Mechanisms of sympathoexcitation via P2Y(6) receptors

Many drugs used in cardiovascular therapy, such as angiotensin receptor antagonists and beta-blockers, may exert at least some of their actions through effects on the sympathetic nervous system, and this also holds true for e.g., P2Y(12) antagonists. A new target at the horizon of cardiovascular drugs is the P2Y(6) receptor which contributes to the development of arteriosclerosis and hypertension. To learn whether P2Y(6) receptors in the sympathetic nervous system might contribute to actions of respective receptor ligands, responses of sympathetic neurons to P2Y(6) receptor activation were analyzed in primary cell culture. UDP in a concentration dependent manner caused membrane depolarization and enhanced numbers of action potentials fired in response to current injections. The excitatory action was antagonized by the P2Y(6) receptor antagonist MRS2578, but not by the P2Y(2) antagonist AR-C118925XX. UDP raised intracellular Ca(2+) in the same range of concentrations as it enhanced excitability and elicited inward currents under conditions that favor Cl(−) conductances, and these were reduced by a blocker of Ca(2+)-activated Cl(−) channels, CaCCInh-A01. In addition, UDP inhibited currents through K(V)7 channels. The increase in numbers of action potentials caused by UDP was not altered by the K(V)7 channel blocker linopirdine, but was enhanced in low extracellular Cl(−) and was reduced by CaCCInh-A01 and by an inhibitor of phospholipase C. Moreover, UDP enhanced release of previously incorporated [3H] noradrenaline, and this was augmented in low extracellular Cl(−) and by linopirdine, but attenuated by CaCCInh-A01. Together, these results reveal sympathoexcitatory actions of P2Y(6) receptor activation involving Ca(2+)-activated Cl(−) channels.