Purpose: Adenine nucleotides control cardiovascular function via P2X and P2Y receptors activation. The P2X4 is the most expressed P2X receptor subtype in human atria. Up-regulation of P2X4 receptor (P2X4R)-mediated inotropism has been observed in animal models of heart failure. This receptor is considered a putative pharmacological target for ischemia/reperfusion. Despite the effects of the P2X4R on cardiovascular pathophysiology, no studies addressed its role on the atrial pacemaker activity.
Methods: Experiments were performed on isolated spontaneously beating right atria and on 4 Hz-paced right ventricle strips from Wistar rats superfused with gassed Tyrode's solution. Isometric muscle tension was monitored with a PowerLab data acquisition system.
Results: ATP (100 μM) and its non-hydrolysable analogue, ATPΓS (100 μM), caused rapid and sustained negative chronotropic effects on spontaneously beating right atria. The negative chronotropic effect of ATP was potentiated by inhibiting ecto-NTPDases with POM-1 (100 μM). The P2X4R antagonist, 5'-BDBD (10 μM), prevented the negative chronotropic effect of ATP. ATP (100 μM) produced a mild decrease in the magnitude of paced ventricular tension, which was further potentiated, rather than attenuated, in the presence of 5'-BDBD (10 μM). Inhibition of the reverse mode of the Na+/Ca2+ exchanger (NCX) with KB-R7943 (3 μM) mimicked the effects of the P2X4R antagonist, 5'-BDBD (10 μM), both on spontaneously beating right atria and paced right ventricle.
Conclusions: Data suggest that P2X4R activation decreases the SA node rate while increasing the ventricular contractile force. The mechanism underlying these dual effects of ATP in the rat heart may involve bolstering of the NCX function in the reverse mode. Na+ influx via P2X4 might inhibit/revert the electrogenic forward mode of the NCX decreasing chronotropy. Likewise, intracellular Ca2+ accumulation due to inhibition and/or reversal of the NCX might explain the positive inotropic effect attributed to P2X4R activation on paced right ventricular strips Thus, targeting the P2X4R activation or its underlying NCX-based mechanism may create novel well-tolerated heart-rate lowering drugs with potential benefits in patients with deteriorated ventricular function.