ACUTE EFFECTS OF NITRIC-OXIDE AND CYCLIC-GMP ON HUMAN MYOCARDIAL-CONTRACTILITY

Evidence that the activity of nitric oxide synthase and the generation of nitric oxide (NO) within the myocardium are enhanced in several ca rdiovascular disorders is increasing. Findings whether NO exerts a dir ect effect on cardiac contractility are contradictory. Therefore, the direct effect of the NO donor sodium nitroprusside (SNP) on isometric force of contraction of human atrial and ventricular myocardium was in vestigated, and the question was addressed whether the effects of NO o n cardiac contractility are mediated via cGMP. Experiments were perfor med on isolated electrically driven (1 Hz, 37 degrees C) human right a trial trabecula and left ventricular papillary muscle preparations fro m nonfailing and terminally failing hearts. SNP led to a concentration -dependent decrease of force of contraction (FOC) with a maximum effec t at 100 mu mol/l. In atrial trabecula, SNP (100 mu mol/l) caused an a cute decrease in basal FOC as well as in FOC after application of isop renaline or IBMX by 12.5 +/- 5% (P < .05), 16.6 +/- 3.7% (P < .05) and 18.3 +/- 4.2% (P < .05), respectively. The negative inotropic effects could be attenuated by the guanylyl cyclase inhibitor methylene blue. In papillary muscle preparations, NO release caused a maximum decreas e in basal and in isoprenaline-enhanced FOC of 11.0 +/- 1.9% (P < .05) and 23.6 +/- 1.5% (P < .05), respectively. In the presence of isopren aline, the reduction of FOC was less pronounced in failing than in non failing papillary muscles, 8-bromo-cGMP caused a 38.2 +/- 5.2% decreas e in atrial trabecula contractility. Both SNP and 8-bromo-cGMP caused a shortening of the contractile twitch with a premature onset of relax ation. As determined by radioimmunoassay, exposure of atrial trabecula to SNP (100 mu mol) led to a 6-fold increase in myocardial cGMP conce ntrations, which could be attenuated by methylene blue. In conclusion, NO exerts a negative inotropic effect on human atrial and ventricular myocardium which seems to be mediated via generation of cGMP. The rel ease of NO within the myocardium in a variety of cardiovascular disord ers might explain decreases in cardiac contractility. The control of N O release could be an important target for future therapeutical interv entions in these pathological conditions.