal neurites inhibited neurite outgrowth and caused axon defasciculation, but did not affect Neural Cell Adhesion Molecule (NCAM) expression or Schwann cell migration in vitro. PolySia substrates in vitro inhibited outgrowth of trigeminal neurites and promoted their fasciculation. In conclusion, polySia is localized on corneal nerves and in their targeting environment during early developing stages of chick embryos. PolySias promote fasciculation of trigeminal axons in vivo and in vitro, whereas, in contrast, their removal promotes defasciculation. PMID:25478909

  5. Origin of primary sensory neurons innervating the buccal stretch receptor.

    PubMed

    Yamamoto, T; Onozuka, M; Nagasaki, S; Watanabe, K; Ozono, S

    1999-01-01

    The primary sensory neurons innervating mechanoreceptors in oro-facial regions have their cell bodies in either the trigeminal ganglion or the mesencephalic nucleus of the trigeminal nerve. The buccal stretch receptor (BSR), a type of mechanoreceptor in the jaw of rodents, has recently been recognized as signaling the position of the mandible. The location of the primary afferent neurons innervating this receptor is unknown. To investigate the cell bodies of the BSR afferent neurons in rats, we applied wheat germ agglutinin-horseradish peroxidase (WGA-HRP) to the proximal stump of the severed nerve branch of the buccal nerve that supplied the BSR. HRP-labeled cell bodies were observed in the posterolateral portion of the ipsilateral trigeminal ganglion. None was found in the contralateral trigeminal ganglion or in the brainstem. All labeled cell bodies were oval or round and closely resembled pseudo-unipolar neurons. The mean diameter of the labeled somata ranged between 25.5 and 52.5 microm, with small (< or = 30 microm), medium (from 31 to 40 microm), and large somata (> or = 41 microm) accounting for 8.8%, 54.9%, and 36.3%, respectively. Among the myelinated nerve fibers in the branch in which WGA-HRP was applied, 78.5% terminated in the BSR and had larger fiber diameters than the rest, indicating that most of the medium and large HRP-labeled cell bodies were BSR afferents. From these results and the ontogenetic origin of this receptor, it is suggested that the BSR differentiated from the mechanoreceptors in the oral mucosa or the fascia of masticatory muscles. PMID:10065945

  6. 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.

  7. 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.

  8. 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

  9. Horseradish peroxidase localization of sympathetic postganglionic and parasympathetic preganglionic neurons innervating the monkey heart.

    PubMed

    Chuang, King-Shun; Liu, Wan-Cherng; Liou, Nien-Hsien; Liu, Jiang-Chuan

    2004-06-30

    The localization of the sympathetic postganglionic and parasympathetic preganglionic neurons innervating the monkey heart were investigated through retrograde axonal transport with horseradish peroxidase (HRP). HRP (4 mg or 30 mg) was injected into the subepicardial and myocardial layers in four different cardiac regions. The animals were euthanized 84-96 hours later and fixed by paraformaldehyde perfusion via the left ventricle. The brain stem and the paravertebral sympathetic ganglia from the superior cervical, middle cervical, and stellate ganglia down to the T9 ganglia were removed and processed for HRP identification. Following injection of HRP into the apex of the heart, the sinoatrial nodal region, or the right ventricle, HRP-labeled sympathetic neurons were found exclusively in the right superior cervical ganglion (64.8%) or in the left superior cervical ganglion (35%). Fewer labeled cells were found in the right stellate ganglia. After HRP injection into the left ventricle, labeled sympathetic cells were found chiefly in the left superior cervical ganglion (51%) or in the right superior cervical ganglion (38.6%); a few labeled cells were seen in the stellate ganglion bilaterally and in the left middle cervical ganglion. Also, in response to administration of HRP into the anterior part of the apex, anterior middle part of the right ventricle, posterior upper part of the left ventricle, or sinoatrial nodal region, HRP-labeled parasympathetic neurons were found in the nucleus ambiguus on both the right (74.8%) and left (25.2%) sides. No HRP-labeled cells were found in the dorsal motor nucleus of the vagus on either side. PMID:15481792

  10. 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

  11. Cardiac metastases

    PubMed Central

    Bussani, R; De‐Giorgio, F; Abbate, A; Silvestri, F

    2007-01-01

    Tumours metastatic to the heart (cardiac metastases) are among the least known and highly debated issues in oncology, and few systematic studies are devoted to this topic. Although primary cardiac tumours are extremely uncommon (various postmortem studies report rates between 0.001% and 0.28%), secondary tumours are not, and at least in theory, the heart can be metastasised by any malignant neoplasm able to spread to distant sites. In general, cardiac metastases are considered to be rare; however, when sought for, the incidence seems to be not as low as expected, ranging from 2.3% and 18.3%. Although no malignant tumours are known that diffuse preferentially to the heart, some do involve the heart more often than others—for example, melanoma and mediastinal primary tumours. This paper attempts to review the pathophysiology of cardiac metastatic disease, epidemiology and clinical presentation of cardiac metastases, and pathological characterisation of the lesions. PMID:17098886

  12. Inner ear hair cells deteriorate in mice engineered to have no or diminished innervation

    PubMed Central

    Kersigo, Jennifer; Fritzsch, Bernd

    2015-01-01

    The innervation of the inner ear critically depends on the two neurotrophins Ntf3 and Bdnf. In contrast to this molecularly well-established dependency, evidence regarding the need of innervation for long-term maintenance of inner ear hair cells is inconclusive, due to experimental variability. Mutant mice that lack both neurotrophins could shed light on the long-term consequences of innervation loss on hair cells without introducing experimental variability, but do not survive after birth. Mutant mice with conditional deletion of both neurotrophins lose almost all innervation by postnatal day 10 and show an initially normal development of hair cells by this stage. No innervation remains after 3 weeks and complete loss of all innervation results in near complete loss of outer and many inner hair cells of the organ of Corti within 4 months. Mutants that retain one allele of either neurotrophin have only partial loss of innervation of the organ of Corti and show a longer viability of cochlear hair cells with more profound loss of inner hair cells. By 10 months, hair cells disappear with a base to apex progression, proportional to the residual density of innervation and similar to carboplatin ototoxicity. Similar to reports of hair cell loss after aminoglycoside treatment, blobbing of stereocilia of apparently dying hair cells protrude into the cochlear duct. Denervation of vestibular sensory epithelia for several months also resulted in variable results, ranging from unusual hair cells resembling the aberrations found in the organ of Corti, to near normal hair cells in the canal cristae. Fusion and/or resorption of stereocilia and loss of hair cells follows a pattern reminiscent of Myo6 and Cdc42 null mice. Our data support a role of innervation for long-term maintenance but with a remarkable local variation that needs to be taken into account when attempting regeneration of the organ of Corti. PMID:25852547

