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(Circulation. 2004;109:3182-3190.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Carvedilol but Not Metoprolol Reduces ß-Adrenergic Responsiveness After Complete Elimination From Plasma In Vivo

Michael Kindermann, MD^*; Christoph Maack, MD^*; Susanne Schaller; Nadine Finkler; Kathrin I. Schmidt; Stephanie Läer, MD; Henrike Wuttke, MD; Hans-Joachim Schäfers, MD; Michael Böhm, MD

From Klinik für Innere Medizin III (M.K., C.M., S.S., N.F., K.I.S., M.B.) and Klinik für Thorax-und Herz-Gefäßchirurgie (H.-J.S.), Universitätsklinikum des Saarlandes, Homburg/Saar, and Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg (S.L., H.W.), Germany. Dr Maack currently is at Johns Hopkins University, Department of Cardiology, Baltimore, Md.

Correspondence to Michael Kindermann, MD, Innere Medizin III, Universitätsklinikum des Saarlandes, D 66421 Homburg/Saar, Germany. E-mail Michael.Kindermann{at}t-online.de

Received December 2, 2003; revision received March 4, 2004; accepted March 15, 2004.

Background— Carvedilol but not metoprolol exhibits persistent binding to ß-adrenergic receptors (ß-ARs) even after washout in cell culture experiments. Here, we determined the significance of this phenomenon on human ß-ARs in vitro and in vivo.

Methods and Results— Experiments were conducted on human atrial trabeculae (n=8 to 10 per group). In the presence of metoprolol, isoproterenol potency was reduced compared with controls (P<0.001). In the presence of carvedilol, isoproterenol identified 2 distinct binding sites of high (36±6%; –8.8±0.4 log mol/L) and low affinity (–6.5±0.2 log mol/L). After ß-blocker washout, isoproterenol potency returned to control values in metoprolol-treated muscles, whereas in carvedilol-treated preparations, isoproterenol potency remained decreased (P<0.001 versus control). In vivo studies were performed in 9 individuals receiving metoprolol succinate (190 mg/d) or carvedilol (50 mg/d) for 11 days in a randomized crossover design. Dobutamine stress echocardiography (5 to 40 µg · kg^–1 · min^–1) was performed before, during, and 44 hours after application of study medication. ß-Blocker medication reduced heart rate, heart rate–corrected velocity of circumferential fiber shortening, and cardiac output compared with baseline (P<0.02 to 0.0001). After withdrawal of metoprolol, all parameters returned to baseline values, whereas after carvedilol, all parameters remained reduced (P<0.05 to 0.001) despite complete plasma elimination of carvedilol.

Conclusions— Carvedilol but not metoprolol inhibits the catecholamine response of the human heart beyond its plasma elimination. The persistent ß-blockade by carvedilol may be explained by binding of carvedilol to an allosteric site of ß-ARs.

Key Words: beta-antagonists • heart failure • receptors, adrenergic, beta

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