VASCULAR INJURY - MECHANISMS AND MANIFESTATIONS

Abnormalities in regulatory mechanisms for calcium handling play a key role in cell death and tissue necrosis. In the cardiovascular system this applies to the vasculature and the myocardium alike. In the aged population, where hypertension is a known risk factor, manifestations of vascular injury include atherogenesis and stroke. The newly developed dihydropyridine-based calcium antagonist amlodipine was used in investigations to determine whether calcium antagonists with sustained activity, in addition to lowering blood pressure, slow the development of atherogenesis in rabbits receiving high cholesterol diets, or reduce mortality in stroke-prone hypertensive rats. To establish whether this drug protects the vasculature against excessive atheroma formation in the presence of high cholesterol intake, rabbits were given 2% cholesterol in addition to their normal food intake and either 0, 1, or 5 mg/kg/day amlodipine orally for either 8 or 12 weeks. One day after the conclusion of the treatment protocol, the thoracic aorta was excised, assayed for calcium or cholesterol concentrations, and stained to identify sudanophilic-positive lesions. Amlodipine caused a time- and dose-dependent reduction in lesion formation, calcium overload, and cholesterol level. In the second series of experiments, amlodipine (5 mg/kg/day) was added to the diets of stroke-prone hypertensive rats. Treatment was initiated at age 5 weeks and continued for 30 weeks. During the treatment period, systolic blood pressure was reduced in the amlodipine-treated rats (166 +/- 9 mm Hg) versus those treated with placebo (248 +/- 12 mm Hg) (p < 0.001). A significant reduction in mortality was observed in the amlodipine-treated rats (p < 0.001), with 93% surviving versus only 26% in the placebo group at the end of the 30-week treatment period. Concomitantly, cardiac hypertrophy was attenuated in the treated group compared with the placebo group (heart-to-body weight ratios of 4.5 +/- 0.01 vs 5.8 +/- 0.6, respectively [p < 0.01]). These results extend the evidence that calcium antagonists provide vascular protection in animal models. This finding may become increasingly important in the management of an aging hypertensive population.