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Bepridil is an antianginal agent with multiple therapeutic actions. It decreases calcium influx through potential-dependent and receptor-operated sarcolemmic calcium channels and acts intracellularly as a calmodulin antagonist and calcium sensitizer. Thus, in cardiac muscle it enhances the sensitivity of troponin C to calcium, stimulates myofibrillar adenosine triphosphatase activity, removes calmodulin's inhibitory effect on sarcoplasmic reticulum calcium release, and inhibits sodium-calcium exchange--actions that tend to offset the effects of calcium influx blockade on cardiac contractile force. However, in vascular smooth muscle where the calcium--calmodulin complex promotes muscle contraction by activating myosin light-chain kinase phosphorylation of contractile proteins, calmodulin antagonism, coupled with bepridil's blockade of calcium influx, leads to vasorelaxation. In animal models of ischemia, bepridil and other calmodulin inhibitors show antiarrhythmic efficacy following reperfusion. Additionally, interfering with calmodulin's role in sympathetic nerve terminal function may help to limit the ischemia-induced catecholamine release that contributes to arrhythmogenesis. Bepridil shows a lidocaine-like fast kinetic block of inward sodium current (as distinct from the slow or intermediate kinetic inhibition expressed by encainide or quinidine, respectively). This inhibition is pH-dependent; activity is expressed to a greater degree at lower pH levels. Thus, this potentially antiarrhythmic mechanism is activated by conditions of ischemia. Bepridil's blockade of outward potassium currents and its inhibition of sodium-calcium exchange increase action potential duration and ventricular refractoriness, prolong the QT interval, and form the basis for a class III antiarrhythmic mechanism. Because hypokalemia also prolongs the QT interval, the addition of bepridil in the presence of hypokalemia can lead to excessive prolongation. Bepridil both increases myocardial oxygen supply through coronary vasodilation and decreases myocardial oxygen demand through mild heart rate and afterload reduction, and shows potential antiarrhythmic activity through class IB, III, and IV mechanisms. In addition, its ability to inhibit receptor-operated calcium influx, a property that distinguishes it from other calcium antagonists, could have additional therapeutic benefits against ischemia and atherosclerosis. (Am J Cardiol 1992;69:11D-16D)

The effects of intravenous infusion of the calcium antagonist, diltiazem (6, 30, and 150 mg/kg/hr) on cardiac and circulatory hemodynamics and on regional blood flow and cardiac output distribution to the major peripheral circulations were studied in conscious, normal Sprague-Dawley rats in the resting state. Therapy with diltiazem consistently increased cardiac output levels, as well as stroke volume, and decreased mean arterial pressure and systemic vascular resistance in a dose-related fashion. Diltiazem had a substantial effect on increasing coronary blood flow and reducing coronary vascular resistance. Effects of similar direction and magnitude were observed in the cerebral and hepatic arterial circulations. In a second study, rats were subjected to a submaximal treadmill exercise protocol during continuous intravenous infusion of either saline solution or diltiazem (DZ) in order to determine the effects of this agent on cardiac output distribution during exercise. The results indicate that the positive effects of diltiazem on cardiac output are maintained during exercise. The increase in cardiac output with diltiazem appears to be distributed throughout the major regional circulations in proportion to regional demand.