Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 58; no. 2; pp. H813 - H822
• Main Authors: POTENZA, Maria A, MARASCIULO, Flora L, CHIEPPA, Delia Mitolo, BRIGIANI, Giovanni Siro, FORMOSO, Gloria, QUON, Michael J, MONTAGNANI, Monica
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Physiological Society 01.08.2005
• Subjects: Biological and medical sciences; Enzymes; Fundamental and applied biological sciences. Psychology; Hypertension; Insulin; Nitric oxide; Rodents; Vertebrates: cardiovascular system; Hypertension; Rat; Rodentia; Cardiovascular disease; Endothelin 1; Endothelium; Vertebrata; Mammalia; Dysfunction; Nitric oxide; Insulin resistance; Circulatory system; endothelin-1
• ISSN: 0363-6135; 1522-1539

Insulin stimulates production of NO in vascular endothelium via activation of phosphatidylinositol (PI) 3-kinase, Akt, and endothelial NO synthase. We hypothesized that insulin resistance may cause imbalance between endothelial vasodilators and vasoconstrictors (e.g., NO and ET-1), leading to hypertension. Twelve-week-old male spontaneously hypertensive rats (SHR) were hypertensive and insulin resistant compared with control Wistar-Kyoto (WKY) rats (systolic blood pressure 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 precontracted with norepinephrine (NE) ex vivo. This depended on intact endothelium and was blocked by genistein, wortmannin, or N{omega}-nitro-L-arginine methyl ester (inhibitors of tyrosine kinase, PI3-kinase, and NO synthases, respectively). Vasodilation in response to insulin (but not ACh) was impaired by 20% in SHR (vs. WKY, P < 0.005). Preincubation 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 pretreatment 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 pretreatment 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 PI3-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. [PUBLICATION ABSTRACT]