ACTIVATION OF P1-PURINOCEPTOR AND P2Y-PURINOCEPTOR BY ADP-RIBOSE IN THE GUINEA-PIG TAENIA-COLI, BUT NOT OF P2X-PURINOCEPTORS IN THE VAS-DEFERENS

1 The activity of adenosine 5'-diphosphoribose (ADP-ribose), a ribosylated purine nucleotide, was investigated on the carbachol-contracted taenia coli, a tissue possessing P1- (A2) and P2Y-purinoceptors and on the guinea-pig vas deferens which possesses P2X-purinoceptors. 2 In the vas deferens, where ATP (1 muM - 1 mM) produced concentration-dependent contractions, ADP-ribose was without effect at concentrations up to 1 mM. 3 In the taenia coli, ADP-ribose (0.1 muM - 1 mM) produced concentration-dependent relaxations with a potency' similar to that of adenosine, but less than that of ATP. The pD2 values for ADP-ribose, adenosine and ATP were 4.5 +/- 0.07 (27), 4.4 +/- 0.10 (9) and 5.5 +/- 0.14 (21), respectively. The time-course of the relaxations elicited by ADP-ribose was found to be significantly longer than that for ATP and significantly shorter than that for adenosine. 4 The P1-purinoceptor antagonist, 8-phenyltheophylline (5 muM), produced parallel rightward shifts in the concentration-response curves of the relaxations of the taenia coli elicited by ADP-ribose and adenosine but not ATP. 5 Dipyridamole (0.3 muM), a purine nucleoside uptake inhibitor, potentiated the responses to adenosine and ADP-ribose in the taenia coli. These potentiations were sensitive to 8-phenyltheophylline (5 muM). 6 Reactive blue 2, a P2Y-purinoceptor antagonist, antagonized the inhibitory responses of ADP-ribose and ATP in the taenia coli, without significantly altering the inhibitory responses of either adenosine or noradrenaline. 7 In the presence of the potassium channel blocker, apamin (0.3 muM), the inhibitory responses of ADP-ribose were severely attenuated, and the inhibitory responses of ATP in the taenia coli were converted to transient contractions. Further addition of 8-PT blocked the residual responses of ADP-ribose. 8 The P2-purinoceptor antagonist, suramin (500 muM), antagonized responses to ATP and ADP-ribose, but not adenosine. Further addition of 8-PT antagonized the residual responses to ADP-ribose, but not to ATP. 9 It is concluded that ADP-ribose has a mixed pharmacological profile, evoking both P1 (A2)-purinoceptor-mediated responses and P2Y-purinoceptor-mediated responses, while being inert at P2X-purinoceptors. It is suggested that ADP-ribose may provide a useful starting point for the generation of structural analogues which have specific activity at the P2Y-purinoceptor.