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CARDIOVASCULAR

A Nonthiazolidinedione Peroxisome Proliferator-Activated Receptor Agonist Reverses Endothelial Dysfunction in Diabetic (db/db^-/-) Mice

Smooth Muscle Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (A.G.H., W.B.W., M.P., Y.J., D.S., T.J.A., C.R.T.); and Department of Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey (J.P.B.)

We have previously reported that endothelium-dependent relaxation to acetylcholine is impaired in small mesenteric arteries from spontaneously diabetic (db/db) mice. The objective of the present study was to examine the effects of treatment of the db/db and the insulin-resistant ob/ob mice with the PPAR agonist 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (COOH). In the db/db model, an 8-week treatment with COOH (30 mg/kg/day) reduced plasma glucose from 48.0 ± 2.5 (untreated) to 12.6 ± 1.1 mM. In contrast, plasma glucose was not elevated in untreated ob/ob mice. Relaxation of small mesenteric arteries mediated by acetylcholine was impaired in the untreated db/db diabetic mice (51.7 ± 7.4% maximal relaxation, n = 6) but not in the ob/ob mice (70.8 ± 8.6% maximal relaxation, n = 3). This impairment was reversed with COOH treatment (86.9 ± 0.4% maximal relaxation, n = 5). Malondialdehyde was elevated in plasma from diabetic db/db mice (13.9 ± 1.1 versus 12.0 ± 0.7 µmol/ml); however, when normalized to total cholesterol, no significant differences in the ratio of lipid peroxidation in plasma were identified. Western blot analysis and quantitative polymerase chain reaction for eNOS was performed on the isolated mesenteric vessels and revealed no differences in the relative levels of eNOS expression in diabetic and control animals; in addition, treatment with COOH had no significant effect on eNOS levels in either group. In summary, endothelial dysfunction and hyperglycemia were completely normalized in COOH-treated db/db mice. In contrast, nonhyperglycemic ob/ob mice exhibited normal vasodilatory responses to acetylcholine and, consequently, COOH treatment had no effect on endothelial function.

Address correspondence to: Dr. Andrew G. Howarth, Rm. 82A, HMRB, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada, T2N 4N1. E-mail: aghowart{at}ucalgary.ca

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