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 the relevance of both nitric oxide (NO) and prostacyclin (PGI2) in regulation of resting coronary perfusion pressure (CPP). In preparations in which NO-synthase was inhibited by NG-monomethyl-L-arginine (L-NMMA, 10 microM), resting CPP increased significantly; this phenomenon was potentiated by indomethacin infusion (3 microM), prevented by L-arginine (100 microM) and significantly reduced by iloprost (55 nM) and defibrotide (200 micrograms/ml). Furthermore, the increase in resting CPP induced by graded doses of endothelin-1 (ET-1 0.6-160 pmol), was further augmented by blocking of prostaglandin biosynthesis with indomethacin (3 microM) and was substantially reduced when the rate of formation of PGI2 was enhanced by defibrotide (200 micrograms/ml). Moreover, the coronary vasoconstriction induced by ET-1 (2, 4, and 8 pmol) was increased in hearts in which NO-synthase was blocked by L-NMMA (10 microM) and this event was abolished in preparations in which PGI2 synthesis was stimulated by defibrotide (200 micrograms/ml). These results further emphasize that rabbit coronary vessels are continuously dilated by NO released from endothelial cells. They also indicate that PGI2 takes part in NO generation in the endothelial-derived relaxing mechanism. Inactivation of this mechanism, owing to decreased formation of NO and PGI2 in rabbit heart, induces hyperreactivity of coronary smooth muscles to ET-1. Finally, an increase in PGI2 production (such as that caused by defibrotide) may counterbalance impaired NO generation and attenuate hyperreactivity of the coronary vasculature.
Berti
F
F
Department of Pharmacology, Chemotherapy, and Medical Toxicology, University of Milan, Italy.
Rossoni
G
G
Della Bella
D
D
Villa
L M
LM
Buschi
A
A
Trento
F
F
Berti
M
M
Tondo
C
C
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels / Q000502:physiology; D016232:Endothelins / Q000502:physiology*; D011464:Epoprostenol / Q000502:physiology*; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009129:Muscle Tonus / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011089:Polydeoxyribonucleotides / Q000494:pharmacology; D011817:Rabbits; D019323:omega-N-Methylarginine
D016232:Endothelins; D010975:Platelet Aggregation Inhibitors; D011089:Polydeoxyribonucleotides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C036901:defibrotide; D001120:Arginine; D011464:Epoprostenol; D007213:Indomethacin