Rapid large artery remodeling following the administration and withdrawal of calcium channel blockers in spontaneously hypertensive rats

Abstract

Chronic treatment with several antihypertensive agents, including calcium channel blockers, may interfere with remodeling of large arteries and increased arterial stiffness. We hypothesize that even a short, seven-day administration of calcium channel blockers might alter an aortic remodeling in spontaneously hypertensive rat (SHR). Male SHR and normotensive WKY rats ( n = 14 each) were treated by either vehicle, vasculoselective calcium channel blocker nifedipine (1 mg/kg/day) or cardiac/vascular calcium channel blockers diltiazem (5 mg/kg/day) or verapamil (4 mg/kg/day, n = 6 for each treatment) subcutaneously twice daily for seven days. Additional SHR rats were randomized for termination 24, 72 or 120 h ( n = 5 each) after the withdrawal of nifedipine. Systolic blood pressure was measured by tail cuff and thoracic aorta was collected for histomorphometric and functional analysis including acetylcholine-induced endothelium-dependent relaxation. Seven-day administration of diltiazem and nifedipine, but not verapamil decreased blood pressure in SHR. All drugs significantly attenuated abnormal aortic wall thickness, cross-sectional area and media-to-lumen ratio, but only nifedipine improved impaired endothelium-dependent relaxation. Following the withdrawal of nifedipine, all measured parameters returned back to control SHR values within 72 h. Seven-day treatment with distinct calcium channel blockers attenuates hypertensive remodeling of aorta, which might be, in case of nifedipine, reactivated even by a very short withdrawal of the drug. Therefore, vasculoprotection by calcium channel blockers is not restricted to a prolonged blood pressure modulation, but occurs rapidly. These findings could be relevant for an intervention in augmented vascular stiffness and related cardiovascular risk.