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1 Pharmacology and Human Physiology, University of Bari - Medical School, Bari, Italy
2 Diabetes Unit, NCCAM, National Institutes of Health, Bethesda, MD, USA
* To whom correspondence should be addressed. E-mail: monica{at}farmacol.uniba.it.
Insulin stimulates production of NO in vascular endothelium via activation of PI 3-kinase, Akt, and eNOS. We hypothesized that insulin resistance may cause imbalance between endothelial vasodilators and vasoconstrictors (e.g., NO and ET-1) leading to hypertension. 12-wk old male SHR were hypertensive and insulin resistant when compared with control WKY rats (systolic BP = 202 ± 11 vs. 132 ± 10 mmHg; fasting plasma insulin = 5 ± 1 vs. 0.9 ± 0.1 ng/ml; p < 0.001). In WKY rats, insulin stimulated dose-dependent relaxation of mesenteric arteries pre-contracted with norepinephrine (NE) ex vivo. This depended on intact endothelium, and was blocked by genistein, wortmannin, or L-NAME (inhibitors of tyrosine kinase, PI 3-kinase, and NO synthases, respectively). Vasodilation in response to insulin (but not acetylcholine) was impaired by 20% in SHR (vs. WKY, p < 0.005). Pre-incubation of arteries with insulin significantly reduced the contractile effect of NE by 20% in WKY but not SHR rats. In SHR, the effect of insulin to reduce NE-mediated vasoconstriction became evident when insulin pre-treatment was accompanied by ET-1 receptor blockade (BQ-123, BQ-788). Similar results were observed during treatment with the MEK inhibitor PD-98059. In addition, insulin-stimulated secretion of ET-1 from primary endothelial cells was significantly reduced by pre-treatment of cells with PD-98059 (but not wortmannin). We conclude that insulin resistance in SHR is accompanied by endothelial dysfunction in mesenteric vessels with impaired PI 3-kinase-dependent NO production and enhanced MAPK-dependent ET-1 secretion. These results may reflect pathophysiology in other vascular beds that directly contribute to elevated peripheral vascular resistance and hypertension.
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