  13. Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP)-mediated Calcium Signaling and Arrhythmias in the Heart Evoked by β-Adrenergic Stimulation*♦

    PubMed Central

    Nebel, Merle; Schwoerer, Alexander P.; Warszta, Dominik; Siebrands, Cornelia C.; Limbrock, Ann-Christin; Swarbrick, Joanna M.; Fliegert, Ralf; Weber, Karin; Bruhn, Sören; Hohenegger, Martin; Geisler, Anne; Herich, Lena; Schlegel, Susan; Carrier, Lucie; Eschenhagen, Thomas; Potter, Barry V. L.; Ehmke, Heimo; Guse, Andreas H.

    2013-01-01

    Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+-releasing second messenger known to date. Here, we report a new role for NAADP in arrhythmogenic Ca2+ release in cardiac myocytes evoked by β-adrenergic stimulation. Infusion of NAADP into intact cardiac myocytes induced global Ca2+ signals sensitive to inhibitors of both acidic Ca2+ stores and ryanodine receptors and to NAADP antagonist BZ194. Furthermore, in electrically paced cardiac myocytes BZ194 blocked spontaneous diastolic Ca2+ transients caused by high concentrations of the β-adrenergic agonist isoproterenol. Ca2+ transients were recorded both as increases of the free cytosolic Ca2+ concentration and as decreases of the sarcoplasmic luminal Ca2+ concentration. Importantly, NAADP antagonist BZ194 largely ameliorated isoproterenol-induced arrhythmias in awake mice. We provide strong evidence that NAADP-mediated modulation of couplon activity plays a role for triggering spontaneous diastolic Ca2+ transients in isolated cardiac myocytes and arrhythmias in the intact animal. Thus, NAADP signaling appears an attractive novel target for antiarrhythmic therapy. PMID:23564460

  14. Ontogeny of the serotonergic projection to rat neocortex: transient expression of a dense innervation to primary sensory areas

    SciTech Connect

    D'Amato, R.J.; Blue, M.E.; Largent, B.L.; Lynch, D.R.; Ledbetter, D.J.; Molliver, M.E.; Snyder, S.H.

    1987-06-01

    The development of serotonergic innervation to rat cerebral cortex was characterized by immunohistochemical localization of serotonin combined with autoradiographic imaging of serotonin-uptake sites. In neonatal rat, a transient, dense, serotonergic innervation appears in all primary sensory areas of cortex. In somatosensory cortex, dense patches of serotonergic innervation are aligned with specialized cellular aggregates called barrels. The dense patches are not apparent after 3 weeks of age, and the serotonergic innervation becomes more uniform in adult neocortex. This precocious neonatal serotonergic innervation may play a transient physiologic role in sensory areas of cortex or may exert a trophic influence on the development of cortical circuitry and thalamocortical connections.

  15. 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.

  16. Effects of cholinergic and beta-adrenergic blockade on orthostatic tolerance in healthy subjects.

    PubMed

    Convertino, V A; Sather, T M

    2000-12-01

    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. PMID:11324988

  17. 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

  18. The Alpha-1A Adrenergic Receptor in the Rabbit Heart.

    PubMed

    Thomas, R Croft; Cowley, Patrick M; Singh, Abhishek; 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

  19. Creating a cardiac pacemaker by gene therapy.

    PubMed

    Anghel, Traian M; Pogwizd, Steven M

    2007-02-01

    While electronic cardiac pacing in its various modalities represents standard of care for treatment of symptomatic bradyarrhythmias and heart failure, it has limitations ranging from absent or rudimentary autonomic modulation to severe complications. This has prompted experimental studies to design and validate a biological pacemaker that could supplement or replace electronic pacemakers. Advances in cardiac gene therapy have resulted in a number of strategies focused on beta-adrenergic receptors as well as specific ion currents that contribute to pacemaker function. This article reviews basic pacemaker physiology, as well as studies in which gene transfer approaches to develop a biological pacemaker have been designed and validated in vivo. Additional requirements and refinements necessary for successful biopacemaker function by gene transfer are discussed. PMID:17139515

  20. Cardiac Lymphoma.

    PubMed

    Jeudy, Jean; Burke, Allen P; Frazier, Aletta Ann

    2016-07-01

    Lymphoma of the heart and pericardium may develop in up to 25% of patients with disseminated nodal disease, but primary cardiac lymphoma is rare. The majority are diffuse large B-cell lymphomas, which arise in immunocompetent older individuals, men twice as often as women. Subsets are found in immunocompromised patients, including those with HIV-AIDS or allograft recipients. Cardiac lymphomas tend to arise in the wall of the right heart, especially right atrium, with contiguous infiltration of epicardium and pericardium. Pericardial implants and effusions are common. The disease is often multifocal in the heart, but cardiac valves are usually spared. PMID:27265603

  1. Decreased Polycystin 2 Levels Result in Non-Renal Cardiac Dysfunction with Aging

    PubMed Central

    Kuo, Ivana Y.; Duong, Sophie L.; Nguyen, Lily; Ehrlich, Barbara E.

