Fundamental mechanisms of action of calcium antagonists in myocardial ischemia

Abstract

The mammalian myocardium exhibits a spectrum of damage during an ischemic episode. After relatively short periods of ischemia the damage is reversible, but with longer periods of ischemia the number of cells that are lethally injured increases. When coronary flow is restored the lethally injured cells become overloaded with Ca++ and fail to regenerate adenosine triphosphate. The calcium antagonists provide protection under these circumstances, but only if used prophylactically. When added only upon reperfusion the calcium antagonists slow, but do not inhibit, the excessive gain in Ca++ that occurs during postischemic reperfusion. Nicotine, in a concentration equivalent to that found in the plasma of smokers (0.15 microgram/ml), exacerbates the reperfusion-induced Ca++ gain. Treatment with the long-acting calcium antagonist, anipamil, on a once-daily basis attenuates the reperfusion-induced Ca++ gain in spontaneously hypertensive rats and its exacerbation by nicotine in Sprague Dawley rats. The prolonged oral administration of at least 1 calcium antagonist, verapamil (50 mg/kg body weight/day), causes a significant (p less than 0.001) depletion of left ventricular norepinephrine.