ADP-BETA-S INDUCES CONTRACTION OF THE HUMAN ISOLATED URINARY-BLADDER THROUGH A PURINOCEPTOR SUBTYPE DIFFERENT FROM P-2X AND P-2Y

The classification of purinergic receptors is seriously hampered by th e lack of specific antagonists. Furthermore, there is increasing evide nce that other purinoceptor subtypes may exist that are different than the relatively well characterized P-2X, P-2Y, P-2Z and P-2T. Human is olated urinary bladder was reported to contract in response to challen ge with alpha,beta-methylene adenosine 5'-triphosphate (alpha,beta-MeA TP) and adenosine 5'-triphosphate (ATP), probably through activation o f P-2X purinoceptors. In this work, we tried to classify the purinocep tors subtypes present in human detrusor muscle by using adenosine 5'-[ beta-thio]diphosphate (ADP beta S), alpha,beta-MeATP, 2-methylthio ade nosine 5'-triphosphate (2-MeSATP), ATP and uridine 5'-triphosphate (UT P). We also examined the activity of two putative P-2 antagonists (p-c hloromercuribenzensulfonic acid [PCMBS] and Reactive Blue 2 [RB-2]). T he agonist rank order of potency was alpha,beta-MeATP = ADP beta S > 2 -MeSATP > ATP >> UTP. Cumulative responses to alpha,beta-MeATP induced a very rapid desensitization, but responses to alpha,beta-MeATP and A DP beta S, both at 100 mu M, were additive. PCMBS antagonized ADP beta S-induced contractions with a pK(B) of 6.49, but it was inactive agai nst (alpha,beta-MeATP. The putative P-2Y antagonist RB-2 had no effect against ADP beta S-induced contraction. We conclude that human detrus or muscle contains two contractile purinoceptor subtypes. One is activ ated by alpha,beta-MeATP and is probably the P-2X subtype; the other i s activated by ADP beta S and appears to be different from those accep ted by the current classification. The similarity between our results and those obtained by other investigators is discussed.