title: Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production.
abstract: 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.
authors.affiliation: Department of Pharmacology and Human Physiology, Univ. of Bari Medical School, Policlinico, Piazza G. Cesare 11, 70124 Bari, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Potenza
authors.forename: Flora L
authors.initials: FL
authors.lastname: Marasciulo
authors.forename: Delia Mitolo
authors.initials: DM
authors.lastname: Chieppa
authors.forename: Giovanni Siro
authors.initials: GS
authors.lastname: Brigiani
authors.forename: Gloria
authors.initials: G
authors.lastname: Formoso
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Quon
authors.forename: Monica
authors.initials: M
authors.lastname: Montagnani
mesh_terms: D000818:Animals; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D008642:Mesenteric Veins / Q000187:drug effects / Q000503:physiopathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000378:metabolism* / Q000494:pharmacology; D014665:Vasodilator Agents / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D007328:Insulin; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases; D009638:Norepinephrine