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(Circulation. 1999;99:65-72.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Activation of ß₂-Adrenergic Receptors Hastens Relaxation and Mediates Phosphorylation of Phospholamban, Troponin I, and C-Protein in Ventricular Myocardium From Patients With Terminal Heart Failure

Alberto Kaumann, MD, PhD; Sabine Bartel, PhD; Peter Molenaar, PhD; Louise Sanders, MA; Kylie Burrell, BScHons; Donathe Vetter; Petra Hempel, MSci; Peter Karczewski, PhD; Ernst-Georg Krause, PhD

From the Babraham Institute, Cambridge, UK (A.K., L.S.); Department of Pharmacology, University of Melbourne, Victoria, Australia (P.M., K.B.); and Max-Delbrück Centre of Molecular Medicine, Cardiology, Berlin, Germany (S.B., D.V., P.H., P.K., E.-G.K.).

Correspondence to Alberto Kaumann, MD, PhD, Babraham Institute, Cambridge CB2 4AT, United Kingdom. E-mail alberto.kaumann{at}bbsrc.ac.uk

Background—Catecholamines hasten cardiac relaxation through ß-adrenergic receptors, presumably by phosphorylation of several proteins, but it is unknown which receptor subtypes are involved in human ventricle. We assessed the role of ß₁- and ß₂-adrenergic receptors in phosphorylating proteins implicated in ventricular relaxation.

Methods and Results—Right ventricular trabeculae, obtained from freshly explanted hearts of patients with dilated cardiomyopathy (n=5) or ischemic cardiomyopathy (n=5), were paced at 60 bpm. After measurement of the contractile and relaxant effects of epinephrine (10 µmol/L) or zinterol (10 µmol/L), mediated through ß₂-adrenergic receptors, and of norepinephrine (10 µmol/L), mediated through ß₁-adrenergic receptors, tissues were freeze clamped. We assessed phosphorylation of phospholamban, troponin I, and C-protein, as well as specific phosphorylation of phospholamban at serine 16 and threonine 17. Data did not differ between the 2 disease groups and were therefore pooled. Epinephrine, zinterol, and norepinephrine increased contractile force to approximately the same extent, hastened the onset of relaxation by 15±3%, 5±2%, and 20±3%, respectively, and reduced the time to half-relaxation by 26±3%, 21±3%, and 37±3%. These effects of epinephrine, zinterol, and norepinephrine were associated with phosphorylation (pmol phosphate/mg protein) of phospholamban 14±3, 12±4, and 12±3; troponin I 40±7, 33±7, and 31±6; and C-protein 7.2±1.9, 9.3±1.4, and 7.5±2.0. Phosphorylation of phospholamban occurred at both Ser16 and Thr17 residues through both ß₁- and ß₂-adrenergic receptors.

Conclusions—Norepinephrine and epinephrine hasten human ventricular relaxation and promote phosphorylation of implicated proteins through both ß₁- and ß₂-adrenergic receptors, thereby potentially improving diastolic function.

Key Words: heart failure • receptors, adrenergic, beta 2 • catecholamines • phosphoproteins • contractility, diastole

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