VASCOR (bepridil hydrochloride) inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. This has been demonstrated in isolated myocardial and vascular smooth muscle preparations in which both the slope of the calcium dose response curve and the maximum calcium-induced inotropic response were significantly reduced by bepridil hydrochloride. In cardiac myocytes in vitro, bepridil hydrochloride was shown to be tightly bound to actin. A negative inotropic effect can be seen in the isolated guinea pig atria.

In in vitro studies, bepridil hydrochloride has also been demonstrated to inhibit the sodium inward current. Reductions in the maximal upstroke velocity and the amplitude of the action potential, as well as increases in the duration of the normal action potential, have been observed. Additionally, bepridil hydrochloride has been shown to possess local anesthetic activity in isolated myocardial preparations. It effects electrophysiological changes that are observed with several classes of anti-arrhythmic agents.

Clinical Studies

In controlled clinical studies with 200-400 mg of VASCOR, given as a once daily dose, exercise tolerance was improved and angina frequency and daily nitroglycerin use was reduced compared to placebo. Improvement in exercise performance was dose related. In one controlled clinical study, VASCOR was added to propranolol in daily doses of up to 240 mg. The 200-400 mg dose of VASCOR was well tolerated [patients entered were not allowed to be in NYHA Class III or IV heart failure] and there was an added effect of VASCOR on exercise tolerance.

In another controlled clinical study, VASCOR in doses of up to 400 mg/day, significantly improved exercise tolerance compared to diltiazem hydrochloride in patients refractory to diltiazem hydrochloride therapy.

Mechanism of Action:   The precise mechanism of action for VASCOR as an anti-anginal agent remains to be fully determined, but is believed to include the following mechanisms:

VASCOR regularly reduces heart rate and arterial pressure at rest and at a given level of exercise by dilating peripheral arterioles and reducing total peripheral resistance (afterload) against which the heart works. In exercise tolerance tests in patients with stable angina the heart rate/blood pressure product was reduced with VASCOR for a given work load.

Hemodynamic Effects:   VASCOR produces dose dependent slowing of the heart, and reflex tachycardia is not seen. The mean decrease in heart rate in US clinical trials was 3 b.p.m. Orally administered VASCOR also produces modest decreases (less than 5 mm Hg) in systolic and diastolic blood pressure in normotensive patients and somewhat larger decreases in hypertensive patients.

Intravenous administration of VASCOR is associated with a modest reduction in left ventricular contractility (dP/dt), and increased filling pressure, but radionuclide cineangiography studies in angina patients demonstrated improvement in ejection fraction at rest and during exercise following oral VASCOR therapy. Patients with impaired cardiac function [overt heart failure] were not included in these studies.

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