d-sotalol reduces heart rate in vivo through a beta-adrenergic receptor-independent mechanism.
d-Sotalol was developed as an antiarrhythmic agent with a relative lack of antagonist activity at beta-adrenergic receptors. Exercise heart rate reduction has been observed after administration to humans. The purpose of this study was to determine directly whether this effect of d-sotalol was attributable to beta-blockade. Plasma samples from normal volunteers who randomly received either atenolol, d-sotalol, or placebo were used in an in vitro radioreceptor assay to determine occupancy of beta 1-adrenergic receptors by antagonist present in the plasma. Occupancy was compared with the observed pharmacologic effects. A reduction in exercise heart rate of 7.7% +/- 3.8% for d-sotalol and 15.9% +/- 3.0% for atenolol occurred with beta 1-adrenergic receptor occupancy of 0% and 33.9% +/- 21.4%, respectively. Absence of antagonist effect in the radioreceptor assay eliminates the potential role of beta 1-blockade in d-sotalol-induced heart rate reduction. This effect is most likely a result of prolongation of the sinus node action potential duration.
Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20007.
S U
SU
Yasuda
J T
JT
Barbey
C
C
Funck-Brentano
A
A
Wellstein
R L
RL
Woosley
D000328:Adult; D000704:Analysis of Variance; D001262:Atenolol / Q000378:metabolism; D004311:Double-Blind Method; D015444:Exercise; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D013015:Sotalol / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism
D011943:Receptors, Adrenergic, beta; D001262:Atenolol; D013015:Sotalol