Abstract
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. Chirality 13:342–346, 2001. © 2001 Wiley‐Liss, Inc.