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

Background Failing human hearts lose beta(1)- but not beta(2)-adrenerg ic receptors. In canine hearts with tachypacing failure, the ratio of beta(2)- to beta(1)-adrenergic receptors is increased. The present stu dy was designed to determine whether heart failure increases sensitivi ty to beta(2)-adrenergic stimulation in isolated canine ventricular ca rdiomyocytes 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 t ransplant recipients were loaded with fura 2-AM and subjected to elect ric 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 t ransients, and L-type Ca2+ currents in healthy canine myocytes. Zinter ol (10(-5) mol/L) elicited large increases in the amplitudes of simult aneously recorded twitches and [Ca2+](i) transients. Zinterol also inc reased L-type Ca2+ currents in the normal canine myocytes; this augmen tation was abolished by 10(-7) mol/L ICI 118,551. cAMP production by s uspensions 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 elic it phospholamban phosphorylation. Conclusions Failing human ventricula r cardiomyocytes contain functional beta(2)-adrenergic receptors. Cani ne myocytes also contain functional beta(2)-adrenergic receptors. The canine ventricular response to beta(2)-agonists is increased in tachyp acing failure. Positive inotropic responses to beta(2)-stimulation are not mediated by increases in cAMP or cAMP-dependent phosphorylation o f phospholamban.