P-2-purinoceptors mediating spasm of the isolated uterus of the non-pregnant guinea-pig

1 The isolated uterus of the non-pregnant guinea-pig has been suggested to contain P-1-, and possibly P-2-purinoceptors mediating spasm. The presence of P-1-purinoceptors has been confirmed and these receptors have been further characterized. 2 In the presence of the adenosine uptake inhibitor, S-(4-nitrobenzyl)-6-thioinosine (NBTI, 300 nM) and a pA(100) concentration of the P-1-purinoceptor antagonist 8-sulphophenyltheophylline (140 mu M), the potency order of agonists as spasmogens was: 2 methylthio ATP >> alpha,beta methylene ATP=UTP=ATP >> beta,gamma methylene ATP. This order is not consistent with any single recognised P-2-purinoceptor subtype. 3 Indomethacin (1 mu M) treatment abolished responses to 2 methylthio ATP, alpha,beta methylene ATP and UTP, while spasm to ATP was significantly inhibited. When the endometrial and circular smooth muscle cell layers were removed, spasmogenic responses to ATP, 2 methylthio ATP, alpha,beta methylene ATP and UTP were significantly reduced. 4 2 methylthio ATP was able to cause desensitization to itself, but not to UTP, indicating that these agonists act at different receptor sites. 5 The P-2-purinoceptor antagonist, suramin antagonized 2 methylthio ATP with a pA(2) of 5.9+/-0.3. Suramin was also an antagonist of ATP and UTP. In the case of ATP, the antagonism was not dependent on suramin concentration, while for UTP the interaction appeared to be non-equilibrium. Pyridoxalphosphate-6-azophenyl-2',4'-dis acid (PPADS, 10 mu M) had no effect on spasm to ATP, UTP or 2 methythio ATP. 6 In the presence of indomethacin, responses to ATP were unaffected by 8-sulphophenyltheophylline (140 mu M) or by suramin (100 mu M), but PPADS (10 mu M) antagonized ATP. 7 These results suggest that the isolated uterus of the non-pregnant guinea-pig contains a mixture of P-2-purinoceptors. P-2U- (Or UTP-selective pyrimidinoceptors) and P-2Y-purinoceptors appear to be present, probably mainly located on the endometrial or circular smooth muscle layer. Activation of these receptors leads to spasm via increases in prostanoid generation. There appears also to be a third class of non-P-2X-, non P-2Y-purinoceptor present, at which ATP is an agonist and PPADS is an antagonist, located on the longitudinal smooth muscle, activation of which causes spasm independent of changes in prostanoids.