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 microM - 1 mM) 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>alpha,beta-methylene-ATP=ADP, whereas ss, gamma-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 omega-Conotoxin-GVIA (100 nM), Cd(2+) (100 microM) and tetrodotoxin (1 microM). 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 nM), 3, 7-dimethyl-1-propargylxanthine (DMPX, 250 nM), or by reactive blue 2 (RB2, 10 microM), antagonists of A(1)-, A(2)- and inhibitory P(2) receptors. Zn(2+) (50 microM), the P(2X)-receptor modulator potentiated, and P(2X) receptor antagonists, i.e. suramin (300 microM), pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 30 microM) and 2'-o-(trinitrophenyl)-adenosine 5'-triphosphate (TNP-ATP, 30 microM) antagonized the ATP (1 mM)-evoked response. RT - PCR study revealed the expression of P(2X2) and P(2X3) receptor mRNAs in guinea-pig superior cervical ganglion. PPADS (30 microM) significantly reduced the EFS-induced [(3)H]-NA outflow in the presence DPCPX (250 nM) and RB2 (10 microM). 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.
Sperlágh
B
B
Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1450 Budapest, POB 67, Hungary.
Erdélyi
F
F
Szabó
G
G
Vizi
E S
ES
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D015870:Gene Expression; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000502:physiology*; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D012313:RNA / Q000235:genetics / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D017783:Superior Cervical Ganglion / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D013805:Theobromine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors; D014316:Tritium; D014970:Xanthines / Q000494:pharmacology; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D013873:Thionucleotides; D014970:Xanthines; D002104:Cadmium; D014316:Tritium; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; C005147:5'-adenylyl (beta,gamma-methylene)diphosphonate; D013779:Tetrodotoxin; D011732:Pyridoxal Phosphate; C057837:3,7-dimethyl-1-propargylxanthine; D000244:Adenosine Diphosphate; D012313:RNA; D000255:Adenosine Triphosphate; D020866:omega-Conotoxin GVIA; C051360:1,3-dipropyl-8-cyclopentylxanthine; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D013805:Theobromine; D009638:Norepinephrine; C008501:2-methylthio-ATP