HOMOLOGOUS DESENSITIZATION OF THE A(1)-ADENOSINE RECEPTOR SYSTEM IN THE GUINEA-PIG ATRIOVENTRICULAR NODE

The objective of this study was to determine whether chronic infusion (7 days) of an A(1)-adenosine receptor (A(1)-AdoR) agonist, R-N-6-phen ylisopropyladenosine (R-PIA), causes homologous and/or heterologous de sensitization of the atrioventricular (AV) nodal A(1)-AdoR system in t he guinea pig. The negative dromotropic effects of adenosine, the A(1) -AdoR agonist N-6-cyclopentyladenosine and the muscarinic cholinergic agonist carbachol on hearts from control and treated animals were comp ared. The potencies of adenosine and N-6-cyclopentyladenosine to prolo ng AV nodal conduction time of hearts from treated animals were signif icantly reduced compared with control. In contrast, no difference in t he potency of carbachol to prolong AV nodal conduction time in the hea rts from control and R-PIA-treated guinea pigs was found. The densitie s of A(1)-AdoRs in atria and ventricles of treated hearts were 54% (P < .05) and 36% (P < .05) lower than in control hearts, respectively. T he number of A(1)-AdoRs with high affinity for agonists was 37% lower (P < .05) in ventricular membranes prepared from hearts of R-PIA-treat ed guinea pigs than in membranes from control hearts. In contrast, atr ial or ventricular muscarinic acetylcholine receptor densities were no t different in hearts of control compared with hearts of treated anima ls. An up-regulation of the density of nucleoside transporter sites wa s observed in hearts of treated animals. The quantities of G(i) and G( o) in atrial membranes prepared from hearts of treated guinea pigs wer e lower by 46% and 80%, respectively, than the quantities of G(i) and G(o) in atrial membranes prepared from hearts of control animals. It w as concluded that chronic administration of R-PIA to guinea pigs desen sitized the AV node to the negative dromotropic effect of adenosine in a homologous but not a heterologous manner and desensitization of the AV node response to adenosine was associated with down-regulation of A(1)-Ado receptors, a decrease in the fraction of A(1)-Ado receptors i n the high-affinity state and a decrease in the contents of G(i) and G (o) proteins.