    2016-01-01

    Mutations in the gene for polycystin 2 (Pkd2) lead to polycystic kidney disease, however the main cause of mortality in humans is cardiac related. We previously showed that 5 month old Pkd2+/- mice have altered calcium-contractile activity in cardiomyocytes, but have preserved cardiac function. Here, we examined 1 and 9 month old Pkd2+/- mice to determine if decreased amounts of functional polycystin 2 leads to impaired cardiac function with aging. We observed changes in calcium handling proteins in 1 month old Pkd2+/- mice, and these changes were exacerbated in 9 month old Pkd2+/- mice. Anatomically, the 9 month old Pkd2+/- mice had thinner left ventricular walls, consistent with dilated cardiomyopathy, and the left ventricular ejection fraction was decreased. Intriguingly, in response to acute isoproterenol stimulation to examine β-adrenergic responses, the 9 month old Pkd2+/- mice exhibited a stronger contractile response, which also coincided with preserved localization of the β2 adrenergic receptor. Importantly, the Pkd2+/- mice did not have any renal impairment. We conclude that the cardiac-related impact of decreased polycystin 2 progresses over time towards cardiac dysfunction and altered adrenergic signaling. These results provide further evidence that polycystin 2 provides a critical function in the heart, independent of renal involvement. PMID:27081851

  2. Extrinsic Sensory Innervation of the Gut: Structure and Function.

    PubMed

    Brookes, Simon; Chen, Nan; Humenick, Adam; Spencer, Nick J; Costa, Marcello

    2016-01-01

    Extrinsic sensory neurons play a key role in the function of the gastrointestinal tract. They are responsible for the sensations that arise in the gut and can initiate automatic reflexes. In some cases, disordered sensation is clinically problematic-pain, bloating, excessive urgency and nausea are well-known examples. Major advances have been made in understanding the function of somatic sensory neurons in the last 50 years. However, the sensory neurons that mediate sensations from the viscera remain less well understood. This is partly because viscera receive a dense autonomic innervation that can be difficult to separate from extrinsic sensory neurons. A key requirement to understand the genesis of sensation is to distinguish the different classes of sensory neurons and the types of stimuli which they encode. The aim of this short paper is to summarise what was known about these matters 30 years ago and highlight some of the major advances in the understanding of the types of extrinsic sensory neurons to the gut. Necessarily, the choice of papers is somewhat idiosyncratic, but they illustrate the range of advances that have been made in distinguishing the different classes of gastrointestinal afferent nerves. PMID:27379635

  3. From innervation density to tactile acuity: 1. Spatial representation.

    PubMed

    Brown, Paul B; Koerber, H Richard; Millecchia, Ronald

    2004-06-11

    We tested the hypothesis that the population receptive field representation (a superposition of the excitatory receptive field areas of cells responding to a tactile stimulus) provides spatial information sufficient to mediate one measure of static tactile acuity. In psychophysical tests, two-point discrimination thresholds on the hindlimbs of adult cats varied as a function of stimulus location and orientation, as they do in humans. A statistical model of the excitatory low threshold mechanoreceptive fields of spinocervical, postsynaptic dorsal column and spinothalamic tract neurons was used to simulate the population receptive field representations in this neural population of the one- and two-point stimuli used in the psychophysical experiments. The simulated and observed thresholds were highly correlated. Simulated and observed thresholds' relations to physiological and anatomical variables such as stimulus location and orientation, receptive field size and shape, map scale, and innervation density were strikingly similar. Simulated and observed threshold variations with receptive field size and map scale obeyed simple relationships predicted by the signal detection model, and were statistically indistinguishable from each other. The population receptive field representation therefore contains information sufficient for this discrimination. PMID:15140641

  4. Dopamine Innervation in the Thalamus: Monkey versus Rat

    PubMed Central

    García-Cabezas, Miguel Ángel; Martínez-Sánchez, Patricia; Sánchez-González, Miguel Ángel; Garzón, Miguel

    2009-01-01

    We recently identified the thalamic dopaminergic system in the human and macaque monkey brains, and, based on earlier reports on the paucity of dopamine in the rat thalamus, hypothesized that this dopaminergic system was particularly developed in primates. Here we test this hypothesis using immunohistochemistry against the dopamine transporter (DAT) in adult macaque and rat brains. The extent and density of DAT-immunoreactive (-ir) axons were remarkably greater in the macaque dorsal thalamus, where the mediodorsal association nucleus and the ventral motor nuclei held the densest immunolabeling. In contrast, sparse DAT immunolabeling was present in the rat dorsal thalamus; it was mainly located in the mediodorsal, paraventricular, ventral medial, and ventral lateral nuclei. The reticular nucleus, zona incerta, and lateral habenular nucleus held numerous DAT-ir axons in both species. Ultrastructural analysis in the macaque mediodorsal nucleus revealed that thalamic interneurons are a main postsynaptic target of DAT-ir axons; this suggests that the marked expansion of the dopamine innervation in the primate in comparison to the rodent thalamus may be related to the presence of a sizable interneuron population in primates. We remark that it is important to be aware of brain species differences when using animal models of human brain disease. PMID:18550594

  5. Anatomical study on the innervation of the elbow capsule☆

    PubMed Central

    Cavalheiro, Cristina Schmitt; Filho, Mauro Razuk; Rozas, João; Wey, João; de Andrade, Antonio Marcos; Caetano, Edie Benedito

    2015-01-01

    Objectives To put forward an anatomical description of the innervation of the elbow capsule, illustrated through morphological analysis on dissections. Methods Thirty elbows from fresh fixed adult cadavers aged 32–74 years, of both sexes, were dissected. Results Among the dissected arms, we observed that the median nerve did not have any branches in two arms, while it had one branch in five arms, two branches in two arms, three branches in ten arms, four branches in nine arms and five branches in two arms. The radial nerve did not have any branches in two arms, while it had one branch in two arms, two branches in nine arms, three branches in ten arms, four branches in five arms and five branches in two arms. The ulnar nerve did not have any branches in three arms, while it had one branch in six arms, two branches in four arms, three branches in five arms, four branches in seven arms, five branches in four arms and six branches in one arm. Conclusions We observed branches of the radial, ulnar and medial nerves in the elbow joint, and a close relationship between their capsular and motor branches. PMID:27218079

