MYOCARDIAL CONTRACTILE RESPONSE TO NITRIC-OXIDE AND CGMP

Background Cardiac endothelium releases a number of factors that may m odulate performance of underlying cardiac muscle. Nitric oxide (NO), w hich accounts for the biological activity of the vascular endothelium- derived relaxing factor and relaxes vascular smooth muscle by elevatin g intracellular cGMP, may be involved in this cardiac modulation. Meth ods and Results We examined the myocardial contractile effects of the NO-releasing nitrovasodilators sodium nitroprusside (SNP), 3-morpholin o-sydnonimine (SIN-1), and S-nitroso-N-acetyl-penicillamine (SNAP); of a cGMP analogue, 8-bromo-cGMP; and of the cGMP-phosphodiesterase inhi bitor zaprinast in isolated cat papillary muscle. Modulation of these effects by endocardial endothelium (EE) and by cholinergic and adrener gic stimulation was also investigated. Concentration-response curves w ith addition of NO-releasing nitrovasodilators (SNP, SIN-1, SNAP) and 8-bromo-cGMP resulted in a biphasic inotropic response. Although admin istration of low concentrations induced a positive inotropic effect, h igher concentrations induced a negative inotropic effect. Both NO-indu ced positive and negative inotropic effects were attenuated by methyle ne blue, suggesting a role for cGMP. The response to high concentratio ns of 8-bromo-cGMP was shifted to the right in muscles with damaged EE , whereas cholinergic stimulation shifted the curve leftward. Zaprinas t caused a monophasic concentration-dependent positive inotropic effec t; damaging the EE shifted the terminal portion of the curve upward. C oncomitant cholinergic or adrenergic stimulation modified the response to zaprinast into a negative inotropic response. Conclusions NO and c GMP induced a concentration-dependent biphasic contractile response. T he myocardial contractile effects of NO and cGMP were modulated by the status of EE and by concomitant cholinergic or adrenergic stimulation .