Local regulation of [ 3 H]‐noradrenaline release from the isolated guinea‐pig right atrium by P 2X ‐receptors located on axon terminals

In this study the regulation of cardiac sympathetic outflow by presynaptic P 2X receptor‐gated ion channels was examined. ATP (30 μ M –1 m M ) and other P2‐receptor agonists elicited [ 3 H]‐noradrenaline ([ 3 H]‐NA) outflow from the isolated guinea‐pig right atrium with the potency order of ATP>2‐methyl‐thioATP>α,β‐methylene‐ATP=ADP, whereas β,γ‐methylene‐ L ‐ATP was inactive. Ca 2+ ‐free conditions abolished both electrical field stimulation (EFS)‐ and ATP‐evoked release of tritium. Unlike from EFS‐induced outflow, ATP‐induced [ 3 H]‐NA outflow was not reduced by ω‐Conotoxin‐GVIA (100 n M ), Cd 2+ (100 μ M ) and tetrodotoxin (1 μ M ). The rapid extracellular decomposition of ATP was revealed by HPLC analysis. However, the effect of ATP to promote [ 3 H]‐NA release was not prevented by 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX, 250 n M ), 3,7‐dimethyl‐1‐propargylxanthine (DMPX, 250 n M ), or by reactive blue 2 (RB2, 10 μ M ), antagonists of A 1 ‐, A 2 ‐ and inhibitory P 2 receptors. Zn 2+ (50 μ M ), the P 2X ‐receptor modulator potentiated, and P 2X receptor antagonists, i.e. suramin (300 μ M ), pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS, 30 μ M ) and 2′‐o‐(trinitrophenyl)‐adenosine 5′‐triphosphate (TNP‐ATP, 30 μ M ) antagonized the ATP (1 m M )‐evoked response. RT–PCR study revealed the expression of P 2X2 and P 2X3 receptor mRNAs in guinea‐pig superior cervical ganglion. PPADS (30 μ M ) significantly reduced the EFS‐induced [ 3 H]‐NA outflow in the presence DPCPX (250 n M ) and RB2 (10 μ M ). 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.British Journal of Pharmacology (2000) 131 , 1775–1783; doi: 10.1038/sj.bjp.0703757