  6. Excitatory and inhibitory enteric innervation of horse lower esophageal sphincter.

    PubMed

    Chiocchetti, R; Giancola, F; Mazzoni, M; Sorteni, C; Romagnoli, N; Pietra, M

    2015-06-01

    The lower esophageal sphincter (LES) is a specialized, thickened muscle region with a high resting tone mediated by myogenic and neurogenic mechanisms. During swallowing or belching, the LES undergoes strong inhibitory innervation. In the horse, the LES seems to be organized as a "one-way" structure, enabling only the oral-anal progression of food. We characterized the esophageal and gastric pericardial inhibitory and excitatory intramural neurons immunoreactive (IR) for the enzymes neuronal nitric oxide synthase (nNOS) and choline acetyltransferase. Large percentages of myenteric plexus (MP) and submucosal (SMP) plexus nNOS-IR neurons were observed in the esophagus (72 ± 9 and 69 ± 8 %, respectively) and stomach (57 ± 17 and 45 ± 3 %, respectively). In the esophagus, cholinergic MP and SMP neurons were 29 ± 14 and 65 ± 24 vs. 36 ± 8 and 38 ± 20 % in the stomach, respectively. The high percentage of nitrergic inhibitory motor neurons observed in the caudal esophagus reinforces the role of the enteric nervous system in the horse LES relaxation. These findings might allow an evaluation of whether selective groups of enteric neurons are involved in horse neurological disorders such as megaesophagus, equine dysautonomia, and white lethal foal syndrome. PMID:25578519

  7. Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells

    PubMed Central

    Bohórquez, Diego V.; Shahid, Rafiq A.; Erdmann, Alan; Kreger, Alex M.; Wang, Yu; Calakos, Nicole; Wang, Fan; Liddle, Rodger A.

    2015-01-01

    Satiety and other core physiological functions are modulated by sensory signals arising from the surface of the gut. Luminal nutrients and bacteria stimulate epithelial biosensors called enteroendocrine cells. Despite being electrically excitable, enteroendocrine cells are generally thought to communicate indirectly with nerves through hormone secretion and not through direct cell-nerve contact. However, we recently uncovered in intestinal enteroendocrine cells a cytoplasmic process that we named neuropod. Here, we determined that neuropods provide a direct connection between enteroendocrine cells and neurons innervating the small intestine and colon. Using cell-specific transgenic mice to study neural circuits, we found that enteroendocrine cells have the necessary elements for neurotransmission, including expression of genes that encode pre-, post-, and transsynaptic proteins. This neuroepithelial circuit was reconstituted in vitro by coculturing single enteroendocrine cells with sensory neurons. We used a monosynaptic rabies virus to define the circuit’s functional connectivity in vivo and determined that delivery of this neurotropic virus into the colon lumen resulted in the infection of mucosal nerves through enteroendocrine cells. This neuroepithelial circuit can serve as both a sensory conduit for food and gut microbes to interact with the nervous system and a portal for viruses to enter the enteric and central nervous systems. PMID:25555217

  8. Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells.

    PubMed

    Bohórquez, Diego V; Shahid, Rafiq A; Erdmann, Alan; Kreger, Alex M; Wang, Yu; Calakos, Nicole; Wang, Fan; Liddle, Rodger A

    2015-02-01

    Satiety and other core physiological functions are modulated by sensory signals arising from the surface of the gut. Luminal nutrients and bacteria stimulate epithelial biosensors called enteroendocrine cells. Despite being electrically excitable, enteroendocrine cells are generally thought to communicate indirectly with nerves through hormone secretion and not through direct cell-nerve contact. However, we recently uncovered in intestinal enteroendocrine cells a cytoplasmic process that we named neuropod. Here, we determined that neuropods provide a direct connection between enteroendocrine cells and neurons innervating the small intestine and colon. Using cell-specific transgenic mice to study neural circuits, we found that enteroendocrine cells have the necessary elements for neurotransmission, including expression of genes that encode pre-, post-, and transsynaptic proteins. This neuroepithelial circuit was reconstituted in vitro by coculturing single enteroendocrine cells with sensory neurons. We used a monosynaptic rabies virus to define the circuit's functional connectivity in vivo and determined that delivery of this neurotropic virus into the colon lumen resulted in the infection of mucosal nerves through enteroendocrine cells. This neuroepithelial circuit can serve as both a sensory conduit for food and gut microbes to interact with the nervous system and a portal for viruses to enter the enteric and central nervous systems. PMID:25555217

  9. Role of GPR55 during Axon Growth and Target Innervation.

    PubMed

    Cherif, Hosni; Argaw, Anteneh; Cécyre, Bruno; Bouchard, Alex; Gagnon, Jonathan; Javadi, Pasha; Desgent, Sébastien; Mackie, Ken; Bouchard, Jean-François

    2015-01-01

    Guidance molecules regulate the navigation of retinal ganglion cell (RGC) projections toward targets in the visual thalamus. In this study, we demonstrate that the G-protein-coupled receptor 55 (GPR55) is expressed in the retina during development, and regulates growth cone (GC) morphology and axon growth. In vitro, neurons obtained from gpr55 knock-out (gpr55(-/-) ) mouse embryos have smaller GCs, less GC filopodia, and have a decreased outgrowth compared with gpr55(+/+) neurons. When gpr55(+/+) neurons were treated with GPR55 agonists, lysophosphatidylinositol (LPI) and O-1602, we observed a chemo-attractive effect and an increase in GC size and filopodia number. In contrast, cannabidiol (CBD) decreased the GC size and filopodia number inducing chemo-repulsion. In absence of the receptor (gpr55(-/-) ), no pharmacologic effects of the GPR55 ligands were observed. In vivo, compared to their wild-type (WT) littermates, gpr55(-/-) mice revealed a decreased branching in the dorsal terminal nucleus (DTN) and a lower level of eye-specific segregation of retinal projections in the superior colliculus (SC) and in the dorsal lateral geniculate nucleus (dLGN). Moreover, a single intraocular injection of LPI increased branching in the DTN, whereas treatment with CBD, an antagonist of GPR55, decreased it. These results indicate that GPR55 modulates the growth rate and the targets innervation of retinal projections and highlight, for the first time, an important role of GPR55 in axon refinement during development. PMID:26730399

