RESPONSE OF FAILING CANINE AND HUMAN HEART-CELLS TO BETA(2)-ADRENERGIC STIMULATION

Background Failing human hearts lose beta(1)- but not beta(2)-adrenergic receptors. In canine hearts with tachypacing failure, the ratio of beta(2)- to beta(1)-adrenergic receptors is increased. The present study was designed to determine whether heart failure increases sensitivity to beta(2)-adrenergic stimulation in isolated canine ventricular cardiomyocytes and to verify that myocytes from failing human ventricles contain functional beta(2)-adrenergic receptors. Methods and Results Myocytes from healthy dogs, dogs with tachypacing failure, and human transplant recipients were loaded with fura 2-AM and subjected to electric field stimulation in the presence of zinterol, a highly selective beta(2)-adrenergic agonist. Zinterol significantly increased [Ca2+](i) transient amplitudes in all three groups. The failing canine myocytes were significantly more responsive than normal to beta(2)-adrenergic stimulation. We also measured isotonic twitches, indo-1 fluorescence transients, and L-type Ca2+ currents in healthy canine myocytes. Zinterol (10(-5) mol/L) elicited large increases in the amplitudes of simultaneously recorded twitches and [Ca2+](i) transients. Zinterol also increased L-type Ca2+ currents in the normal canine myocytes; this augmentation was abolished by 10(-7) mol/L ICI 118,551. cAMP production by suspensions of healthy and failing canine myocytes was not increased by zinterol (10(-9) to 10(-5) mol/L), nor did 10(-5) mol/L zinterol elicit phospholamban phosphorylation. Conclusions Failing human ventricular cardiomyocytes contain functional beta(2)-adrenergic receptors. Canine myocytes also contain functional beta(2)-adrenergic receptors. The canine ventricular response to beta(2)-agonists is increased in tachypacing failure. Positive inotropic responses to beta(2)-stimulation are not mediated by increases in cAMP or cAMP-dependent phosphorylation of phospholamban.