cGMP elevation does not mediate muscarinic agonist-induced negative inotropy in rat ventricular cardiomyocytes.
Guanosine 3',5'-cyclic monophosphate (cGMP) has been suggested to be involved in the negative inotropic effects of muscarinic receptor agonists in beta-adrenergic receptor agonist-stimulated ventricular preparations. To test this hypothesis, changes in contractility induced by acetylcholine or carbachol, or the nitrovasodilator sodium nitroprusside (SNP), in the presence of 1 nM isoproterenol were measured in electrically stimulated rat ventricular cardiomyocytes. In parallel experiments, cardiomyocytes were treated with the same agonists, and cGMP and adenosine 3',5'-cyclic monophosphate (cAMP) levels were estimated. After 2 min, isoproterenol increased the magnitude of cell shortening by 60% and accelerated contraction and relaxation rates. Carbachol (1 and 10 microM) and acetylcholine (1 and 10 microM) inhibited the positive inotropic effects of isoproterenol, whereas SNP (10 and 100 microM) had no inotropic effect. All three agents increased cGMP levels but had no effect on isoproterenol-stimulated cAMP levels. SNP caused the largest elevations in cGMP. These results suggest that the negative inotropic effects of muscarinic agonists observed in isoproterenol-stimulated rat ventricular cardiomyocytes are not mediated by alterations in cGMP and/or cAMP levels.
MacDonell
K L
KL
Faculty of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, University of British Columbia, Vancouver, Canada.
Tibbits
G F
GF
Diamond
J
J
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002469:Cell Separation; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016276:Ventricular Function / Q000187:drug effects*
D018721:Muscarinic Agonists; D009599:Nitroprusside; D002217:Carbachol; D000242:Cyclic AMP; D006152:Cyclic GMP; D007545:Isoproterenol