EFFECT OF ALPHA(1)-ADRENERGIC RECEPTOR ANTAGONISTS ON SUSCEPTIBILITY TO MALIGNANT ARRHYTHMIAS - PROTECTION FROM VENTRICULAR-FIBRILLATION

alpha-Adrenergic receptor responsiveness has been reported to increase during myocardial ischemia, correlating with onset of malignant arrhy thmias. If alpha-adrenoceptor mechanisms play a significant role in in duction of life-threatening arrhythmias, inhibition of these receptors with specific alpha-adrenoceptor antagonists should protect against d isturbances in cardiac rhythm. To test this hypothesis, we induced ven tricular fibrillation (VF) in 21 mongrel dogs with healed myocardial i nfarctions (MI) by 2-min coronary artery occlusion during exercise. On a subsequent day, the exercise plus ischemia test was repeated after the alpha(1)-adrenoceptor antagonist prazosin HCl (0.5 mg/kg intraveno usly, i.v.; n = 14) or the alpha(1A)-adrenergic receptor subtype antag onist WB4101 (2.0 mg/kg i.v., n = 9). Prazosin elicited a significant reduction in left ventricular systolic pressure (LVSP, control 157.0 /- 6.5 vs. prazosin 118.5 +/- 2.7 mm Hg) and prevented arrhythmias in 13 of 14 animals (chi square p < 0.001). No other hemodynamic paramete rs, either before or during the coronary occlusion, were altered by pr azosin. WB4101 did not alter any hemodynamic parameters either before or during coronary artery occlusion, yet prevented VF in 7 of 9 animal s (chi square p < 0.025), delaying onset of malignant arrhythmias in t he remaining animals. A second control exercise plus ischemia test rep roducibly induced VF in all animals. Together these data demonstrate t hat alpha-adrenoceptor antagonists can prevent VF independent of hemod ynamic changes. In particular, the data suggest that activation of the alpha(1A)-adrenergic receptor subtype may contribute importantly to d evelopment of malignant arrhythmias. Therefore, alpha(1)-adrenoceptor subtype antagonists may represent a novel approach for management of m alignant arrhythmias in patients with ischemic heart disease.