CARDIOPROTECTIVE AND HYPOLIPIDEMIC EFFECTS OF NISOLDIPINE IN THE JCR-LA-CP RAT

The JCR:LA-cp rat exhibits the obesity/insulin resistance/hypertriglyc eridemia syndrome in an extreme form. These normotensive rats spontane ously develop advanced atherosclerosis and ischemic myocardial lesions . The calcium channel antagonist, nisoldipine, was administered to obe se rats of the JCR:LA-cp strain in drinking water at a dose of 1 mg/kg from age 6 weeks. Nisoldipine-treated rats showed no change in food c onsumption or body weight compared with control animals. Plasma glucos e and insulin levels also were unchanged in the nisoldipine-treated ra ts. Insulin-mediated total glucose turnover, an index of insulin sensi tivity as measured by euglycemic insulin clamp, was similarly not impr oved. Serum triglyceride levels in obese male rats were markedly reduc ed (57%; p < 0.001, at age 12 weeks), whereas obese female rats showed no significant change in triglyceride levels and an in crease in este rified cholesterol in response to nisoldipine treatment. The impaired endothelium-dependent (nitric oxide-mediated) vascular relaxation of t he male cp/cp rats was not improved by nisoldipine treatment. The seve rity of atherosclerotic raised lesions in the aortic arch of male cp/c p rats was significantly reduced (p < 0.01) by nisoldipine treatment, and this was accompanied by a major reduction in the incidence of isch emic myocardial lesions (85%; p < 0.01). Thus nisoldipine treatment am eliorates atherosclerotic damage and myocardial injury even in the pre sence of gross obesity, hyperinsulinemia, and significant hyperlipidem ia. This effect appears to involve protection of the vascular wall fro m atherogenesis and probably antivasocontractile effects at the smooth muscle level as well.