Response of Failing Canine and Human Heart Cells to β ₂ -Adrenergic Stimulation

Background Failing human hearts lose β 1 - but not β 2 -adrenergic receptors. In canine hearts with tachypacing failure, the ratio of β 2 - to β 1 -adrenergic receptors is increased. The present study was designed to determine whether heart failure increases sensitivity to β 2 -adrenergic stimulation in isolated canine ventricular cardiomyocytes and to verify that myocytes from failing human ventricles contain functional β 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 β 2 -adrenergic agonist. Zinterol significantly increased [Ca 2+ ] i transient amplitudes in all three groups. The failing canine myocytes were significantly more responsive than normal to β 2 -adrenergic stimulation. We also measured isotonic twitches, indo-1 fluorescence transients, and L-type Ca 2+ currents in healthy canine myocytes. Zinterol (10 −5 mol/L) elicited large increases in the amplitudes of simultaneously recorded twitches and [Ca 2+ ] i transients. Zinterol also increased L-type Ca 2+ 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 β 2 -adrenergic receptors. Canine myocytes also contain functional β 2 -adrenergic receptors. The canine ventricular response to β 2 -agonists is increased in tachypacing failure. Positive inotropic responses to β 2 -stimulation are not mediated by increases in cAMP or cAMP-dependent phosphorylation of phospholamban.