The aim of the proposed research is to understand how volatile anesthetics affect muscarinic acetylcholine receptor function in the heart. All volatile anesthetics have undesirable effects on the cardiovascular system, some of which may be mediated through cholinergic effector mechanisms. We have shown that several anesthetics, including halothane and isoflurane, alter ligand binding to the muscarinic receptor in the heart and central nervous system. In addition, we have recently discovered a novel mechanism by which muscarinic receptor-mediated processes in the brain are inhibited by volatile anesthetics, i.e. by disruption of receptor coupling to guanine nucleotide dependent-transducer proteins. The hypothesis to be tested is: Volatile general anesthetics alter the coupling of muscarinic acetylcholine receptors to effector mechanisms in cardiac membranes, thereby affecting ligand binding to the receptor and regulation of cardiac function by muscarinic agonists. Accordingly, the effects of four volatile anesthetics (halothane, isoflurane, enflurane, cyclopropane) on several muscarinic receptor functions in rat hearts will be determined, including 1) antagonist binding (receptor density, affinity, and thermodynamics) using (3H)methylscopolamine as the probe, 2) agonist binding (affinities and subpopulation distribution) using carbamylcholine and (3H)oxotremorine-M as probes, 3) guanine nucleotide regulation of agonist binding, as an index of receptor-G protein coupling, 4) muscarinic receptor-mediated inhibition of adenylate cyclase activity, and 5) negative chronotropic and inotropic influences of muscarinic agonists on isolated atria. The reversibility of anesthetic actions will be determined after removal of each anesthetic. This research will increase our understanding of muscarinic receptor organization and function in the atrium and provide insight into the molecular bases for anesthetic action on muscarinic processes in the heart.
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