Adenosine A1-receptor occupancy predicts A1-receptor antagonist effects of N-0861*

Autor: Satoru Nagashima, Raymond L. Woosley, Erwin Douyon, Sally Usdin Yasuda, Jean T. Barbey, Robert E. Benton
Rok vydání: 1998
Předmět:
Zdroj: Clinical Pharmacology & Therapeutics. 64:536-541
ISSN: 1532-6535
0009-9236
Popis: Objective To evaluate the relationship between dose of N-0861 ([±]N6-endo-norbornan-2-yl-9-methyladenine), N-0861 plasma concentrations, and antagonism of adenosine-induced slowing of atrioventricular nodal conduction and to evaluate A1-receptor occupancy by antagonist present in plasma of subjects after administration of N-0861 to determine A1-selectivity of these effects. Methods The study was conducted in patients undergoing a clinically indicated electrophysiology study to evaluate atrioventricular nodal conduction. Nineteen subjects were enrolled in the study and received adenosine (60 to 140 μg/kg) before or during a bolus dose and maintenance infusion of specific doses of N-0861. Adenosine-induced slowing of atrioventricular nodal conduction was determined by measuring A-H intervals on the intracardiac electrocardiograms. Plasma concentrations of N-0861 were determined with an HPLC method. A1-Receptor occupancy by antagonist present in plasma from identical time points was determined with use of a radioreceptor assay. Results A linear relationship was shown between plasma concentration and dose of N-0861. A-H interval lengthening by 60 μg/kg adenosine was reduced by administration of N-0861. A linear relationship was observed between A1 occupancy and N-0861 concentration and between occupancy and antagonism of adenosine-induced A-H prolongation. Conclusion The results suggest that the effect of N-0861 on antagonism of adenosine-induced prolongation of A-H interval, at the doses used in this study, were the result of effects at the A1 receptor. Clinical Pharmacology & Therapeutics (1998) 64, 536–541; doi
Databáze: OpenAIRE
Externí odkaz: