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-beta,gamma-dibromomethyleneATP (ARL 67156). Field stimulation of the parasympathetic nerves innervating guinea-pig urinary bladder muscle strips (1-8 Hz for 20 s) produced characteristic biphasic contractions, the peak magnitudes of which were significantly increased by 29-32% by ARL 67156 (100 mu M). A similar degree of enhancement was seen in the presence of atropine (1 mu M), consistent with ARL 67156 acting to enhance the action of neuronally released ATP. The effects of ARL 67156 reversed rapidly on washout of the drug. Contractions evoked by exogenous ATP (100 mu M) were also potentiated by ARL 67156 (100 mu M), but those to the stable analogue alpha,beta-methyleneATP (5 mu M) were unaffected. ARL 67156 (100 mu M) also enhanced contractions to exogenous acetylcholine (1 mu M) and histamine (3 mu M). but this potentiation was abolished by pyridoxalpbosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) (100 mu M). It is concluded that when ATP acts as a neurotransmitter its postjunctional actions are attenuated by enzymatic degradation. ARL 67156 inhibits this breakdown. (C) 1997 Elsevier Science B.V.