P2 purinergic receptor activation enhances cardiac contractility in isolated rat and mouse hearts

Activation of P2 purinergic receptors exerts a potent positive inotropic effect in the cardiac myocyte. However, it is unknown whether its activation can also cause an increased contractility in intact heart. With the use of isolated rat and mouse hearts, the objective of the present study was to investigate the effect of P2 receptor agonist on the function of the intact heart. In both Langendorff rat hearts and working rat and mouse heart models, the P2X receptor agonist 2-methylthio-ATP (2-meSATP) caused dose-dependent increases in left ventricular developed pressure, rate of contraction, and rate of relaxation. The extent of P2X receptor agonist-stimulated increase in contractility was significantly less than that stimulated by the beta-adrenergic agonist isoproterenol. However, the increase in contractility occurred without a significant effect on the basal heart rate, in contrast to that caused by isoproterenol. In isolated rat ventricular myocytes, both ATP and the P2X receptor agonist 2-meSATP stimulated large increases in the myocyte contractile amplitude (107 +/- 13% and 99 +/- 9%, n = 17 cells from 5 rats and n = 19 cells from 6 rats, respectively). 2-meSATP caused only a slight increase in phospholipase C activity and could stimulate myocyte contractility in the presence of phospholipase C inhibitor U-73122, consistent with the role of a phospholipase C-independent P2X receptor in mediating the positive inotropic effect of 2-meSATP. The data provide evidence for a potentially important physiological role of the cardiac P2X receptor and for the concept that agonist at this receptor may be beneficial for the treatment of cardiac dysfunction.