title: Control of cardiac muscle cell function by an endogenous nitric oxide signaling system.
abstract: Nitric oxide (NO) synthesized from L-arginine is a ubiquitous intracellular chemical messenger and is involved in signal transduction in diverse mammalian cells, including vascular endothelium and neuronal tissues. The role of the NO-signaling pathway in the direct modulation of cardiac function is less well characterized. In this report, the effects of inhibitors of NO synthase (NOS) were examined in isolated neonatal and adult rat ventricular myocytes exposed to either muscarinic or adrenergic agonists. Carbachol (10 microM) caused a 91% inhibition of the spontaneous beating rate of cultured neonatal rat cardiac myocytes. N omega-monomethyl-L-arginine, an L-arginine analog that inhibits NOS, and methylene blue, an inhibitor of NO, blocked the negative chronotropic effect of carbachol but had no effect on the basal beating rate of these cells. The inhibition by N omega-monomethyl-L-arginine of the negative chronotropic effect of carbachol was reversed by adding excess L-arginine. The negative chronotropic effect of carbachol was also mimicked by analogs of cGMP, a second messenger implicated in mediating the action of NO in other cell types. Production of NO could be detected directly in carbachol-stimulated neonatal myocytes by using a reporter cell bioassay. The regulation of adrenergic responsiveness by the NO signaling system was also documented in studies of adult cardiac myocyte contractility. The NOS inhibitor N omega-nitro-L-arginine significantly increased the inotropic effect of the beta-adrenergic agonist isoproterenol on electrically stimulated adult rat ventricular myocytes, whereas this inhibitor had no effect on basal contractility. Inhibition of NO production by N omega-monomethyl-L-arginine in these cells, as measured by reporter cell bioassay, was also reversible with excess L-arginine. Thus, the physiologic response of isolated neonatal and adult ventricular myocytes to both muscarinic cholinergic and beta-adrenergic stimulation is mediated, at least in part, by products of an endogenous NOS.
authors.affiliation: Cardiovascular and Renal Divisions, Brigham and Women's Hospital, Boston, MA.
authors.forename: J L
authors.initials: JL
authors.lastname: Balligand
authors.forename: R A
authors.initials: RA
authors.lastname: Kelly
authors.forename: P A
authors.initials: PA
authors.lastname: Marsden
authors.forename: T W
authors.initials: TW
authors.lastname: Smith
authors.forename: T
authors.initials: T
authors.lastname: Michel
mesh_terms: D000375:Aging / Q000502:physiology; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects*; D006352:Heart Ventricles; D007545:Isoproterenol / Q000494:pharmacology; D008751:Methylene Blue / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase; D010108:Oxyhemoglobins / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D019323:omega-N-Methylarginine
chemical_list: D010108:Oxyhemoglobins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D002217:Carbachol; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D006152:Cyclic GMP; D007545:Isoproterenol; D008751:Methylene Blue