Modulation of Endothelin-1 Effects on Rat Hearts and Cardiomyocytes by Nitric Oxide and 8-Bromo cyclic GMP

Endothelin-1 (ET-1) has been demonstrated to produce numerous cardiac effects and increased production of the peptide has been shown in cardiac disease states. Although the cardiac effects of ET-1 have been examined extensively on its own, few studies have reported potential cross-talk between ET-1 with other endothelium-derived factors. We examined whether nitric oxide (NO) can modulate the effects of ET-1 on isolated rat hearts or ventricular myocytes. At 0.05 n , ET-1 produced no effects on either systolic or diastolic function although a two-fold increase in left ventricular end-diastolic pressure (LVEDP) was observed in hearts pretreated with 10μ of the NO synthase inhibitor L-NAME. Higher concentrations of ET-1 (0.5 and 5 n ) produced a direct elevation in LVEDP which was enhanced by L-NAME and totally blocked by the NO donor S-nitrosoacetylpenicillamine (SNAP, 10μ ) although responses to 5 n ET-1 were highly variable with no significant differences between treatment groups. SNAP totally prevented ventricular fibrillation produced by either 0.05 or 0.5 n ET-1 whereas the pro-fibrillatory actions of 5 n ET-1 were unaffected. In cardiac myocytes, SNAP significantly attenuated the elevation in intracellular Ca2 +produced by ET-1 (5 n ). The positive inotropic actions of ET-1 on either hearts or myocytes were unaffected by any treatment. The protective effect of SNAP against ET-1 in both isolated hearts (reduction in LVEDP and incidence of fibrillation) as well as ventricular myocytes (attenuation of the elevation in intracellular Ca2 +) was mimicked by 8-bromo-cyclic GMP (50μ ). Our study suggests that NO protects against the cardiotoxic effects of ET-1, possibly via inhibition of intracellular Ca2 +elevations, a property shared by cGMP, the likely mediator of the biological effects of NO.