Abstract:
BACKGROUND:There has been increasing interest in the development of agents that utilize endogenous adenosine to exert their actions. We tested the hypothesis that substances that either potentiate the activity (allosteric enhancers) or increase the interstitial concentration (inhibitors of metabolism) of endogenous adenosine may cause event (tachycardia)-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 inhibitor of adenosine deaminase), draflazine (a nucleoside transport blocker), and PD81,723 (an allosteric enhancer of the A1 adenosine receptor binding) on the stimulus-to-His bundle (SH) interval, a measure of AV nodal conduction, were determined in guinea pig hearts and compared with those of adenosine and diltiazem. All drugs depressed AV nodal conduction in a frequency-dependent manner. The ratios of SH interval 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 prolongation 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 effects of draflazine, ITU, EHNA, and PD81,723 were reversed by the A1 adenosine receptor antagonist 8-cyclopentyltheophylline and adenosine deaminase, implicating endogenous adenosine acting at the A1 adenosine 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 supraventricular arrhythmias and control of ventricular rate during atrial fibrillation or flutter.
journal_name
Circulationjournal_title
Circulationauthors
Dennis DM,Raatikainen MJ,Martens JR,Belardinelli Ldoi
10.1161/01.cir.94.10.2551subject
Has Abstractpub_date
1996-11-15 00:00:00pages
2551-9issue
10eissn
0009-7322issn
1524-4539journal_volume
94pub_type
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