Cardioprotective and Hypolipidemic Effects of Nisoldipine in the JCR:LA-cp Rat

The JCR:LA-cp rat exhibits the obesity/insulin resistance/hypertriglyceridemia syndrome in an extreme form. These normotensive rats spontaneously develop advanced atherosclerosis and ischemic myocardial lesions. The calcium channel antagonist, nisoldipine, was administered to obese 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 consumption or body weight compared with control animals. Plasma glucose and insulin levels also were unchanged in the nisoldipine-treated rats. Insulin-mediated total glucose turnover, an index of insulin sensitivity as measured by euglycemic insulin clamp, was similarly not improved. Serum triglyceride levels in obese male rats were markedly reduced (57%; p < 0.001, at age 12 weeks), whereas obese female rats showed no significant change in triglyceride levels and an increase in esterified cholesterol in response to nisoldipine treatment. The impaired endothelium-dependent (nitric oxide-mediated) vascular relaxation of the male cp/cp rats was not improved by nisoldipine treatment. The severity of atherosclerotic raised lesions in the aortic arch of male cp/cp rats was significantly reduced (p < 0.01) by nisoldipine treatment, and this was accompanied by a major reduction in the incidence of ischemic myocardial lesions (85%; p < 0.01). Thus nisoldipine treatment ameliorates atherosclerotic damage and myocardial injury even in the presence of gross obesity, hyperinsulinemia, and significant hyperlipidemia. This effect appears to involve protection of the vascular wall from atherogenesis and probably antivaso-contractile effects at the smooth muscle level as well.