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 endogenous NO-production in the isolated normal rat heart has an effect on myocardial contractility. Hearts of male Wistar rats were investigated using a constant flow perfused non-paced Langendorff preparation. Changes of contractile parameters such as left ventricular peak pressure, dP/dt(max) and dP/dt(min), and of coronary perfusion pressure and heart rate were recorded after infusion of the NO-synthase inhibitors N omega-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 inhibitor of soluble guanylate cyclase 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-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 presence of an equimolar concentration of L-arginine. ODQ reduced contractile force and coronary perfusion pressure in parallel. By contrast, L-arginine and DEA/NO improved the contractile force of the left ventricle and DEA/NO decreased coronary perfusion pressure. Heart rate was reduced 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 contraction that is mediated by activation of guanylate cyclase. In addition, NO might be involved in regulation of heart rate. (C) 1997 Elsevier Science B.V.