Treatment of spontaneously hypertensive rats with rosiglitazone and/or enalapril restores balance between vasodilator and vasoconstrictor actions of insulin with simultaneous improvement in hypertension and insulin resistance.
Spontaneously hypertensive rats (SHRs) exhibit endothelial dysfunction and insulin resistance. Reciprocal relationships between endothelial dysfunction and insulin resistance may contribute to hypertension by causing imbalanced regulation of endothelial-derived vasodilators (e.g., nitric oxide) and vasoconstrictors (e.g., endothelin-1 [ET-1]). Treatment of SHRs with rosiglitazone (insulin sensitizer) and/or enalapril (ACE inhibitor) may simultaneously improve hypertension, insulin resistance, and endothelial dysfunction by rebalancing insulin-stimulated production of vasoactive mediators. When compared with WKY control rats, 12-week-old vehicle-treated SHRs were hypertensive, overweight, and insulin resistant, with elevated fasting levels of insulin and ET-1 and reduced serum adiponectin levels. In mesenteric vascular beds (MVBs) isolated from vehicle-treated SHRs and preconstricted with norepinephrine (NE) ex vivo, vasodilator responses to insulin were significantly impaired, whereas the ability of insulin to oppose vasoconstrictor actions of NE was absent (versus WKY controls). Three-week treatment of SHRs with rosiglitazone and/or enalapril significantly reduced blood pressure, insulin resistance, fasting insulin, and ET-1 levels and increased adiponectin levels to values comparable with those observed in vehicle-treated WKY controls. By restoring phosphatidylinositol 3-kinase-dependent effects, rosiglitazone and/or enalapril therapy of SHRs also significantly improved vasodilator responses to insulin in MVB preconstricted with NE ex vivo. Taken together, our data provide strong support for the existence of reciprocal relationships between endothelial dysfunction and insulin resistance that may be relevant for developing novel therapeutic strategies for the metabolic syndrome.
Potenza
Maria A
MA
Department of Pharmacology and Human Physiology, Section of Pharmacology, Medical School, University of Bari, Policlinico-Piazza G. Cesare 11, 70124 Bari, Italy.
Marasciulo
Flora L
FL
Tarquinio
Mariela
M
Quon
Michael J
MJ
Montagnani
Monica
M
D052242:Adiponectin / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D004656:Enalapril / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy*; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D051381:Rats; D011918:Rats, Inbred SHR; D012016:Reference Values; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D052242:Adiponectin; D001786:Blood Glucose; D007328:Insulin; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D004656:Enalapril