MODULATION OF ATRIOVENTRICULAR NODAL FUNCTION BY METABOLIC AND ALLOSTERIC REGULATORS OF ENDOGENOUS ADENOSINE IN GUINEA-PIG HEART

Background There has been increasing interest in the development of ag ents that utilize endogenous adenosine to exert their actions. We test ed the hypothesis that substances that either potentiate the activity (allosteric enhancers) or increase the interstitial concentration (inh ibitors of metabolism) of endogenous adenosine may cause event (tachyc ardia)-specific depression of AV nodal conduction. Methods and Results The frequency-dependent effects of iodotubercidin (ITU, an inhibitor of adenosine kinase), erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, an i nhibitor of adenosine deaminase), draflazine (a nucleoside transport b locker), and PD81,723 (an allosteric enhancer of the A(1) adenosine re ceptor binding) on the stimulus-to-His bundle (SH) interval, a measure of AV nodal conduction, were determined in guinea pig hearts and comp ared with those of adenosine and diltiazem. Al drugs depressed AV noda l conduction in a frequency-dependent manner. The ratios of SH interva l prolongations at fast to slow pacing rates for draflazine, ITU+EHNA, PD81,723, adenosine, and diltiazem were 17.5+/-3.4, 11.1+/-5.0, 3.5+/ -0.9, 10.1+/-2.8, and 8.3+/-3.5, respectively. Coincident with the pro longation of the SH interval at rapid pacing rates, draflazine and ITU +EHNA increased the epicardial fluid adenosine concentrations by 2.2- and 2.6-fold, respectively. In contrast, epicardial transudate levels of adenosine do not change in the presence of PD81,723. The AV nodal e ffects of draflazine, ITU, EHNA, and PD81,723 were reversed by the A(1 ) adenosine receptor antagonist 8-cyclopentyltheophylline and adenosin e deaminase, implicating endogenous adenosine acting at the A(1) adeno sine receptor. Conclusions Adenosine-regulating agents that act in an event- and site-specific manner represent a novel drug design strategy that may potentially be valuable for the long-term treatment of supra ventricular arrhythmias and control of ventricular rate during atrial fibrillation or flutter.