β ₂ -Adrenergic Receptor Antagonists Protect Against Ventricular Fibrillation

<jats:p> <jats:italic>Background</jats:italic> The ventricular myocardium contains functional β <jats:sub>2</jats:sub> -adrenergic receptors that when activated increase intracellular Ca <jats:sup>2+</jats:sup> transients. Because elevated Ca <jats:sup>2+</jats:sup> has been implicated in the induction of ventricular fibrillation (VF), it is possible that the activation of these receptors may also provoke malignant arrhythmias. </jats:p> <jats:p> <jats:italic>Methods and Results</jats:italic> 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 <jats:sub>2</jats:sub> -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 ( <jats:italic>P</jats:italic> <.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 <jats:sub>2</jats:sub> -adrenergic receptor agonist zinterol on Ca <jats:sup>2+</jats:sup> transient amplitudes were examined in ventricular myocytes. Zinterol elicited significantly greater increases in Ca <jats:sup>2+</jats:sup> transient amplitudes at all doses tested (10 <jats:sup>−9</jats:sup> to 10 <jats:sup>−6</jats:sup> mol/L) in myocytes prepared from susceptible versus resistant animals. The cardiomyocyte response to isoproterenol (10 <jats:sup>−7</jats:sup> mol/L) in the presence or absence of the selective β <jats:sub>1</jats:sub> - (CGP-20712A, 300 nmol/L) or β <jats:sub>2</jats:sub> - (ICI 118,551, 100 nmol/L) adrenergic receptor antagonist was also examined. Isoproterenol elicited larger Ca <jats:sup>2+</jats:sup> transient increases in the susceptible myocytes, which were eliminated by ICI but not by CGP. </jats:p> <jats:p> <jats:italic>Conclusions</jats:italic> When considered together, these data demonstrate that canine myocytes contain functional β <jats:sub>2</jats:sub> -adrenergic receptors that are activated to a greater extent in the susceptible animals. The resulting cytosolic Ca <jats:sup>2+</jats:sup> transient increases may lead to afterpotentials that ultimately trigger VF in these animals. </jats:p>