Atrioventricular nodal accommodation in isolated guinea pig hearts: Physiological significance and role of adenosine

Abstract

The progressive prolongation of atrioventricular node (AVN) conduction time to a new steady-state value caused by sudden and maintained increases in atrial rate is the most common form of AV nodal accommodation. This study was undertaken to 1) characterize AV nodal accommodation in isolated perfused guinea pig hearts, 2) investigate the influence of potential modulators of this phenomenon such as acetylcholine and adenosine, and 3) determine the physiological significance of AV nodal accommodation on cardiac function. Beat-by-beat changes in AVN conduction time caused by single- or multiple-step increases in atrial pacing rate were measured during control conditions and in the presence of atropine (1 μM), propranolol (1 μM), and the adenosine antagonist BW-A1433 (1 μM). BW-A1433 was the only intervention that significantly reduced the cumulative and frequency-dependent prolongation of AVN conduction time but this was only observed at atrial cycle lengths ≤ 170 msec. In addition, BW-A1433 shortened the Wenckebach cycle length from 163 ± 2 to 153 ± 2 during normoxia and from 172 ± 3 to 164 ± 4 during mild hypoxia. In contrast, dipyridamole (1 μM), an adenosine uptake blocker, markedly accentuated the AVN conduction time prolongation, accentuated the AV block associated with fast atrial rates, and significantly increased the Wenckebach cycle length. These effects of dipyridamole were prevented and antagonized by BW-A1433 and adenosine deaminase. When O2 supply was limited and at the same time demand increased secondary to fast atrial pacing, the rate of adenosine release increased from a control of 125 ± 27 to 580 ± 54 pmol/min/g. This was accompanied by a significant prolongation in AVN conduction time that invariably progressed to AV block. Once AV block occurred, O2 consumption decreased, O2 supply-to-demand ratio improved and the rate of adenosine release dropped to 310 ± 61 pmol/min/g. Reversal of the AV block with adenosine antagonists resulted in a decrease in O2 supply-to-demand ratio and a severalfold increase in the rate of adenosine release. In this feedback system, adenosine signals the imbalance between O2 supply and demand, causes AV block and, thus, reduces demand to compensate for the limited O2 supply. On the other hand, adenosine deaminase and antagonists act as 'error signals' by attenuating the effect of adenosine, whereas dipyridamole enhances the 'gain' of the system by potentiating the effects of adenosine. We concluded that 1) AV nodal accommodation is an intrinsic property of the AVN that can be influenced by adenosine, and 2) under conditions of low O2 supply-to-demand ratio, adenosine is produced as a negative feedback signal that protects the ventricles from excessive work by causing AV block.