INHIBITION OF NITRIC-OXIDE SYNTHASE AND SOLUBLE GUANYLATE-CYCLASE INDUCES CARDIODEPRESSIVE EFFECTS IN NORMAL RAT HEARTS

Exogenous nitric oxide (NO) has been shown to modulate the contractile force of rat cardiac myocytes. We sought to determine whether endogen ous NO-production in the isolated normal rat heart has an effect on my ocardial contractility. Hearts of male Wistar rats were investigated u sing a constant flow perfused non-paced Langendorff preparation. Chang es of contractile parameters such as left ventricular peak pressure, d P/dt(max) and dP/dt(min), and of coronary perfusion pressure and heart rate were recorded after infusion of the NO-synthase inhibitors N ome ga-nitro-L-arginine (L-NOARG, 0.1 mM, 1.0 mM, n = 6), N omega-methyl-L -arginine (L-NMMA, 0.1 mM, 1.0 mM, n = 9) and methylene blue (2 mu M, 20 mu M, n = 6), the NO-donor sodium (Z)-1-(N,N-diethylamino)diazen-1- ium-1,2-diolat (DEA/NO, 0.01 mu M, 0.1 mu M, n = 12), the specific inh ibitor of soluble guanylate cyclase 1H-[1,2,4]oxadiazolo[4,3-a]quinoxa lin-1-one (ODQ, 0.1 mu M, n = 7) and L-arginine (0.1 mM, 1.0 mM, n = 6 ). All NO-synthase inhibitors reduced the contractile function of the ventricular muscle before changes in coronary perfusion pressure were evident. The negative inotropic effect of L-NMMA was absent in the pre sence of an equimolar concentration of L-arginine. ODQ reduced contrac tile force and coronary perfusion pressure in parallel. By contrast, L -arginine and DEA/NO improved the contractile force of the left ventri cle and DEA/NO decreased coronary perfusion pressure. Heart rate was r educed by L-NOARG (1 mM) and methylene blue (20 mu M), while DEA/NO (0 .1 mu M) and L-arginine (1 mM) had a positive chronotropic effect. All these changes were significant (P < 0.05). These results suggest that endogenous NO-production exerts a positive effect on myocardial contr action that is mediated by activation of guanylate cyclase. In additio n, NO might be involved in regulation of heart rate. (C) 1997 Elsevier Science B.V.