THE ECTO-ATPASE INHIBITOR ARL-67156 ENHANCES PARASYMPATHETIC NEUROTRANSMISSION IN THE GUINEA-PIG URINARY-BLADDER

The influence of enzymatic degradation on the neurotransmitter actions of ATP was studied using the ecto-ATPase inhibitor 6-N,N-diethyl-D-be ta,gamma-dibromomethyleneATP (ARL 67156). Field stimulation of the par asympathetic nerves innervating guinea-pig urinary bladder muscle stri ps (1-8 Hz for 20 s) produced characteristic biphasic contractions, th e peak magnitudes of which were significantly increased by 29-32% by A RL 67156 (100 mu M). A similar degree of enhancement was seen in the p resence of atropine (1 mu M), consistent with ARL 67156 acting to enha nce the action of neuronally released ATP. The effects of ARL 67156 re versed rapidly on washout of the drug. Contractions evoked by exogenou s ATP (100 mu M) were also potentiated by ARL 67156 (100 mu M), but th ose to the stable analogue alpha,beta-methyleneATP (5 mu M) were unaff ected. ARL 67156 (100 mu M) also enhanced contractions to exogenous ac etylcholine (1 mu M) and histamine (3 mu M). but this potentiation was abolished by pyridoxalpbosphate-6-azophenyl-2',4'-disulphonic acid (P PADS) (100 mu M). It is concluded that when ATP acts as a neurotransmi tter its postjunctional actions are attenuated by enzymatic degradatio n. ARL 67156 inhibits this breakdown. (C) 1997 Elsevier Science B.V.