  10. Role of GPR55 during Axon Growth and Target Innervation

    PubMed Central

    Cherif, Hosni; Argaw, Anteneh; Cécyre, Bruno; Bouchard, Alex; Gagnon, Jonathan; Javadi, Pasha; Desgent, Sébastien; Mackie, Ken

    2015-01-01

    Abstract Guidance molecules regulate the navigation of retinal ganglion cell (RGC) projections toward targets in the visual thalamus. In this study, we demonstrate that the G-protein-coupled receptor 55 (GPR55) is expressed in the retina during development, and regulates growth cone (GC) morphology and axon growth. In vitro, neurons obtained from gpr55 knock-out (gpr55-/-) mouse embryos have smaller GCs, less GC filopodia, and have a decreased outgrowth compared with gpr55+/+ neurons. When gpr55+/+ neurons were treated with GPR55 agonists, lysophosphatidylinositol (LPI) and O-1602, we observed a chemo-attractive effect and an increase in GC size and filopodia number. In contrast, cannabidiol (CBD) decreased the GC size and filopodia number inducing chemo-repulsion. In absence of the receptor (gpr55-/-), no pharmacologic effects of the GPR55 ligands were observed. In vivo, compared to their wild-type (WT) littermates, gpr55-/- mice revealed a decreased branching in the dorsal terminal nucleus (DTN) and a lower level of eye-specific segregation of retinal projections in the superior colliculus (SC) and in the dorsal lateral geniculate nucleus (dLGN). Moreover, a single intraocular injection of LPI increased branching in the DTN, whereas treatment with CBD, an antagonist of GPR55, decreased it. These results indicate that GPR55 modulates the growth rate and the targets innervation of retinal projections and highlight, for the first time, an important role of GPR55 in axon refinement during development. PMID:26730399

  11. Sympathetic neural signaling via the β2-adrenergic receptor suppresses T-cell receptor-mediated human and mouse CD8(+) T-cell effector function.

    PubMed

    Estrada, Leonardo D; Ağaç, Didem; Farrar, J David

    2016-08-01

    Postganglionic sympathetic neurons innervate secondary lymphoid organs and secrete norepinephrine (NE) as the primary neurotransmitter. NE binds and signals through five distinct members of the adrenergic receptor family. In this study, we show elevated expression of the β2-adrenergic receptor (ADRB2) on primary human CD8(+) effector memory T cells. Treatment of both human and murine CD8(+) T cells with NE decreased IFN-γ and TNF-α secretion and suppressed their cytolytic capacity in response to T-cell receptor (TCR) activation. The effects of NE were specifically reversed by β2-specific antagonists. Adrb2(-/-) CD8(+) T cells were completely resistant to the effects of NE. Further, the ADRB2-specific pharmacological ligand, albuterol, significantly suppressed effector functions in both human and mouse CD8(+) T cells. While both TCR activation and stimulation with IL-12 + IL-18 were able to induce inflammatory cytokine secretion, NE failed to suppress IFN-γ secretion in response to IL-12 + IL18. Finally, the long-acting ADRB2-specific agonist, salmeterol, markedly reduced the cytokine secretion capacity of CD8(+) T cells in response to infection with vesicular stomatitis virus. This study reveals a novel intrinsic role for ADRB2 signaling in CD8(+) T-cell function and underscores the novel role this pathway plays in adaptive T-cell responses to infection. PMID:27222010

  12. Adrenergic metabolic and hemodynamic effects of octopamine in the liver.

    PubMed

    de Oliveira, Andrea Luiza; de Paula, Mariana Nascimento; Comar, Jurandir Fernando; Vilela, Vanessa Rodrigues; Peralta, Rosane Marina; Bracht, Adelar

    2013-01-01

    The fruit extracts of Citrus aurantium (bitter orange) are traditionally used as weight-loss products and as appetite suppressants. A component of these extracts is octopamine, which is an adrenergic agent. Weight-loss and adrenergic actions are always related to metabolic changes and this work was designed to investigate a possible action of octopamine on liver metabolism. The isolated perfused rat liver was used to measure catabolic and anabolic pathways and hemodynamics. Octopamine increased glycogenolysis, glycolysis, oxygen uptake, gluconeogenesis and the portal perfusion pressure. Octopamine also accelerated the oxidation of exogenous fatty acids (octanoate and oleate), as revealed by the increase in ¹⁴CO₂ production derived from ¹⁴C labeled precursors. The changes in glycogenolysis, oxygen uptake and perfusion pressure were almost completely abolished by α₁-adrenergic antagonists. The same changes were partly sensitive to the β-adrenergic antagonist propranolol. It can be concluded that octopamine accelerates both catabolic and anabolic processes in the liver via adrenergic stimulation. Acceleration of oxygen uptake under substrate-free perfusion conditions also means acceleration of the oxidation of endogenous fatty acids, which are derived from lipolysis. All these effects are compatible with an overall stimulating effect of octopamine on metabolism, which is compatible with its reported weight-loss effects in experimental animals. PMID:24196353

  13. 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.

