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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM037948-02
Application #
3293831
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1987-07-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Ravindra, R; Aronstam, R S (1993) Effect of colchicine and taxol on stimulation of G protein GTPase activity in anterior pituitary lobe of rats by gonadotrophin- and thyrotrophin-releasing hormones. J Reprod Fertil 97:27-33
Martin, D C; Pruett, J K; Aronstam, R S (1993) Test-tube equilibration of volatile anaesthetic concentrations. Br J Anaesth 70:365-7
Ravindra, R; Aronstam, R S (1992) Stimulation of the release of [32P]guanosine 5'-diphosphate from G proteins in the rat anterior pituitary lobe by gonadotrophin-releasing and thyrotrophin-releasing hormones. J Reprod Fertil 95:669-77
Ravindra, R; Aronstam, R S (1992) Progesterone, testosterone and estradiol-17 beta inhibit gonadotropin-releasing hormone stimulation of G protein GTPase activity in plasma membranes from rat anterior pituitary lobe. Acta Endocrinol (Copenh) 126:345-9
Swanson, K L; Albuquerque, E X (1992) Progress in understanding the nicotinic acetylcholine receptor function at central and peripheral nervous system synapses through toxin interactions. Md Med J 41:623-31
Martin, D C; Dennison, R L; Introna, R P et al. (1991) Influence of halothane on the interactions of serotonin1A and adenosine A1 receptors with G proteins in rat brain membranes. Biochem Pharmacol 42:1313-6
Swanson, K L; Aronstam, R S; Wonnacott, S et al. (1991) Nicotinic pharmacology of anatoxin analogs. I. Side chain structure-activity relationships at peripheral agonist and noncompetitive antagonist sites. J Pharmacol Exp Ther 259:377-86
Ravindra, R; Aronstam, R S (1991) Colchicine inhibits acetylcholine receptor stimulation of G protein GTPase activity in rat striatum. Pharmacol Toxicol 69:259-62
Martin, D C; Abraham, J E; Plagenhoef, M et al. (1991) Volatile anesthetics and NMDA receptors. Enflurane inhibition of glutamate-stimulated [3H]MK-801 binding and reversal by glycine. Neurosci Lett 132:73-6
Ravindra, R; Aronstam, R S (1991) Acetylcholine stimulates GTP binding to G proteins in rat striatum. Neuroreport 2:127-30

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