Original Article 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 Maria A. Potenza, 1 Flora L. Marasciulo, 1 Mariela Tarquinio, 1 Michael J. Quon, 2 and Monica Montagnani 1 Spontaneously hypertensive rats (SHRs) exhibit endothe- lial dysfunction and insulin resistance. Reciprocal relation- ships between endothelial dysfunction and insulin resistance may contribute to hypertension by causing im- balanced 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 simulta- neously improve hypertension, insulin resistance, and en- dothelial 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 ele- vated 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 re- duced 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– de- pendent 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 dysfunc- tion and insulin resistance that may be relevant for devel- oping novel therapeutic strategies for the metabolic syndrome. Diabetes 55:3594 –3603, 2006 V ascular endothelium contributes importantly to regulation of cardiovascular and metabolic ho- meostasis (1,2). Reciprocal relationships be- tween endothelial dysfunction and insulin resistance may help couple hemodynamic and metabolic abnormalities observed in important interrelated public health problems, including diabetes, obesity, hyperten- sion, coronary heart disease, atherosclerosis, and the metabolic syndrome (3,4). In addition to its essential metabolic actions, insulin also has important endothelial- dependent vasodilator actions mediated by nitric oxide (NO) via phosphatidylinositol 3-kinase (PI 3-kinase)– de- pendent activation of endothelial NO synthase (5–9). These vasodilator actions of insulin contribute signifi- cantly to metabolic actions of insulin by increasing deliv- ery of substrate and insulin to metabolic target tissues (10). Interestingly, insulin also has vasoconstrictor actions mediated by mitogen-activated protein kinase (MAPK)- dependent endothelial secretion of endothelin-1 (ET-1) (11–13). Insulin resistance is characterized by selective impairment in PI 3-kinase– dependent signaling pathways regulating metabolic actions of insulin in skeletal muscle (with intact MAPK signaling pathways) (14). In vascular endothelium, a similar selective impairment of PI 3-kinase pathways (with intact MAPK pathways) may contribute to endothelial dysfunction (13,15). Insulin resistance is ac- companied by compensatory hyperinsulinemia that serves to overcome impairment in PI 3-kinase signaling to main- tain euglycemia. However, this hyperinsulinemia is pre- dicted to overdrive unaffected MAPK signaling that may promote pathological actions of insulin, including in- creased secretion of ET-1 (13,16), increased expression of vascular adhesion molecules (15,17–19), proliferation of vascular smooth muscle (20), increased expression of proinflammatory cytokines (21), and activation of cation pumps (22). These factors may shift the balance between vasodilator and vasoconstrictor actions of insulin and result in predisposition to hypertension in insulin-resistant states. From the 1 Department of Pharmacology and Human Physiology, Medical School, University of Bari, Bari, Italy; and the 2 Diabetes Unit, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland. Address correspondence and reprint requests to Monica Montagnani, MD, PhD, Department of Pharmacology and Human Physiology, Section of Phar- macology, Medical School, University of Bari, Policlinico-Piazza G. Cesare, 11, 70124 Bari, Italy. E-mail: monica@farmacol.uniba.it. Received for publication 15 May 2006 and accepted in revised form 25 August 2006. ACh, acetylcholine; ARB, angiotensin II type 1 receptor blocker; ET-1, endothelin-1; MAPK, mitogen-activated protein kinase; MEK, MAP/extracellu- lar signal–related kinase kinase; MVB, mesenteric vascular bed; NE, norepi- nephrine; PI 3-kinase, phosphatidylinositol 3-kinase; SBP, systolic blood pressure; SHR, spontaneously hypertensive rat. DOI: 10.2337/db06-0667 © 2006 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 3594 DIABETES, VOL. 55, DECEMBER 2006