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

Objective: To evaluate the relationship between dose of N-0861 ([+/-]N-6-endo-norbornan-2-yl-9-methyladenine), N-0861 plasma concentrations, and antagonism of adenosine-induced slowing of atrioventricular nodal conduction and to evaluate A(1)-receptor occupancy by antagonist present in plasma of subjects after administration of N-0861 to determine A(1)-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 mu g/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, A(1)-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 mu g/kg adenosine was reduced by administration of N-0861. A linear relationship was observed between A(1) 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 A(1) receptor.