(Circulation. 1995;92:1612-1618.)
© 1995 American Heart Association, Inc.
Articles |
Response of Failing Canine and Human Heart Cells to ß2-Adrenergic Stimulation
From the Departments of Medical Biochemistry (R.A.A., J.H., L.C., C.M.H.), Physiology (G.E.B.), Pharmacology (R.H.F.), Radiology (P.-M.L.R.), Internal Medicine (Division of Cardiology) (R.C.S.), and Veterinary Physiology and Pharmacology (R.L.H.), Ohio State University, Columbus; Krannert Institute of Cardiology, University of Indiana, Indianapolis (L.R.J.); and the Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Md (R.-P.X., E.G.L.).
Correspondence to Dr Ruth A. Altschuld, Ohio State University, Department of Medical Biochemistry, 333 Hamilton Hall, 1645 Neil Ave, Columbus OH 43210-1218. E-mail raltschu@magnus.acs.ohio-state.edu.
Background Failing human hearts lose ß1- but not ß2-adrenergic receptors. In canine hearts with tachypacing failure, the ratio of ß2- to ß1-adrenergic receptors is increased. The present study was designed to determine whether heart failure increases sensitivity to ß2-adrenergic stimulation in isolated canine ventricular cardiomyocytes and to verify that myocytes from failing human ventricles contain functional ß2-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 ß2-adrenergic agonist. Zinterol significantly increased [Ca2+]i transient amplitudes in all three groups. The failing canine myocytes were significantly more responsive than normal to ß2-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 ß2-adrenergic receptors. Canine myocytes also contain functional ß2-adrenergic receptors. The canine ventricular response to ß2-agonists is increased in tachypacing failure. Positive inotropic responses to ß2-stimulation are not mediated by increases in cAMP or cAMP-dependent phosphorylation of phospholamban.
Key Words: calcium channels • cells • heart failure • myocardial contraction • receptors, adrenergic, beta • sarcoplasmic reticulum
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