Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Kindermann, M. et al.

Kindermann, Maack, Schaller, Finkler, Schmidt, Läer, Wuttke, Schäfers, Böhm,

Carvedilol but not metoprolol reduces beta-adrenergic responsiveness after complete elimination from plasma in vivo.

BACKGROUND: Carvedilol but not metoprolol exhibits persistent binding to beta-adrenergic receptors (beta-ARs) even after washout in cell culture experiments. Here, we determined the significance of this phenomenon on human beta-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 beta-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 microg x kg(-1) x min(-1)) was performed before, during, and 44 hours after application of study medication. Beta-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 beta-blockade by carvedilol may be explained by binding of carvedilol to an allosteric site of beta-ARs.[1]

References

Carvedilol but not metoprolol reduces beta-adrenergic responsiveness after complete elimination from plasma in vivo. Kindermann, M., Maack, C., Schaller, S., Finkler, N., Schmidt, K.I., Läer, S., Wuttke, H., Schäfers, H.J., Böhm, M. Circulation (2004) [Pubmed]

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