ИСТИНА

Diadenosine polyphosphates (Ap(n)A) are recently considered as endogenous signaling compounds which are present in numerous mammalian tissues, including heart. Extracellular Ap(n)A cause suppression of working myocardium contractility, induce inhibitory effects in cardiac pacemaker and alter bioelectrical activity via P1- or P2-purine receptors. However, the particular intracellular mechanisms which underlie Ap(n)A cardiac effects remain unknown. In the present study we show the role of P2Y-associated regulatory pathway in mediation of Ap4A effects in the rat heart. Effects of Ap4A on myocardial contractility were estimated in isolated Langendorff-perfused paced (4 Hz) hearts of male Wistar rats. Action potentials (APs) were recorded with sharp microelectrodes in isolated multicellular preparations. Alteration of cytosolic calcium ([Ca2+]i) transients was measured using Fluo-4 fluorescent dye in enzymatically isolated rat ventricular myocytes. Diadenosine tetraphosphate (10 µM, n=7) induced significant decrease in left ventricular developed pressure, maximal rate of contraction and relaxation in isolated rat heart. Inhibitory effects of Ap4A were significantly suppressed by proteinkinase C (PKC) blocker chelerythrine (5 µM, n=7). Also, Ap4A (10 µM, n=12) produced AP shortening in both atrial and ventricle myocardial preparations. Chelerythrine (5 µM, n=7) application significantly reduced effect of Ap4A on AP duration. In addition, substantial suppression of cytoplasm [Ca2+]i transients was observed in the presence of Ap4A (10 µM, n=6). PKC inhibitor (5 µM) significantly restored the amplitude of [Ca2+]i transients (n=7). Thus, we suggest that negative effects of Ap4A in the rat heart are mediated by PKC dependent pathways. This study was supported by Russian Science Foundation [grant no. 14-15-00268].