NITRIC-OXIDE AND PROSTACYCLIN INFLUENCE CORONARY VASOMOTOR TONE IN PERFUSED RABBIT HEART AND MODULATE ENDOTHELIN-1 ACTIVITY

Using isolated perfused rabbit heart electrically paced, we assessed t he relevance of both nitric oxide (NO) and prostacyclin (PGI2) in regu lation of resting coronary perfusion pressure (CPP). In preparations i n which NO-synthase was inhibited by N-monomethyl-L-arginine (L-NMMA, 10 muM), resting CPP increased significantly; this phenomenon was pote ntiated by indomethacin infusion (3 muM), prevented by L-arginine (100 muM) and significantly reduced by iloprost (55 nM) and defibrotide (2 00 mug/ml). Furthermore, the increase in resting CPP induced by graded doses of endothelin-1 (ET-1 0.6-160 pmol), was further augmented by b locking of prostaglandin biosynthesis with indomethacin (3 muM) and wa s substantially reduced when the rate of formation of PGI2 was enhance d by defibrotide (200 mug/ml). Moreover, the coronary vasoconstriction induced by ET-1 (2, 4, and 8 pmol) was increased in hearts in which N O-synthase was blocked by L-NMMA (10 muM) and this event was abolished in preparations in which PGI2 synthesis was stimulated by defibrotide (200 mug/ml). These results further emphasize that rabbit coronary ve ssels are continuously dilated by NO released from endothelial cells. They also indicate that PGI2 takes part in NO generation in the endoth elial-derived relaxing mechanism. Inactivation of this mechanism, owin g to decreased formation of NO and PGI2 in rabbit heart, induces hyper reactivity of coronary smooth muscles to ET-1. Finally, an increase in PGI2 production (such as that caused by defibrotide) may counterbalan ce impaired NO generation and attenuate hyperreactivity of the coronar y vasculature.