Objective: The insulin resistance syndrome is associated with atherosclerosis and cardiovascular events; however, the underlying mechanism of vascular dysfunction is unknown. The purpose of the current study was to assess endothelium- and smooth-muscle-mediated vasodilation in isolated coronary arteries from insulin-resistant rats and to determine whether insulin resistance alters the activity of the specific endothelium-derived relaxing factors. Methods: Male Sprague-Dawley rats were randomized to insulin resistance or control. Insulin resistance was induced by a fructose-rich diet. After 4 weeks of diet, coronary arteries were removed and vascular function was assessed in vitro using videomicroscopy. Acetylcholine (10–9–3 × 10–5 M)- or sodium-nitroprusside (10–9–3 × 10–4 M)-induced relaxations were determined. To evaluate the role of the specific endothelium-derived relaxing factors, several inhibitors were used, including N-nitro-L-arginine (LNNA), charybdotoxin/apamin (CTX/apamin), and indomethacin. Results: Studies with nitroprusside showed that smooth-muscle-dependent relaxation did not differ between insulin resistance and control groups. In contrast, maximal relaxation (Emax) to acetylcholine was decreased in the insulin resistance group (56 ± 7%) versus control (93 ± 3%). LNNA pretreatment further impaired Emax in the IR group from 56 ± 7 to 17 ± 2% (p < 0.01). In control, Emax was only 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 group, while pretreatment with the combination of LNNA and CTX/ apamin completely abolished relaxation in both groups. Conclusions: Endothelium-dependent relaxation is impaired in small coronary arteries from insulin-resistant rats. The mechanism of this defect is related to a decrease in an endothelium-dependent, nitric oxide/prostanoid-independent relaxing factor or endothelium-derived hyperpolarizing factor.

Keywords:
Coronary arteries, Insulin resistance, Endothelium-mediated relaxation, Endothelium-derived hyperpolarizing factor
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© 1999 S. Karger AG, Basel
1999
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