Antihypertensive, antiatherosclerotic, and plasma lipid-lowering effects of monatepil, a novel calcium antagonist with alpha 1-adrenoceptor-blocking activity in experimental animals.

Traditional antihypertensive therapy has been shown to reduce the incidence of hypertension-related vascular injuries; however, it is not fully effective against cardiovascular abnormalities. In some animal models, calcium antagonists have been demonstrated to possess antiatherogenic properties but to have no effects on plasma lipid levels, whereas alpha 1-adrenoceptor blockers have been shown to reduce plasma lipid levels. Monatepil is a new type of calcium antagonist that also has alpha 1-adrenoceptor-blocking activity. Therefore, it is thought that monatepil may have both antiatherosclerotic and plasma lipid-lowering effects in addition to its slow-onset and long-lasting antihypertensive effect. To determine the antiatherosclerotic effects of monatepil, we examined its effect on experimental atherosclerosis induced by feeding a high-cholesterol diet to monkeys, whose lipid metabolism resembles that of humans. Monatepil, at a daily dose of 30 mg/kg, at which plasma levels are equivalent to those in clinical antihypertensive therapy, was administered orally for 6 months. Monatepil suppressed elevation of cholesterol in the aorta and reduced the atherogenic (sudanophilic) area. Histologic examination revealed that monatepil-treated monkeys exhibited little aggregation of foam cells in either the aorta or coronary arteries compared with vehicle-treated atherogenic monkeys. In addition, monatepil showed preventive effects against increases in total cholesterol and low density lipoprotein (LDL), and against decreases in high density lipoprotein in plasma caused by cholesterol loading. The plasma lipid-lowering effect may be mediated through up-regulation of the number of hepatic LDL receptors by the alpha 1-adrenoceptor-blocking activity, and the antiatherosclerotic effect may be produced by the combined calcium antagonist, alpha 1-adrenoceptor-blocking, and antilipid peroxidation activities. In summary, monatepil is an antihypertensive agent belonging to a new class with antiatherogenic properties and the ability to reduce plasma lipid levels.