  14. Adrenergic Metabolic and Hemodynamic Effects of Octopamine in the Liver

    PubMed Central

    de Oliveira, Andrea Luiza; de Paula, Mariana Nascimento; Comar, Jurandir Fernando; Vilela, Vanessa Rodrigues; Peralta, Rosane Marina; Bracht, Adelar

    2013-01-01

    The fruit extracts of Citrus aurantium (bitter orange) are traditionally used as weight-loss products and as appetite suppressants. A component of these extracts is octopamine, which is an adrenergic agent. Weight-loss and adrenergic actions are always related to metabolic changes and this work was designed to investigate a possible action of octopamine on liver metabolism. The isolated perfused rat liver was used to measure catabolic and anabolic pathways and hemodynamics. Octopamine increased glycogenolysis, glycolysis, oxygen uptake, gluconeogenesis and the portal perfusion pressure. Octopamine also accelerated the oxidation of exogenous fatty acids (octanoate and oleate), as revealed by the increase in 14CO2 production derived from 14C labeled precursors. The changes in glycogenolysis, oxygen uptake and perfusion pressure were almost completely abolished by α1-adrenergic antagonists. The same changes were partly sensitive to the β-adrenergic antagonist propranolol. It can be concluded that octopamine accelerates both catabolic and anabolic processes in the liver via adrenergic stimulation. Acceleration of oxygen uptake under substrate-free perfusion conditions also means acceleration of the oxidation of endogenous fatty acids, which are derived from lipolysis. All these effects are compatible with an overall stimulating effect of octopamine on metabolism, which is compatible with its reported weight-loss effects in experimental animals. PMID:24196353

  15. Immunohistochemical evidence for preserved innervation of the human cervix during pregnancy.

    PubMed

    Bryman, I; Norström, A; Dahlström, A; Lindblom, B

    1987-01-01

    Morphological evidence for a denervation of the human myometrium during pregnancy has previously been demonstrated. In the present study the innervation of the human cervix has been investigated in nonpregnant, early pregnant and term pregnant women. An indirect immunofluorescence method, using an antiserum to the Schwann cell specific S-100 protein, was applied to document the distribution of nerve fibers in cervical tissue biopsies. In nonpregnant, as well as in pregnant women, the cervix was by far more densely innervated than the rest of the uterus. No obvious difference in nerve density was observed between nonpregnant, early pregnant and term pregnant women, and still during labor the innervation appeared morphologically preserved. It is suggested that the segmental difference in innervation of the human uterus (corpus versus cervix) may have specific importance for myometrial and cervical contractility during pregnancy and parturition. PMID:3653786

  16. Correlation between automated writing movements and striatal dopaminergic innervation in patients with Wilson's disease.

    PubMed

    Hermann, Wieland; Eggers, Birk; Barthel, Henryk; Clark, Daniel; Villmann, Thomas; Hesse, Swen; Grahmann, Friedrich; Kühn, Hans-Jürgen; Sabri, Osama; Wagner, Armin

    2002-08-01

    Handwriting defects are an early sign of motor impairment in patients with Wilson's disease. The basal ganglia being the primary site of copper accumulation in the brain suggests a correlation with lesions in the nigrostiatal dopaminergic system. We have analysed and correlated striatal dopaminergic innervation using [(123)I]beta-CIT-SPECT and automated handwriting movements in 37 patients with Wilson's disease. There was a significant correlation of putaminal dopaminergic innervation with fine motor ability (p < 0,05 for NIV [number of inversion in velocity], NIA [number of inversion in acceleration], frequency). These data suggest that loss of dorsolateral striatal dopaminergic innervation has a pathophysiological function for decreased automated motor control in Wilson's disease. Furthermore analysis of automated handwriting movements could be useful for therapy monitoring and evaluation of striatal dopaminergic innervation. PMID:12195459

  17. Cardiac rehabilitation

    MedlinePlus

    ... 123-210. Thomas PD. Exercise-Based, Comprehensive Cardiac Rehabilitation. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine . 9th ed. Philadelphia, PA: Saunders Elsevier; 2011: ...

  18. Cardiac rehabilitation

    MedlinePlus

    ... goal of cardiac rehab is to: Improve your cardiovascular function Improve your overall health and quality of ... E, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine . 10th ed. Philadelphia, PA: Elsevier Saunders; 2015: ...

  19. Cardiac arrest

    MedlinePlus

    ... treatment for cardiac arrest. It is a medical device that gives an electrical shock to the heart. The shock can get the heart beating normally again. Small, portable defibrillators are often available in public areas for ...

  20. Cardiac amyloidosis

    MedlinePlus

    ... the way electrical signals move through the heart (conduction system). This can lead to abnormal heart beats ( ... due to medication) Sick sinus syndrome Symptomatic cardiac conduction system disease (arrhythmias related to abnormal conduction of ...

  1. Cardiac Sarcoidosis

    MedlinePlus

    ... is Cardiac Sarcoidosis? Sarcoidosis is a poorly understood disease that commonly affects the lungs. It can also involve the lymph nodes, liver, spleen, eyes, skin, bones, salivary glands and heart. ...

  2. Human myometrial adrenergic receptors during pregnancy: identification of the alpha-adrenergic receptor by (/sup 3/H) dihydroergocryptine binding

    SciTech Connect

    Jacobs, M.M.; Hayashida, D.; Roberts, J.M.

    1985-07-15

    The radioactive alpha-adrenergic antagonist (/sup 3/H) dihydroergocryptine binds to particulate preparations of term pregnant human myometrium in a manner compatible with binding to the alpha-adrenergic receptor (alpha-receptor). (/sup 3/H) Dihydroergocryptine binds with high affinity (KD = 2 nmol/L and low capacity (receptor concentration = 100 fmol/mg of protein). Adrenergic agonists compete for (/sup 3/H) dihydroergocryptine binding sites stereo-selectively ((-)-norepinephrine is 100 times as potent as (+)-norepinephrine) and in a manner compatible with alpha-adrenergic potencies (epinephrine approximately equal to norepinephrine much greater than isoproterenol). Studies in which prazosin, an alpha 1-antagonist, and yohimbine, and alpha 2-antagonist, competed for (/sup 3/H) dihydroergocryptine binding sites in human myometrium indicated that approximately 70% are alpha 2-receptors and that 30% are alpha 1-receptors. (/sup 3/H) dihydroergocryptine binding to human myometrial membrane particulate provides an important tool with which to study the molecular mechanisms of uterine alpha-adrenergic response.

