Effects of calcium entry blockers on coronary constriction and myocardial ischemia due to leukotriene D₄

Recent studies show that leukotrienes (LTs) produce profound coronary artery constriction. Although calcium entry blockers are commonly used to remedy coronary vasospasm, their capacity to interfere with LT-mediated coronary constriction is unknown. Therefore, we compared effects of intracoronary LTD₄ before and during treatment with calcium entry blockers in the in situ, blood-perfused hearts of domestic pigs. Intravenous administration of verapamil (0.1-1.6 mg/kg), nifedipine (10 or 100 μg/kg) or diltiazem (0.6-2.0 mg/kg), sufficient to increase base-line coronary blood flow (CBF) and decrease mean arterial pressure, did not change decrement in CBF after LTD₄. Infusion of verapamil (0.01-0.04 mg/min) into the left anterior descending coronary artery raised pre-LTD₄ CBF almost 2-fold without alteration in mean arterial pressure, heart rate or left ventricular end-diastolic pressure. Intracoronary boluses of LTD₄ (0.3, 1.0 and 3.0 μg) during verapamil infusion into the same vessel caused dose-dependent decreases in CBF identical to those observed when LTD₄ was injected during control infusion. ECGs showed myocardial ischemia during severe flow reduction after high dose intracoronary LTD₄ (3.0 or 10.0 μg). When the same LTD₄ doses were injected during intracoronary verapamil, electrocardiographic changes did not occur despite similar decreases in CBF. The capacity of verapamil to prevent LTD₄-induced ischemia may be caused by higher residual CBF after LTD₄ even though the magnitude of LTD₄-induced CBF decrement was unaltered. LTD₄-induced coronary constriction seems to be mediated by a mechanism unrelated to calcium entry channels blocked by verapamil, nifedipine or diltiazem.