β 2 -Adrenergic Receptor Antagonists Protect Against Ventricular Fibrillation

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Abstract
Background The ventricular myocardium contains functional β 2 -adrenergic receptors that when activated increase intracellular Ca 2+ transients. Because elevated Ca 2+ has been implicated in the induction of ventricular fibrillation (VF), it is possible that the activation of these receptors may also provoke malignant arrhythmias. Methods and Results To test this hypothesis, a 2-minute occlusion of the left circumflex coronary artery was made during the last minute of exercise in 28 dogs with healed anterior myocardial infarctions: 17 had VF (susceptible) and 11 did not (resistant). On a subsequent day, this test was repeated after administration of the β 2 -adrenergic receptor antagonist ICI 118,551 (0.2 mg/kg). This drug did not alter the hemodynamic response to the coronary occlusion, yet it prevented VF in 10 of 11 animals tested ( P <.001). However, heart rate was reduced in 6 animals. Therefore, the ICI 118,551 exercise-plus-ischemia test was repeated with heart rate held constant by ventricular pacing (n=3). ICI 118,551 still prevented VF when heart rate was maintained. Next, the effects of increasing doses of the β 2 -adrenergic receptor agonist zinterol on Ca 2+ transient amplitudes were examined in ventricular myocytes. Zinterol elicited significantly greater increases in Ca 2+ transient amplitudes at all doses tested (10 −9 to 10 −6 mol/L) in myocytes prepared from susceptible versus resistant animals. The cardiomyocyte response to isoproterenol (10 −7 mol/L) in the presence or absence of the selective β 1 - (CGP-20712A, 300 nmol/L) or β 2 - (ICI 118,551, 100 nmol/L) adrenergic receptor antagonist was also examined. Isoproterenol elicited larger Ca 2+ transient increases in the susceptible myocytes, which were eliminated by ICI but not by CGP. Conclusions When considered together, these data demonstrate that canine myocytes contain functional β 2 -adrenergic receptors that are activated to a greater extent in the susceptible animals. The resulting cytosolic Ca 2+ transient increases may lead to afterpotentials that ultimately trigger VF in these animals.