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 growth factor I (IGF-I) attenuate endothelin-induced contraction of porcine coronary epicardial arteries in vitro.


BACKGROUND
Endothelin-induced 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 artery smooth muscle.


METHODS
Epicardial arteries harvested from juvenile pigs were contracted with cumulative concentrations of endothelin-1 (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, endothelin-1 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 relative to the response to 60 mM KCl.


RESULTS
The maximal contractions to endothelin-1 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 (at 10(-7)-10(-6) M) and IGF-I (at 10(-6.5)-10(-6) M) attenuated the contraction to endothelin-1 in vessels with intact endothelium, as well as in vessels without endothelium (at 10(-7) and 10(-6) M for insulin and 10(-7.5)-10(-6) M for IGF-I). The maximal contractions to sarafotoxin-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 and IGF-I did not affect the response to sarafotoxin-6c in vessels with and without endothelium.


CONCLUSIONS
Insulin and IGF-I attenuated ETA-receptor-mediated coronary contraction through an endothelium-independent mechanism. The IGF axis may serve as an endogenous modulator of endothelin-mediated vasoconstriction.
Hasdai
D
D
Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA.
Holmes
D R
DR
Richardson
D M
DM
Izhar
U
U
Lerman
A
A
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology*
D019332:Endothelin-1; D007328:Insulin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D007334:Insulin-Like Growth Factor I; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid