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Muscarinic Agonists (muscarinic + agonist)
Selected AbstractsReal-time measurement of serotonin release and motility in guinea pig ileumTHE JOURNAL OF PHYSIOLOGY, Issue 2 2006Paul P. Bertrand Enterochromaffin (EC) cells are sensors that detect chemical or mechanical stimuli and respond with release of serotonin (5-HT). 5-HT activates local motor reflexes, but whether local motor reflexes also evoke 5-HT release is unknown. The aim of the present study was to establish the relationship between the release of 5-HT and the enteric neural circuits controlling the movements of the intestine. Recordings were made from full-thickness preparations of guinea pig ileum using electrochemical techniques with carbon fibre electrodes to measure local concentrations of 5-HT. The tension in the circular muscle (CM) and longitudinal muscle (LM) was recorded with force transducers. The release of 5-HT from the EC cells was detected selectively and the timing of the events quantified. Pressure-evoked peristalsis caused detectable 5-HT release only when the recording site was invaded by a ring of CM contraction. Spontaneous and stretch-evoked reflex contraction of the CM and LM occurred simultaneously with 5-HT release. Paralysis of the smooth muscle significantly reduced the stretch-evoked release. Muscarinic agonists evoked reflexes that were associated with increases in tension in CM and LM simultaneous with 5-HT release. Tetrodotoxin abolished the coordination between the CM contraction and 5-HT release but not the direct activation of the CM and EC cells by the agonists. In conclusion, the correlation between local motor reflexes and 5-HT release observed in the present study is caused primarily by the contraction of the smooth muscle and subsequent deformation of the mucosa. The EC cell is, thus, a site of convergence for mechanical forces that contribute to the release of 5-HT during motor reflexes. [source] Membrane Hyperpolarization Is Not Required for Sustained Muscarinic Agonist-Induced Increases in Intracellular Ca2+ in Arteriolar Endothelial CellsMICROCIRCULATION, Issue 2 2005KENNETH D. COHEN ABSTRACT Objective: Hyperpolarization modulates Ca2+ influx during agonist stimulation in many endothelial cells, but the effects of hyperpolarization on Ca2+ influx in freshly isolated arteriolar endothelial cells are unknown. Therefore, the purpose of the present study was to characterize agonist-induced Ca2+ transients in freshly isolated arteriolar endothelial cells and to test the hypothesis that membrane hyperpolarization augments agonist-induced Ca2+ influx into these cells. Methods: Arterioles were removed from hamster cremaster muscles and arteriolar endothelial cells were enzymatically isolated. Endothelial cells were loaded with Fura 2-AM and the Fura 2 ratio measured photometrically as an index of intracellular Ca2+. The cells were then stimulated with the muscarinic, cholinergic agonist, methacholine, and the resulting Ca2+ transients were measured. Results: Methacholine (1 , M) increased the endothelial cell Fura 2 ratio from a baseline of 0.81 ± 0.02 to an initial peak of 1.17 ± 0.05 (n = 17) followed by a sustained plateau of 1.12 ± 0.07. The plateau phase of the Ca2+ transient was inhibited by removal of extracellular Ca2+ (n = 12, p < .05), or the nonselective cation channel blockers Gd3+ (30 , M; n = 7, p < .05) or La3+ (50 , M; n = 7, p < .05) without significant effect on the baseline or peak (p > .05). The initial peak of methacholine-induced Ca2+ transients was inhibited by the IP3 -receptor antagonist xestospongin D (10 , M, n = 5, p < .05). The methacholine-induced Ca2+ transients were accompanied by endothelial cell hyperpolarization of approximately 14,18 mV, as assessed by experiments using the potentiometric dye, di-8-ANEPPS as well as by patch-clamp experiments. However, inhibition of hyperpolarization by blockade of Ca2+ -activated K+ channels with charybdotoxin (100 nM) and apamin (100 nM) (n = 5), or exposure of endothelial cells to 80 or 145 mM KCl (both n = 7) had no effect on the plateau phase of methacholine-induced Ca2+ transients (p > .05). Conclusions: Freshly isolated arteriolar endothelial cells display agonist-induced Ca2+ transients. For the muscarinic agonist, methacholine, these Ca2+ transients result from release of Ca2+ from intracellular stores through IP3 receptors, followed by sustained influx of extracellular Ca2+. While these changes in intracellular Ca2+ are associated with endothelial cell hyperpolarization, the methacholine-induced, sustained increase in intracellular Ca2+ appears to be independent from this change in membrane potential. These data suggest that arteriolar endothelial cells may possess a novel Ca2+ influx pathway, or that the relationship between intracellular Ca2+ and Ca2+ influx is more complex than that observed in other endothelial cells. [source] Adrenergic-Cholinergic Interaction that Modulates Repolarization in the Atrium is Altered with AgingJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 4 2002EUGENE A. SOSUNOV