Stereoselective effects of (R)- and (S)-carvedilol in humans.
Carvedilol is currently used as the racemic mixture, (R,S)-carvedilol, consisting of equal amounts of (R)-carvedilol, an alpha-blocker, and (S)-carvedilol, an alpha- and beta-blocker, which have never been tested in their optically pure forms in human subjects. We performed a randomized, double-blind, placebo-controlled, crossover study in 12 healthy male volunteers. Subjects received single oral doses of 25 mg (R,S)-carvedilol, 12.5 mg (R)-carvedilol, 12.5 mg (S)-carvedilol, and placebo at 8 AM as well as at 8 PM. Exercise was performed at 11 AM, and heart rate and blood pressure were measured at rest and after 10 min of exercise. Urine was collected between 10 AM and 6 PM, as well as between 10 PM and 6 AM, and the amounts of urinary 6-hydroxy-melatonin sulfate (aMT6s) were determined by RIA. Compared to placebo, (R)-carvedilol increased heart rate during exercise (+4%, P < 0.05) and recovery (+10%, P < 0.05); (S)-carvedilol decreased heart rate during exercise (-14%, P < 0.05) and recovery (-6%, P < 0.05), and systolic blood pressure during exercise (-12%, P < 0.05); (R,S)-carvedilol decreased heart rate during exercise (-11%, P < 0.05), and systolic blood pressure at rest (-7%, P < 0.05) and during exercise (-10%, P < 0.05). None of the agents had any significant effect on the release of aMT6s. Our results indicate that only (S)-carvedilol causes beta-blockade, whereas (R)-carvedilol appears to increase sympathetic tone, presumably as a physiological reaction to the decrease of blood pressure caused by alpha-blockade. None of the drugs had any influence on melatonin release. The weak clinical net effect of beta-blockade of (R,S)-carvedilol at rest might be one reason why this drug causes fewer side effects than other beta-blockers, such as a reduction of nocturnal melatonin release.
Stoschitzky
K
K
Department of Medicine / Division of Cardiology, Karl Franzens University, Graz, Austria. kurt.stoschitzky@kfunigraz.ac.at
Koshucharova
G
G
Lercher
P
P
Maier
R
R
Sakotnik
A
A
Klein
W
W
Liebmann
P M
PM
Lindner
W
W
D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005080:Exercise Test; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008550:Melatonin / Q000031:analogs & derivatives / Q000652:urine; D010919:Placebos; D011412:Propanolamines / Q000494:pharmacology*; D013237:Stereoisomerism
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D010919:Placebos; D011412:Propanolamines; D000077261:Carvedilol; C054513:6-sulfatoxymelatonin; D008550:Melatonin