Published Online
on June 7, 2004

A more recent version of this article appeared on June 29, 2004

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Submitted on December 2, 2003
Revised on March 4, 2004
Accepted on March 15, 2004

Carvedilol but Not Metoprolol Reduces -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, and 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.

^* To whom correspondence should be addressed. E-mail: Michael.Kindermann{at}t-online.de.

Background--Carvedilol but not metoprolol exhibits persistent binding to -adrenergic receptors (-ARs) even after washout in cell culture experiments. Here, we determined the significance of this phenomenon on human -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 -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. -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 -blockade by carvedilol may be explained by binding of carvedilol to an allosteric site of -ARs.

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

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