Protective action of calcium channel antagonists in atherogenesis and experimental vascular injury

Experimental research using in vitro and in vivo models of vascular injury have delineated several common mechanisms that characterize the arterial damage in diseases such as atherosclerosis and hypertension. Changes in endothelial permeability, smooth muscle cell proliferation, and accumulation of connective tissue matrix are major common mechanisms. Chronic hyperlipidemia is a major determinant of the proliferative arterial lesions in atherogenic models. Calcium antagonists of very diverse structure and function have been shown to have antiatherogenic potential in several animal model systems of arterial injury. Calcium channel-blockers of several chemical classes have been demonstrated to alter endothelial function, intimal smooth muscle proliferation, and lipid accumulation in the arterial wall. Cell culture model systems have elucidated several potential mechanisms that may contribute to the antiatherogenic potential of the calcium channel-blockers. These activities may in part involve protection of arterial cells from calcium overload via inhibition of calcium flux across voltage-regulated ion channels. However, other activities of these drugs, such as inhibition of cholesterol esterification and matrix protein formation, appear to function independently of calcium flux. A hypothesis is presented that lipophilic calcium channel-blockers are accumulated in cell membranes and perturb metabolic function as a result of altering local membrane structure.