Impaired endothelium-mediated relaxation in coronary arteries from insulin-resistant rats

The insulin resistance syndrome is associated with atherosclerosis and card iovascular events; however, the underlying mechanism of vascular dysfunctio n is unknown. The purpose of the current study was to assess endothelium- a nd smooth-muscle-mediated vasodilation in isolated coronary arteries from i nsulin-resistant rats and to determine whether insulin resistance alters th e activity of the specific endothelium-derived relaxing factors. Methods: M ale Sprague-Dawley rats were randomized to insulin resistance or control. I nsulin resistance was induced by a fructose-rich diet. After 4 weeks of die t, coronary arteries were removed and vascular function was assessed in vit ro using videomicroscopy. Acetylcholine (10(-9)-3 x 10(-5) M)- or sodium-ni troprusside (10(-9)-3 x 10(-4) M)-induced relaxations were determined. To e valuate the role of the specific endothelium-derived relaxing factors, seve ral inhibitors were used, including N-nitro-L-arginine (LNNA), charybdotoxi n/apamin (CTX/apamin), and indomethacin. Results: Studies with nitroprussid e showed that smooth-muscle-dependent relaxation did not differ between ins ulin resistance and control groups. In contrast, maximal relaxation (E-max) to acetylchotine was decreased in the insulin resistance group (56 +/- 7%) versus control (93 +/- 3%). LNNA pretreatment further impaired E-max in th e IR group from 56 +/- 7 to 17 +/- 2% (p < 0.01). In control, E-max was onl y slightly impaired by LNNA (93 +/- 3 to 63 +/- 6%; p < 0.05). The addition of CTX/apamin also decreased relaxation in the control group (93 +/- 3 to 47 +/- 7%; p < 0.05), whereas relaxation in insulin-resistant rats was not affected (45 +/- 5% with CTX/apamin vs. 56 +/- 7% with acetylcholine alone, NS). Pretreatment with indomethacin did not affect relaxation in either gr oup, while pretreatment with the combination of LNNA and CTX/apamin complet ely abolished relaxation in both groups. Conclusions: Endothelium-dependent relaxation is impaired in small coronary arteries from insulin-resistant r ats. The mechanism of this defect is related to a decrease in an endotheliu m-dependent, nitric oxide/prostanoid-independent relaxing factor or endothe lium-derived hyperpolarizing factor. Copyright (C) 1999 S. Karger AG. Basel .