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.