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

Activation of P2 purinergic receptors exerts a potent positive inotropic ef fect 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 in vestigate the effect of P2 receptor agonist on the function of the intact h eart. In both Langendorff rat hearts and working rat and mouse heart models , the P2X receptor agonist 2-methylthio-ATP (2-meSATP) caused dose-dependen t increases in left ventricular developed pressure, rate of contraction, an d rate of relaxation. The extent of P2X receptor agonist-stimulated increas e in contractility was significantly less than that stimulated by the beta -adrenergic agonist isoproterenol. However, the increase in contractility o ccurred without a significant effect on the basal heart rate, in contrast t o 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 fro m 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 c ontractility in the presence of phospholipase C inhibitor U-73122, consiste nt 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 f or the concept that agonist at this receptor may be beneficial for the trea tment of cardiac dysfunction.