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.


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.
Kindermann
Michael
M
Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany. Michael.Kindermann@t-online.de
Maack
Christoph
C
Schaller
Susanne
S
Finkler
Nadine
N
Schmidt
Kathrin I
KI
Läer
Stephanie
S
Wuttke
Henrike
H
Schäfers
Hans-Joachim
HJ
Böhm
Michael
M
D000317:Adrenergic alpha-Antagonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D000483:Alleles; D000495:Allosteric Site / Q000187:drug effects; D001665:Binding Sites; D002227:Carbazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D002302:Cardiac Output / Q000187:drug effects; D000077261:Carvedilol; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D004280:Dobutamine; D025401:Echocardiography, Stress; D005838:Genotype; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D008790:Metoprolol / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D011412:Propanolamines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D011943:Receptors, Adrenergic, beta / Q000096:biosynthesis / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D000077261:Carvedilol; D004280:Dobutamine; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol; D007545:Isoproterenol