NG-methyl-L-arginine decreases contractility, cGMP and cAMP in isoproterenol-stimulated rat hearts in vitro.
NG-Methyl-L-arginine (NMA), an inhibitor of nitric oxide synthesis by vascular endothelium, depresses cardiac function and causes systemic vasoconstriction in vivo. The mechanism of cardiac depression is unclear. Since cGMP inhibits one isoform of myocardial phosphodiesterase (PDE), we hypothesized that a decrease in cGMP might increase PDE activity and lower myocardial cAMP levels, resulting in decreased contractility. Experiments were conducted in isolated, paced, Langendorff-perfused (constant flow) rat hearts under control or isoproterenol-stimulated conditions. In non-stimulated hearts, a 15 min infusion of 30 microM NMA had no effect on cAMP content or on left ventricular dP/dt; however, myocardial cGMP content was decreased. Infusion of 0.01 microM isoproterenol caused dP/dt to increase and caused coronary resistance to fall; myocardial cAMP levels increased while cGMP remained unchanged by isoproterenol. In this stimulated condition, infusion of 30 microM NMA decreased dP/dt and myocardial cGMP and cAMP concentrations. NMA caused coronary resistance to increase to similar maximal values in isoproterenol-stimulated and non-stimulated hearts. Although coronary flow was kept constant during NMA administration, NMA depressed cardiac contractility in isoproterenol-stimulated hearts, but not in non-stimulated hearts, and the depressed contractility in isoproterenol-treated hearts was associated with a decrease in myocardial content of cGMP and cAMP. Therefore, these results are consistent with the hypothesis that NMA may decrease myocardial contractility by decreasing cGMP which leads to increased PDE activity and decreased cAMP.
Klabunde
R E
RE
Department of Pharmacology, Abbott Laboratories, Abbott Park, IL 60064.
Kimber
N D
ND
Kuk
J E
JE
Helgren
M C
MC
Förstermann
U
U
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019323:omega-N-Methylarginine
D019323:omega-N-Methylarginine; D001120:Arginine; D000242:Cyclic AMP; D006152:Cyclic GMP; D007545:Isoproterenol