Response of failing canine and human heart cells to β₂-adrenergic stimulation

Background: Failing human hearts lose β₁- but not β₂-adrenergic receptors. In canine hearts with tachypacing failure, the ratio of β₂- to β₁-adrenergic receptors is increased. The present study was designed to determine whether heart failure increases sensitivity to β₂-adrenergic stimulation in isolated canine ventricular cardiomyocytes and to verify that myocytes from failing human ventricles contain functional β₂-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 β₂-adrenergic agonist. Zinterol significantly increased [Ca²⁺](i) transient amplitudes in all three groups. The failing canine myocytes were significantly more responsive than normal to β₂-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 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 β₂-adrenergic receptors. Canine myocytes also contain functional β₂- adrenergic receptors. The canine ventricular response to β₂-agonists is increased in tachypacing failure. Positive inotropic responses to β₂- stimulation are not mediated by increases in cAMP or cAMP-dependent phosphorylation of phospholamban.