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 2005-08, Vol.289 (2), p.H813-H822
• Main Authors: Potenza, Maria A, Marasciulo, Flora L, Chieppa, Delia Mitolo, Brigiani, Giovanni Siro, Formoso, Gloria, Quon, Michael J, Montagnani, Monica
• Format: Article
• Language: English
• Subjects: Animals; Endothelin-1 - biosynthesis; Endothelin-1 - metabolism; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiopathology; Hypertension - genetics; Hypertension - metabolism; Hypertension - physiopathology; In Vitro Techniques; Insulin - pharmacology; Insulin Resistance; Male; Mesenteric Arteries - drug effects; Mesenteric Arteries - physiopathology; Mesenteric Veins - drug effects; Mesenteric Veins - physiopathology; Mitogen-Activated Protein Kinases - metabolism; Nitric Oxide - biosynthesis; Norepinephrine - pharmacology; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasoconstriction - drug effects; Vasoconstrictor Agents - metabolism; Vasoconstrictor Agents - pharmacology; Vasodilator Agents - metabolism; Vasodilator Agents - pharmacology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00092.2005

1 Department of Pharmacology and Human Physiology, University of Bari Medical School, Bari, Italy; and 2 Diabetes Unit, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland Submitted 31 January 2005 ; accepted in final form 18 March 2005 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 -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. hypertension; endothelin-1; nitric oxide Address for reprint requests and other correspondence: M. Montagnani, Dept. of Pharmacology and Human Physiology, Section of Pharmacology, Univ. of Bari Medical School, Policlinico, Piazza G. Cesare 11, 70124 Bari, Italy (E-mail: monica{at}farmacol.uniba.it )