Diadenosine-5-phosphate exerts A1-Receptor-mediated proarrhythmic effects in rabbit atrial myocardium

1 Diadenosine polyphosphates have been described to be present in the myocardium and exert purinergic- and nonreceptor-mediated effects. Since the electrophysiological properties of atrial myocardium are effectively regulated by A(1) receptors, we investigated the effect of diadenosine pentaphosphate (Ap(5)A) in rabbit myocardium. 2 Parameters of supraventricular electrophysiology and atrial vulnerability were measured in Langendorff-perfused rabbit hearts. Muscarinic potassium current (I-K(ACh/Ado)) and ATP-sensitive potassium current (I-K(ATP)) were measured by using the whole-cell voltage clamp method. 3 Ap(5)A prolonged the cycle length of spontaneously beating Langendorff perfused hearts from 225+/-14 (control) to 1823+/-400 ms (Ap(5)A 50 muM; n = 6; P < 0.05). This effect was paralleled by higher degree of atrio-ventricular block. Atrial effective refractory period (AERP) in control hearts was 84+/-14 ms (n = 6). Ap(5)A >= 1 mu M reduced AERP (100 mu M, 58+/-11 ms; n = 6). 4 Extrastimuli delivered to hearts perfused with Ap(5)A- or adenosine (>= mu M)-induced atrial fibrillation, the incidence of which correlated to the concentration added to the perfusate. The selective A(1)-receptor antagonist CPX (20 mu M) inhibited the Ap(5)A- and adenosine-induced decrease of AERP. Atrial fibrillation was no longer observed in the presence of CPX. 5 The described Ap(5)A-induced effects in the multicellular preparation were enhanced by dipyridamole (10 mu M), which is a cellular adenosine uptake inhibitor. Dipyridamole-induced enhancement was inhibited by CPX. 6 Ap(5)A (<= 1 mM) did neither induce I-K(Ado) nor I-K(ATP). No effect on activated I-K(Ado/ATP) was observed in myocytes superfused with Ap(5)A. However, effluents from Langendorff hearts perfused with Ap(5)A 100 mu M activated I-K(Ado) by using A(1) receptors. 7 Ap(5)A did not activate A(1) receptors in rabbit atrial myocytes. The Ap(5)A induced A(1)-receptor-mediated effects on supraventricular electrophysiology and vulnerability suggest that in the multicellular preparation Ap(5)A is hydrolyzed to yield adenosine, which acts via A(1) receptors. An influence on atrial electrophysiology or a facilitation of atrial fibrillation under conditions resulting in increased interstitial Ap(5)A concentrations might be of physiological/pathophysiological relevance.