β-Adrenoreceptor Antagonist Potency and Pharmacodynamics of ASL-8123, the Primary Acid Metabolite of Esmolol

Summary: The β-adrenoreceptor antagonist properties of ASL-8123, the primary metabolite of esmolol, were determined in vitro and in vivo. ASL-8123 demonstrated weak competitive β-adrenoreceptor blocking activity in isolated guinea pig right atria with a pA2 of 3.73 ± 0.07; no agonist-like activity was observed in this tissue at concentrations of ASL-8123 from 3 × 10−5 to 1 × 10−2M. In anesthetized dogs, ASL-8123 was infused at increasing dosages from 0.2-25.6 mg/kg/min, each dose rate maintained for 20 min. The compound produced a slight decrease in heart rate of 15-22 beats/min at cumulative doses of 508-1,020 mg/kg and decreased diastolic blood pressure by 14-47 mm Hg at cumulative doses of 252-1,020 mg/kg. ASL-8123 dose-dependently inhibited the heart rate and diastolic blood pressure responses to isoproterenol (0.5 μg/kg i.v.). Blood levels of ASL-8123 were linearly correlated with inhibition of the heart rate response to isoproterenol (r = 0.95-0.99 for each dog, n = 6). The blood level of ASL-8123 that produced a 50% inhibition of isoproterenol-induced tachycardia averaged 293 ± 65 μg/ml. Recovery from β-adrenoreceptor blockade after terminating the infusion of ASL-8123 occurred slowly, decreasing from 81% at the end of the infusion to 55% 60 min later, and was paralleled by a slow decrease in blood levels of ASL-8123. Thus, ASL-8123 is a weak β-adrenoreceptor antagonist which is approximately 1,600-1,900 times less potent than its parent, esmolol.