Ph.D. Autonomic Modulation of Atrial Repolarization.Introduction: Aging is associated with involution of both limbs of the autonomic nervous system, and the prejunctional and postjunctional effects of adrenergic and cholinergic stimulation are altered with senescence. Hence, postjunctional age-related changes in adrenergic-cholinergic interaction are a likely occurrence and may contribute to an altered substrate for arrhythmias. Methods and Results: Microelectrode techniques were used to record action potentials from epicardial slices of Bachmann's bundles of dogs aged 3 to 5 years (adult) and 8 to 12 years (old) in the absence or presence of acetylcholine and isoproterenol (separately and in combination). In control, action potential duration to 90% repolarization (APD) was longer in old atria. Acetylcholine (10,8 to 10,5 mol/L) in a concentration-dependent manner hyperpolarized and shortened APD in both tissues, with more prominent effects in the old. The effects of isoproterenol (10,9 to 10,6 mol/L) to elevate the plateau and shorten APD were about the same in both adult and old tissues. In adults, low concentrations of isoproterenol (10,9 and 10,8 mol/L) significantly prolonged APD, which had been first shortened by acetylcholine. This effect of isoproterenol was decreased in old atrial tissue, resulting in shorter APD in old than adult atria in the combined presence of beta-adrenergic and muscarinic agonists. Conclusion: In adult Bachmann's bundle, beta-adrenergic stimulation effectively operates as a "brake" to decrease the extent of cholinergic-induced APD shortening. The action of beta-adrenergic stimulation to antagonize acetylcholine-induced acceleration of repolarization declines with age, which may contribute to an altered arrhythmogenic substrate. [source] ADAMs family members as amyloid precursor protein ,-secretasesJOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2003Tobias M.J. Allinson Abstract In the non-amyloidogenic pathway, the Alzheimer's amyloid precursor protein (APP) is cleaved within the amyloid-, domain by ,-secretase precluding deposition of intact amyloid-, peptide. The large ectodomain released from the cell surface by the action of ,-secretase has several neuroprotective properties. Studies with protease inhibitors have shown that ,-secretase is a zinc metalloproteinase, and several members of the adamalysin family of proteins, tumour necrosis factor-, convertase (TACE, ADAM17), ADAM10, and ADAM9, all fulfil some of the criteria required of ,-secretase. We review the evidence for each of these ADAMs acting as the ,-secretase. What seems to be emerging from numerous studies, including those with mice in which each of the ADAMs has been knocked out, is that there is a team of zinc metalloproteinases able to cleave APP at the ,-secretase site. We also discuss how upregulation of ,-secretase activity by muscarinic agonists, cholesterol-lowering drugs, steroid hormones, non-steroidal anti-inflammatory drugs, and metal ions may explain some of the therapeutic actions of these agents in Alzheimer's disease. © 2003 Wiley-Liss, Inc. [source] Inhibition of oxotremorine-induced desensitization of guinea-pig ileal longitudinal muscle in Ca2+ -free conditionsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2001Shuhei Horio The aim of this study was to investigate the differences between oxotremorine-induced and acetylcholine (ACh)-induced desensitization, particularly under Ca2+ -free conditions, in guinea-pig ileal longitudinal muscle, and to elucidate the different mechanisms of desensitization that might exist between these two muscarinic agonists. Pretreatment of the tissue with 10,7 , 10,5 M oxotremorine (desensitizing treatment) in normal Tyrode solution caused desensitization of the responses to ACh, as did the desensitizing treatment with ACh. However, Ca2+ -free conditions significantly reduced oxotremorine-induced desensitization, contrary to the previous findings that Ca2+ -free conditions enhanced ACh-induced desensitization. The desensitizing treatment with oxotremorine caused suppression of the responses to high K+ (tonic phase), as did the ACh treatment. Ca2+ -free conditions removed this suppression, whereas this condition enhanced ACh-induced suppression of the K+ response. A protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (10,4 M) had no effect on oxotremorine-induced desensitization of the ACh response. The results suggest that a voltage-gated Ca2+ channel was involved in oxotremorine-induced desensitization, as in ACh-induced desensitization, but that the process of inactivation of Ca2+ channels was different between oxotremorine and ACh, and that oxotremorine-induced desensitization was due not only to Ca2+ channel, but also to other unknown factors. Protein kinase C did not participate in oxotremorine-induced desensitization. [source] Synthesis, structure and muscarinic agonist activity of substituted N -(silatran-1-ylmethyl)acetamidesAPPLIED ORGANOMETALLIC CHEMISTRY, Issue 3 2010Vera G. Pukhalskaya Abstract Substituted N -(silatran-1-ylmethyl)acetamides, N -methyl- N -[1-(3,,7,,10,-trimethylsilatran-1-yl)methyl]acetamide (2a) and N -(2-hydroxyethyl)- N -[1-(3,,7,,10,-trimethylsilatran-1-yl)methyl]acetamide (2b) were prepared by the reactions of triisopropanolamine with N -methyl- N -(trimethoxysilylmethyl)acetamide (1a) and 2,2-dimethoxy-4-acetyl-1-oxa-4-aza-2-silacyclohexane (1b), respectively. According to X-ray data, the structures of the silatrane moieties are superpositions of unsymmetrical and symmetrical stereoisomers. The O , Si coordination between the central atom and exocyclic substituent is absent in both compounds. Silatranes 2a and 2b are partial muscarinic agonists which demonstrate submaximal effect and mimic the effect of acetylcholine by binding directly to cholinoreceptors of the ileal smooth muscle. Copyright © 2009 John Wiley & Sons, Ltd. [source] Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic functionAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2006R. M. Eglen Summary 1 Muscarinic M1,M5 receptors mediate the metabotropic actions of acetylcholine in the nervous system. A growing body of data indicate they also mediate autocrine functions of the molecule. The availability of novel and selective muscarinic agonists and antagonists, as well as in vivo gene disruption techniques, has clarified the roles of muscarinic receptors in mediating both functions of acetylcholine. 2 Selective M1 agonists or mixed M1 agonists/M2 antagonists may provide an approach to the treatment of cognitive disorders, while M3 antagonism, or mixed M2/M3 antagonists, are approved for the treatment of contractility disorders including overactive bladder and chronic obstructive pulmonary disease. Preclinical data suggest that selective agonism of the M4 receptor will provide novel anti-nociceptive agents, while therapeutics-based upon agonism or antagonism of the muscarinic M5 receptor have yet to be reported. 3 The autocrine functions of muscarinic receptors broadly fall into two areas , control of cell growth or proliferation and mediation of the release of chemical mediators from epithelial cells, ultimately causing muscle relaxation. The former particularly are involved in embryological development, oncogenesis, keratinocyte function and immune responsiveness. The latter regulate contractility of smooth muscle in the vasculature, airways and urinary bladder. 4 Most attention has focused on muscarinic M1 or M3 receptors which mediate lymphocyte immunoresponsiveness, cell migration and release of smooth muscle relaxant factors. Muscarinic M4 receptors are implicated in the regulation of keratinocyte adhesion and M2 receptors in stem cell proliferation and development. Little data are available concerning the M5 receptor, partly due to the difficulties in defining the subtype pharmacologically. 5 The autocrine functions of acetylcholine, like those in the nervous system, involve activation of several muscarinic receptor subtypes. Consequently, the role of these subtypes in autocrine, as well neuronal cholinergic systems, significantly expands their importance in physiology and pathophysiology. [source] DESENSITIZATION OF GUINEA-PIG TAENIA CAECI SMOOTH MUSCLE INDUCED BY A LOW CONCENTRATION OF CARBACHOLCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 11 2007Shigeru Hishinuma SUMMARY 1In guinea-pig taenia caeci smooth muscle we have found that 10,4 mol/L carbachol-induced desensitization to muscarinic agonists develops within 15,30 s, followed by transient resensitization at 1 min, whereas the desensitization to depolarizing high K+ develops with maximal desensitization at 1 min followed by sustained resensitization up to 30 min. In both cases, Ca2+ -dependent processes play a crucial role in determining the development of desensitization. 2To elucidate whether these peculiar processes of desensitization/resensitization may be induced by a lower concentration of carbachol, we examined the development of desensitization induced by 10,6 mol/L carbachol, because at this concentration carbachol is known to induce biphasic changes in intracellular Ca2+ concentrations, with a smaller transient increase followed by a larger sustained increase than seen with 10,4 mol/L carbachol. 3Contractile responses to muscarinic agonists (carbachol or AHR-602) and high K+ were desensitized by pretreatment with 10,6 mol/L carbachol for 30 min in a manner dependent on the presence of extracellular Ca2+. 4The development of 10,6 mol/L carbachol-induced desensitization to these muscarinic agonists in the presence of extracellular Ca2+ showed three successive phases: fast desensitization within 30 s, followed by transient resensitization at 1 min and the subsequent development of desensitization up to 30 min. In contrast, desensitization to high K+ did not develop up to 10 min and significant desensitization occurred at 30 min, with no apparent resensitization phase. 5These results suggest that the characteristics of the Ca2+ -dependent development of desensitization to muscarinic agonists, but not to high K+, are well maintained in desensitization induced by a lower concentration of carbachol. [source] | ||||||||||||||||||||||