Carvedilol but not metoprolol reduces β-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 mug . kg(-1) . 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.