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


RESULTS
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.


CONCLUSIONS
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.
Yasuda
S U
SU
Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20007, USA.
Nagashima
S
S
Douyon
E
E
Benton
R E
RE
Woosley
R L
RL
Barbey
J T
JT
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D000328:Adult; D000368:Aged; D001283:Atrioventricular Node / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009636:Norbornanes / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology*; D058915:Purinergic P1 Receptor Antagonists
D009636:Norbornanes; D058915:Purinergic P1 Receptor Antagonists; C073387:N 0861; D000225:Adenine