  3. β-Adrenergic Receptor Signaling in Prostate Cancer

    PubMed Central

    Braadland, Peder Rustøen; Ramberg, Håkon; Grytli, Helene Hartvedt; Taskén, Kristin Austlid

    2015-01-01

    Enhanced sympathetic signaling, often associated with obesity and chronic stress, is increasingly acknowledged as a contributor to cancer aggressiveness. In prostate cancer, intact sympathetic nerves are critical for tumor formation, and sympathectomy induces apoptosis and blocks tumor growth. Perineural invasion, involving enrichment of intra-prostatic nerves, is frequently observed in prostate cancer and is associated with poor prognosis. β2-adrenergic receptor (ADRB2), the most abundant receptor for sympathetic signals in prostate luminal cells, has been shown to regulate trans-differentiation of cancer cells to neuroendocrine-like cells and to affect apoptosis, angiogenesis, epithelial–mesenchymal transition, migration, and metastasis. Epidemiologic studies have shown that use of β-blockers, inhibiting β-adrenergic receptor activity, is associated with reduced prostate cancer-specific mortality. In this review, we aim to present an overview on how β-adrenergic receptor and its downstream signaling cascade influence the development of aggressive prostate cancer, primarily through regulating neuroendocrine differentiation. PMID:25629002

  4. Elements toward novel therapeutic targeting of the adrenergic system.

    PubMed

    Ghanemi, Abdelaziz; Hu, Xintian

    2015-02-01

    Adrenergic receptors belong to the family of the G protein coupled receptors that represent important targets in the modern pharmacotherapies. Studies on different physiological and pathophysiological properties of the adrenergic system have led to novel evidences and theories that suggest novel possible targeting of such system in a variety of pathologies and disorders, even beyond the classical known therapeutic possibilities. Herein, those advances have been illustrated with selected concepts and different examples. Furthermore, we illustrated the applications and the therapeutic implications that such findings and advances might have in the contexts of experimental pharmacology, therapeutics and clinic. We hope that the content of this work will guide researches devoted to the adrenergic aspects that combine neurosciences with pharmacology. PMID:25481798

  5. Primate gastric circulation: effects of catecholamines and adrenergic blockade.

    PubMed

    Zinner, M J; Kerr, J C; Reynolds, D G

    1976-02-01

    The effects of intra-arterial injections and infusions of epinephrine, norepinephrine, and isoproterenol on gastric blood flow were studied in anesthetized baboons. Blood flow was measured electromagnetically before and after adrenergic blockade. The results for injected epinephrine and norepinephrine indicate these agents to be pure vasoconstrictors in the primate gastric circulation, and this response is attenuated by alpha-adrenergic blockade with phenoxybenzamine. Isoproterenol is a pure vasodilator, and its response is attenuated following beta-adrenergic blockade with propranolol. Intra-arterial infusions of epinephrine and norepinephrine (.05 mug kg-1 min-1) resulted in sustained vasoconstriction with no evidence of autoregulatory escape and no postinfusion "over-shoot." This study suggests that epinephrine and norepinephrine might provide alternatives to vasopressin as a vasoconstrictor for the control of upper gastrointestinal bleeding. PMID:1259012

  6. Autoradiographic quantification of adrenergic receptors in rat kidney

    SciTech Connect

    Calianos, T. II; Muntz, K.H. )

    1990-07-01

    The adrenergic nervous system is active in kidney function, and the kidney has large numbers of adrenergic receptor subtypes. Because of the cellular complexity of the kidney, it is difficult to obtain direct assessments of adrenergic receptor binding characteristics over specific tissue compartments. Qualitative autoradiography allows the localization of adrenergic receptors over tissue types in the kidney, but quantitative autoradiography allows direct comparison of adrenergic receptor number over different cellular compartments. The purpose of this study was to obtain direct assessments of alpha 1, alpha 2, and beta adrenergic receptor numbers over different tissue compartments of the kidney using quantitative autoradiography. Sections of Sprague-Dawley rat kidney were incubated in several concentrations of 3H-dihydroalprenolol to label beta receptors, 3H-prazosin to label alpha 1 receptors and 3H-rauwolscine to label the alpha 2 receptors. Sections of rat heart incubated in 3H-dihydroalprenolol were included as standards. The sections were then prepared for receptor autoradiography. After processing, the grains were then quantified on an image analysis system, and binding curves constructed from the specific binding. In some animals, the proximal tubules were stained to localize the proximal convoluted tubules. Significant Scatchard analyses were obtained in the glomeruli with dihydroalprenolol (5.18 X 10(9) receptors/mm3) and with rauwolscine (2.48 X 10(9) receptors/mm3). Significant Scatchard analyses were obtained in the cortex with rauwolscine (9.47 X 10(9) receptors/mm3) and with prazosin (3.9 X 10(9)). In addition, specific binding was seen with rauwolscine and prazosin to the kidney arterioles.

  7. Vagal postganglionic innervation of the canine sinoatrial node.

    PubMed

    Randall, W C; Ardell, J L; Wurster, R D; Milosavljevic, M

    1987-07-01

    Differential, selective distribution of parasympathetic, postganglionic innervation to the atrioventricular nodal (AVN) region of the canine heart was recently described. Ablation of parasympathetic pathways to the AVN by disruption of the epicardial fat pad at the junction of the inferior vena cava and inferior left atrium did not interfere with normal vagal control of the sinoatrial node (SAN) function. In sharp contrast, surgical dissection of the fat pad overlying the right pulmonary vein-left atrial junction interrupted the major right and left vagal inputs to the SAN region. The pulmonary vein fat pad (PVFP) in the dog heart is triangular in shape with roughly equilateral dimensions of approximately 1 cm, its base extending from superior to inferior veins, and its apex extending nearly to the sinus nodal artery as it courses rostrally in the sulcus terminalis. Careful dissection of smaller fat pads around the circumference of the pulmonary veins and particularly over the rostral-dorsal surfaces of the right superior pulmonary vein and adjacent right atrium, completed SAN parasympathetic denervation. Care in making these dissections left the vagal supply to the AVN region essentially intact, and preserved the sympathetic supplies to both SAN and AVN regions. Autonomic ganglia, varying in size from 1 or 2 cells to 80-100 cells, were found scattered throughout the ventral PVFP (overlying and surrounding the right pulmonary vein-left atrial junction). The ganglia were generally imbedded in fatty connective tissue, although they commonly rested very close to, or were loosely surrounded by epicardial muscle. Ganglia were also found in smaller fat pads on the dorsal surfaces of the atrium between the azygos and the right superior pulmonary vein. PMID:3655182

