The activation of P1‐ and P2‐purinoceptors in the guinea‐pig left atrium by diadenosine polyphosphates

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Abstract
1 The effects of P1, P2-di(adenosine) pyrophosphate (AP2A), P1, P3-di(adenosine) triphosphate (AP3A), P1, P4-di(adenosine) tetraphosphate (AP4A), P1, P5-di(adenosine) pentaphosphate (AP5A), ATP, α, β-methylene ADP and 2-chloroadenosine (2-ClAd) were examined in the guinea-pig driven left atrium. 2 All these purine compounds except α, β-methylene ADP produced a negative inotropic response with a rank order of potency of: 2-ClAd> > AP2A ≥ ATP ≥ AP4A = AP3A = AP5A. The EC50 value for 2-ClAd was approximately 1 μm, while those for the remaining compounds were in the range 10 μm-100 μm, α, β-Methylene ADP (10–300 μm), a selective P2Y-purinoceptor agonist, produced a small positive inotropism. 3 The P1-purinoceptor antagonist, 8-para-sulphophenyltheophylline (8-pSPT, 20 μm) caused a rightward shift in the concentration-response curves for 2-ClAd, ATP and AP2A, but converted the responses of AP3A, AP4A, and AP5A into positive inotropisms. 4 The non-selective P2-purinoceptor antagonist, suramin (300 μm), had no significant effect on the concentration-response curves for 2-ClAd, ATP or AP2A, but significantly antagonized inhibitory responses to AP3A, AP4A and AP5A, and excitatory responses to α, β-methylene ADP. 5 In the presence of 8-pSPT (20 μm), suramin (300 μm) abolished the positive inotropic responses evoked by the dinucleotides. 6 ATP was degraded far more rapidly than any of the dinucleotides, and AP3A was the least stable of the diadenosine compounds. The relative order of stability was AP2A > AP4A = AP5A > AP3A > > ATP. Suramin (300 μm) reduced the rate of degradation of ATP and AP3A by approximately 30%. Suramin had no significant effect on the degradation of AP2A, AP4A or AP5A. 7 It is concluded that the diadenosine polyphosphates cause negative inotropic responses via P1-purinoceptors and a hitherto undefined suramin-sensitive P2-purinoceptor, and that they appear to have positive inotropic effects mediated via another suramin-sensitive P2-purinoceptor.