Effect of α1-Adrenergic Receptor Antagonists on Susceptibility to Malignant Arrhythmias

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Abstract
α-Adrenergic receptor responsiveness has been reported to increase during myocardial ischemia, correlating with onset of malignant arrhythmias. If α-adrenoceptor mechanisms play a significant role in induction of life-threatening arrhythmias, inhibition of these receptors with specific α-adrenoceptor antagonists should protect against disturbances in cardiac rhythm. To test this hypothesis, we induced ventricular fibrillation (VF) in 21 mongrel dogs with healed myocardial infarctions (MI) by 2-min coronary artery occlusion during exercise. On a subsequent day, the exercise plus ischemia test was repeated after the α1-adrenoceptor antagonist prazosin HCl (0.5 mg/kg intravenously, i.v.; n = 14) or the α1A-adrenergic receptor subtype antagonist 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 parameters, either before or during the coronary occlusion, were altered by prazosin. WB4101 did not alter any hemodynamic parameters either before or during coronary artery occlusion, yet prevented VF in 7 of 9 animals (chi square p < 0.025), delaying onset of malignant arrhythmias in the remaining animals. A second control exercise plus ischemia test re-producibly induced VF in all animals. Together these data demonstrate that α-adrenoceptor antagonists can prevent VF independent of hemodynamic changes. In particular, the data suggest that activation of the α1A-adrenergic receptor subtype may contribute importantly to development of malignant arrhythmias. Therefore, α1-adrenoceptor subtype antagonists may represent a novel approach for management of malignant arrhythmias in patients with ischemic heart disease.

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