  8. Nitrergic innervation of trigeminal and hypoglossal motoneurons in the cat.

    PubMed

    Pose, Ines; Fung, Simon; Sampogna, Sharon; Chase, Michael H; Morales, Francisco R

    2005-04-11

    The present study was undertaken to determine the location of trigeminal and hypoglossal premotor neurons that express neuronal nitric oxide synthase (nNOS) in the cat. Cholera toxin subunit b (CTb) was injected into the trigeminal (mV) or the hypoglossal (mXII) motor nuclei in order to label the corresponding premotor neurons. CTb immunocytochemistry was combined with NADPH-d histochemistry or nNOS immunocytochemistry to identify premotor nitrergic (NADPH-d(+)/CTb(+) or nNOS(+)/ CTb(+) double-labeled) neurons. Premotor trigeminal as well as premotor hypoglossal neurons were located in the ventro-medial medullary reticular formation in a region corresponding to the nucleus magnocellularis (Mc) and the ventral aspect of the nucleus reticularis gigantocellularis (NRGc). Following the injection of CTb into the mV, this region was found to contain a total of 60 +/- 15 double-labeled neurons on the ipsilateral side and 33 +/- 14 on the contralateral side. CTb injections into the mXII resulted in 40 +/- 17 double-labeled neurons in this region on the ipsilateral side and 16 +/- 5 on the contralateral side. Thus, we conclude that premotor trigeminal and premotor hypoglossal nitrergic cells coexist in the same medullary region. They are colocalized with a larger population of nitrergic cells (7200 +/- 23). Premotor neurons in other locations did not express nNOS. The present data demonstrate that a population of neurons within the Mc and the NRGc are the source of the nitrergic innervation of trigeminal and hypoglossal motoneurons. Based on the characteristics of nitric oxide actions and its diffusibility, we postulate that these neurons may serve to synchronize the activity of mV and mXII motoneurons. PMID:15804497

  9. Innervation pattern of a pool of nine excitatory motor neurons in the flexor tibiae muscle of a locust hind leg

    PubMed

    Sasaki; Burrows

    1998-05-21

    The flexor tibiae muscle of a locust hind leg consists of 10-11 pairs of fibre bundles in the main body of the muscle and a distal pair of bundles that form the accessory flexor muscle, all of which insert onto a common tendon. It is much smaller than the antagonistic extensor tibiae muscle and yet it is innervated by nine excitatory motor neurons, compared with only two for the extensor. To determine the pattern of innervation within the muscle by individual motor neurons, branches of the nerve (N5B2) that supplies the different muscle bundles were backfilled to reveal somata in the metathoracic ganglion. This showed that different muscle bundles are innervated by different numbers of excitatory motor neurons. Physiological mapping of the innervation was then carried out by intracellular recordings from the somata of flexor motor neurons in the metathoracic ganglion using microelectrodes. Spikes were evoked in these neurons by the injection of current, and matching junctional potentials were sought in fibres throughout the muscle using a second intracellular electrode. Each motor neuron innervates only a restricted array of muscle fibres and, although some innervate a larger array than others, none innervates fibres throughout the muscle. Some motor neurons innervate only proximal fibres and others only more distal fibres, so that the most proximal and most distal bundles of muscle fibres are innervated by non-overlapping sets of motor neurons. More motor neurons innervate proximal bundles than distal ones, and there are some asymmetries in the number of motor neurons innervating corresponding bundles on either side of the tendon. Individual motor neurons cause slow, fast or intermediate movements of the tibia, but their patterns of innervation overlap in the different muscle bundles. Furthermore, individual muscle fibres may also be innervated by motor neurons with different properties. PMID:9600870

  10. Characterization of the Human Platelet α-Adrenergic Receptor

    PubMed Central

    Alexander, R. Wayne; Cooper, Barry; Handin, Robert I.

    1978-01-01

    Human platelets aggregate and undergo a release reaction when incubated with catecholamines. Indirect evidence indicates that these events are mediated through α-adrenergic receptors. We used [3H]dihydroergocryptine, an α-adrenergic antagonist, to identify binding sites on platelets that have the characteristics of α-adrenergic receptors. Catecholamines compete for the binding sites in a stereo-specific manner with the potency series of (−) epinephrine > (−) norepinephrine > (±) phenylephrine > (−) isoproterenol. The dissociation constant (Kd) of (−) epinephrine is 0.34 μM. Binding is saturable using a platelet particulate fraction but not with intact platelets. There are 0.130 pmol binding sites per milligram protein in fresh platelet membranes. This number represents approximately 100 binding sites per platelet. The Kd for [3H]-dihydroergocryptine was 0.003−0.01 μM. The α-adrenergic antagonist phentolamine (Kd = 0.0069 μM) was much more potent than the β-adrenergic antagonist (±) propranolol (Kd = 27 μM) in competing for the binding sites. The binding data were correlated with catecholamine-induced platelet aggregation and inhibition of basal and prostaglandin E1-stimulated adenylate cyclase. (−) Epinephrine was more potent than (−) norepinephrine in producing aggregation whereas (−) isoproterenol was ineffective. The threshold dose for inducing aggregation by (−) epinephrine was 0.46 μM. Phentolamine and dihydroergocyrptine blocked this response, whereas (±) propranolol had no effect. (−) Epinephrine and (−) norepinephrine inhibited basal and prostaglandin E1-stimulated adenylate cyclase in a dose-related manner. The concentration of (−) epinephrine inhibiting adenylate cyclase 50% was 0.7 μM. This inhibition was also blocked by phentolamine and dihydroergocryptine but not by (±) propranolol. The specificity of binding and the close correlation with α-adrenergic receptor-mediated biochemical and physiological responses