INSULIN AND IGF-I ATTENUATE THE CORONARY VASOCONSTRICTOR EFFECTS OF ENDOTHELIN-1 BUT NOT OF SARAFOTOXIN 6C

Objective: To examine the hypothesis that insulin and insulin-like gro wth factor I(IGF-I) attenuate endothelin-induced contraction of porcin e coronary epicardial arteries in vitro. Background: Endothelin-induce d coronary vasoconstriction is mediated by two types of receptors, A ( ETA) and B (ETB), resulting in calcium influx. Both insulin and IGF-I attenuate endothelin-induced calcium influx into porcine coronary arte ry smooth muscle. Methods: Epicardial arteries harvested from juvenile pigs were contracted with cumulative concentrations of endothelin-l ( ETA- and ETB-receptor agonist; 10(-10)-10(-6) M) or of sarafotoxin-6c (ETB-receptor agonist; 10(-11)-10(-7) M). In additional experiments, e ndothelin-l or sarafotoxin-6c were added after incubation with 10(-8) M regular insulin or IGF-I. These experiments were repeated in vessels without endothelium. Contraction for each vessel was calculated relat ive to the response to 60 mM KCI. Results: The maximal contractions to endothelin-l in vessels with and without endothelium were 158+/-8 and 200+/-21%, respectively (p<0.05 at 10(-8.5)-10(-6.5) M). Both insulin (ae 10(-7)-10(-6) M) and IGF-I (at 10(-6.5)-10(-6) M) attenuated the contraction to endothelin-l in vessels with intact endothelium, as wel l as in vessels without endothelium (at 10(-7) and 10(-6) M for insuli n and 10(-7.5)-10(-6) M for IGF-I). The maximal contractions to sarafo toxin-6c in vessels with and without endothelium were 54+/-13 and 84+/ -7%, respectively (p<0.05 at 10(-9), 10(-8.5) and 10(-7) M). Insulin a nd IGF-I did not affect the response to sarafotoxin-6c in vessels with and without endothelium. Conclusion: Insulin and IGF-I attenuated ETA -receptor-mediated coronary contraction through an endothelium-indepen dent mechanism. The IGF axis may serve as an endogenous modulator of e ndothelin-mediated vasoconstriction. (C) 1998 Elsevier Science B.V. Al l rights reserved.