Relaxation of rat thoracic aorta by fibrate drugs correlates with their potency to disturb intracellular calcium of VSMCs

Abstract

Phenotypic modifications of vascular smooth muscle cells (VSMCs) contribute to pathological changes in atherosclerosis where modulation of intracellular calcium plays an important role. In this study, three fibrate drugs, namely gemfibrozil (Gem), fenofibric acid (Fa) and bezafibrate (Beza), were revealed to relax thoracic aorta associated with their potency to reduce intracellular calcium ([Ca2+]i) in cultured VSMCs. Relaxation effect of Gem, Fa and Beza was assayed on precontracted rat aortic rings. [Ca2+]i level in VSMCs following addition of these fibrates was measured by laser scanning confocal microscopy or flow cytometry. Resultantly, three fibrates showed activity for vasodilation with potency order of Gem>Fa>Beza. Sustained potent reduction of [Ca2+]i was observed with Gem 50mg/L and mild reduction with Fa 400–600mg/L, while no effect had been detected for Beza under our current system. Thus, the potency of these fibrates to relax aortic rings correlate well with their effect on [Ca2+]i reduction, strongly implicating an underlying causal relationship. Considering that Gem potently reduces [Ca2+]i in its clinical concentration range, this study suggests an insight to in situ pharmacological effects of anti-atherosclerosis and clinical toxicity risk.