Response of failing canine and human heart cells to beta 2-adrenergic stimulation
Altschuld, R.A.; Starling, R.C.; Hamlin, R.L.; Billman, G.E.; Hensley, J.; Castillo, L.; Fertel, R.H.; Hohl, C.M.; Robitaille, P.M.; Jones, L.R.
Circulation 92(6): 1612-1618
1995
ISSN/ISBN: 0009-7322 PMID: 7664448 Document Number: 450392
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 (Ca-2+)-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 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 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.