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Vascular injury: mechanisms and manifestations
1Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia.
Insights
Amlodipine, a calcium antagonist, reduced atherosclerosis and mortality in animal models. This drug shows promise for protecting the vasculature in aging hypertensive populations by lowering blood pressure and preventing vascular injury.
Area of Science:
- Cardiovascular Pharmacology
- Vascular Biology
- Hypertension Research
Background:
- Calcium handling abnormalities are implicated in cell death and cardiovascular diseases like atherosclerosis and stroke.
- Hypertension is a significant risk factor for vascular injury, particularly in aging populations.
- Dihydropyridine calcium antagonists are used to manage hypertension and may offer vascular protection.
Purpose of the Study:
- To investigate the efficacy of amlodipine in preventing diet-induced atherogenesis in rabbits.
- To determine if amlodipine reduces mortality and cardiac hypertrophy in stroke-prone hypertensive rats.
- To assess the vascular protective effects of amlodipine beyond its blood pressure-lowering capabilities.
Main Methods:
- Rabbits on a high-cholesterol diet received varying doses of amlodipine (0, 1, or 5 mg/kg/day) for 8 or 12 weeks.
- Thoracic aortas were analyzed for calcium, cholesterol, and lesion formation.
- Stroke-prone hypertensive rats were treated with amlodipine (5 mg/kg/day) from 5 to 30 weeks of age.
- Systolic blood pressure, mortality rates, and heart-to-body weight ratios were recorded.
Main Results:
- Amlodipine demonstrated a dose- and time-dependent reduction in aortic lesion formation, calcium, and cholesterol levels in rabbits.
- In rats, amlodipine significantly reduced systolic blood pressure (166 vs 248 mm Hg) and mortality (93% survival vs 26%).
- Cardiac hypertrophy was significantly attenuated in amlodipine-treated rats compared to placebo.
Conclusions:
- Amlodipine provides significant vascular protection against atherogenesis and reduces mortality in animal models.
- These findings support the role of calcium antagonists like amlodipine in managing vascular complications in aging hypertensive individuals.
- Amlodipine's benefits extend beyond blood pressure reduction, offering protection against vascular injury.
Abstract:
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 less than 0.001). A significant reduction in mortality was observed in the amlodipine-treated rats (p less than 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 less than 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.