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

• Published in: Clinical pharmacology and therapeutics Vol. 64; no. 5; p. 536
• Main Authors: Yasuda, S U, Nagashima, S, Douyon, E, Benton, R E, Woosley, R L, Barbey, J T
• Format: Journal Article
• Language: English
• Published: United States 01.11.1998
• Subjects: Adenine - administration & dosage; Adenine - analogs & derivatives; Adenine - blood; Adenine - pharmacology; Adult; Aged; Atrioventricular Node - drug effects; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Female; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Middle Aged; Norbornanes - administration & dosage; Norbornanes - blood; Norbornanes - pharmacology; Purinergic P1 Receptor Antagonists
• ISSN: 0009-9236
• DOI: 10.1016/S0009-9236(98)90136-9

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. 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 microg/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. A linear relationship was shown between plasma concentration and dose of N-0861. A-H interval lengthening by 60 microg/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. 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.