Local regulation of [3H]-noradrenaline release from the isolated guinea-pig right atrium by P2X-receptors located on axon terminals

1 In this study the regulation of cardiac sympathetic outflow by presynaptic P-2X receptor-gated ion channels was examined. 2 ATP (30 muM-1 mM) and other P2-receptor agonists elicited [H-3]-noradrenaline ([H-3]-NA) outflow from the isolated guinea-pig right atrium with the potency order of ATP>2-methylthioATP > alpha,beta -methylene-ATP = ADP, whereas beta,gamma -methylene-L-ATP was inactive. 3 Ca2+-free conditions abolished both electrical field stimulation (EFS)- and ATP-evoked release of tritium. Unlike from EFS-induced outflow, ATP-induced [SH]-NA outflow was not reduced by omega -Conotoxin-GVIA (100 nM), Cd2+ (100 muM) and tetrodotoxin (1 muM). 4 The rapid extracellular decomposition of ATP was revealed by HPLC analysis. However, the effect of ATP to promote [H-3]-NA release was not prevented by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 250 nM), 3,7-dimethyl-1-propargylxanthine (DMPX, 250 nM), or by reactive blue 2 (RB2, 10 muM), antagonists of A(1)-, A(2)- and inhibitory P-2 receptors. 5 Zn2+ (50 muM), the P-2X-receptor modulator potentiated, and P-2X receptor antagonists, i.e. suramin (300 muM), pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 30 muM) and 2'-o-(trinitrophenyl)-adenosine 5'-triphosphate (TNP-ATP, 30 muM) antagonized the ATP (1 mM)-evoked response. 6 RT-PCR study revealed the expression of P-2X2 and P-2X3 receptor mRNAs in guinea-pig superior cervical ganglion. 7 PPADS (30 muM) significantly reduced the EFS-induced [H-3]-NA outflow in the presence DPCPX (250 nM) and RB2 (10 muM). 8 In summary a P-2X-type purinoceptor regulates noradrenaline release from the isolated right atrium of the guinea-pig. The pharmacological profile of the receptor resemble to homo-oligomeric P-2X3 Or hetero-oligomeric P-2X2/P-2X3 complexes, and provide a new target to intervene on sympathetic neuroeffector transmission at the presynaptic site.