Cohen, Pinchas

Abstract —Insulin and insulin-like growth factor (IGF) 1 affect coronary vasoactivity. Experimental hypercholesterolemia is associated with coronary atherogenesis and altered vasomotor regulation. Because the IGF axis is altered during atherogenesis, we postulated that experimental hypercholesterolemia is associated with an altered coronary vasoactive response to IGF-1 in vitro. Coronary arteries and arterioles from pigs fed either a normal or high-cholesterol diet for 10 weeks were contracted with endothelin-1 and relaxed with cumulative concentrations of insulin or IGF-1 (10 −12 to 10 −7 mol/L). Control arterioles were also incubated with the nitric oxide synthase inhibitor 10 −4 mol/L N G -monomethyl- l -arginine (L-NMMA) or the potassium channel blocker 10 −2 mol/L tetraethylammonium (TEA), contracted with endothelin-1, and relaxed with insulin or IGF-1. Experimental hypercholesterolemia (1) increased serum cholesterol (9.5±1.0 versus 1.9±0.08 mmol/L; P <0.0001), (2) caused coronary arterial and arteriolar endothelial dysfunction in vitro (attenuated vasorelaxation to bradykinin), (3) did not alter the epicardial response to either insulin ( P =0.80) or IGF-1 ( P =0.12), and (4) significantly attenuated the arteriolar response to IGF-1 (maximal relaxation of 79±6% versus 42±8%; P =0.01) but not insulin (43±6% versus 53±7%; P =0.99). Control arteriolar vasorelaxation to IGF-1 was attenuated by both L-NMMA ( P <0.001) and TEA ( P =0.01), whereas only L-NMMA attenuated insulin ( P <0.001). Staining for IGF-1 and IGF binding protein 2 was increased ( P <0.05) in arterioles of cholesterol-fed pigs. IGF-1 and insulin are therefore coronary arteriolar vasorelaxants through different mechanisms. Experimental hypercholesterolemia is associated with resistance to the coronary arteriolar vasorelaxing effects of IGF-1 but not insulin, in conjunction with increased ligand and binding-protein expression. The IGF axis may contribute to the altered coronary vasoactivity in hypercholesterolemia.

Abstract—Insulin and insulin-like growth factor-I (IGF-I) may play a role in the modulation of coronary artery tone, yet there are few data regarding their vasoactive effects on the coronary vascular bed. We evaluated the vasorelaxation effects of insulin and IGF-I on porcine coronary epicardial vessels in vitro and elucidated possible mechanisms. Porcine epicardial arteries were contracted with 10−7mol/L endothelin-1 and relaxed with cumulative concentrations of either insulin or IGF-I (10−12to 10−7mol/L). The above experiments were repeated in vessels without endothelium. Vessels were also incubated with the nitric oxide synthase inhibitorNG-monomethyl-l-arginine (L-NMMA; 10−4mol/L) with and without 10−3.5mol/Ll-arginine, the potassium channel blocker tetraethylammonium (TEA; 10−2mol/L), and the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-α]quinoxalin-1-one (ODQ; 10−5.5mol/L); vessels were then contracted with endothelin-1 and relaxed with insulin or IGF-I. Insulin and IGF-I were also added after contraction with 60 mmol/L KCl. Insulin and IGF-I caused a similar decrease in coronary epicardial tension after contraction with endothelin-1 (relaxation of 28±4% [n=7] and 25±3% [n=8] with insulin and IGF-I, respectively;P<0.0001 for both peptides). Removal of the endothelium did not affect these responses. Incubation with L-NMMA, but not ODQ, attenuated the vasorelaxation response to insulin and IGF in vessels without endothelium.l-Arginine did not reverse this effect of L-NMMA. KCl and TEA attenuated the vasorelaxation effect of both insulin and IGF-I. Thus, both insulin and IGF-I caused non–endothelium-dependent coronary vasorelaxation in vitro, probably through a mechanism involving the activation of potassium channels. These findings suggest that insulin and IGF-I participate in the regulation of coronary vasomotor tone.