A mechanism of D-(+)-sotalol effects on heart rate not related to beta-adrenoceptor antagonism.
1. In order to determine whether the effects of d- or (+)-sotalol on heart rate are mediated by beta-adrenoceptor antagonism or might be due to other actions, we administered (+)-sotalol (400 mg every 12 h), atenolol (50 mg every 12 h) and placebo to eight healthy volunteers in a randomized, double-blind, crossover study. We also studied the affinity of human lymphocyte beta 2-adrenoceptor for (+)-sotalol, (-)-sotalol, and (+/-)-propranolol. 2. Compared with placebo, atenolol significantly reduced resting, standing and peak exercise heart rate whereas (+)-sotalol significantly reduced standing and peak exercise heart rate, but not resting heart rate. Atenolol significantly reduced resting, standing and peak exercise blood pressure while (+)-sotalol had no effect. 3. (+)-sotalol and atenolol both shifted the relationship between isoprenaline dose and heart rate to the right by similar degrees at the dosages tested. 4. (+)-sotalol but not atenolol significantly prolonged QTc interval. The degree of QTc prolongation due to (+)-sotalol, which has been shown to parallel action potential prolongation in the sinus node, correlated significantly with the reduction in peak exercise. heart rate it produced (r = 0.71, n = 8, P less than 0.05). 5. The affinity of the human lymphocyte beta 2-adrenoceptor was approximately 60-fold greater for (-)-sotalol (Ki, 108 +/- 12 nM) than for (+)-sotalol (Ki, 6,410 +/- 1,020 nM), and approximately 20,000-fold greater for (+/-)-propranolol (Ki, 0.33 +/- 0.08 nM) than for (+)-sotalol.(ABSTRACT TRUNCATED AT 250 WORDS)
Funck-Brentano
C
C
Department of Medicine, Vanderbilt University, Nashville, TN 37232.
Silberstein
D J
DJ
Roden
D M
DM
Wood
A J
AJ
Woosley
R L
RL
D000328:Adult; D001262:Atenolol / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D011433:Propranolol / Q000378:metabolism; D011897:Random Allocation; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013015:Sotalol / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism
D011943:Receptors, Adrenergic, beta; D001262:Atenolol; D011433:Propranolol; D013015:Sotalol