P2-purinoceptor-mediated inhibition of noradrenaline release in rat atria.
1. We looked for P2-purinoceptors modulating noradrenaline release in rat heart atria. Segments of the atria were preincubated with [3H]-noradrenaline and then superfused with medium containing desipramine (1 microM) and yohimbine (1 microM) and stimulated electrically, by 30 pulses/1 Hz unless stated otherwise. 2. The adenosine A1-receptor agonist, N6-cyclopentyl-adenosine (CPA; EC50 9.7 nM) and the nucleotides, ATP (EC50 6.6 microM) and adenosine-5'-O-(3-thiotriphosphate) (ATP gamma S; EC50 4.8 microM), decreased the evoked overflow of tritium. The adenosine A2a-agonist, 2-p-(2-carbonylethyl)-phenethylamino-5'-N-ethylcarboxamido-a denosine (CGS-21680; 0.03-0.3 microM) and the P2x-purinoceptor agonist beta, gamma-methylene-L-ATP (30 microM) caused no change. 3. The concentration-response curve of CPA was shifted to the right by the adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropyl-xanthine (DPCPX; 3 nM; apparent pKB value 9.7) but hardly affected by the P2-purinoceptor antagonist, cibacron blue 3GA (30 microM). In contrast, the concentration-response curves of ATP and ATP gamma S were shifted to the right by DPCPX (3 nM; apparent pKB values 9.3 and 9.4, respectively) as well as by cibacron blue 3GA (30 microM; apparent pKB values 5.0 and 5.1, respectively). Combined administration of DPCPX and cibacron blue 3GA caused a much greater shift of the concentration-response curve of ATP than either antagonist alone. The concentration-response curve of ATP was not changed by indomethacin, atropine or the 5'-nucleotidase blocker alpha, beta-methylene-ADP. 4. Cibacron blue 3GA (30 microM) increased the evoked overflow of tritium by about 70%. The increase was smaller when the slices were stimulated by 9 pulses/O00 Hz instead of 30 pulses/I Hz.5. The results indicate that the postganglionic sympathetic axons in rat atria possess P2-purinoceptors in addition to the known adenosine Al-receptor. Both mediate inhibition of noradrenaline release. Some adenine nucleotides such as ATP and ATP gamma S act at both receptors. The presynaptic P2-purinoceptor seems to be activated by an endogenous ligand, presumably ATP, under the condition of these experiments. This is the first evidence for presynaptic P2-purinoceptors at cardiac postganglionic sympathetic axons.
von Kügelgen
I
I
Pharmakologisches Institut, Universität Freiburg, Germany.
Stoffel
D
D
Starke
K
K
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D010627:Phenethylamines / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D013498:Suramin / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology
D000959:Antihypertensive Agents; D010627:Phenethylamines; D011500:Protein Synthesis Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D058919:Purinergic P2 Receptor Antagonists; D018047:Receptors, Purinergic P1; D018048:Receptors, Purinergic P2; D014227:Triazines; D014970:Xanthines; C523965:alpha,beta-methyleneadenosine 5'-diphosphate; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D015016:Yohimbine; C005147:5'-adenylyl (beta,gamma-methylene)diphosphonate; C022571:adenosine 5'-O-(3-thiotriphosphate); C048599:N(6)-cyclopentyladenosine; C012842:Cibacron Blue F 3GA; D013498:Suramin; D000244:Adenosine Diphosphate; D001285:Atropine; D000255:Adenosine Triphosphate; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D003891:Desipramine; D009638:Norepinephrine; D007213:Indomethacin