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 microM). A similar degree of enhancement was seen in the presence of atropine (1 microM), 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 microM) were also potentiated by ARL 67156 (100 microM), but those to the stable analogue alpha,beta-methyleneATP (5 microM) were unaffected. ARL 67156 (100 microM) also enhanced contractions to exogenous acetylcholine (1 microM) and histamine (3 microM), but this potentiation was abolished by pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) (100 mciroM). It is concluded that when ATP acts as a neurotransmitter its postjunctional actions are attenuated by enzymatic degradation. ARL 67156 inhibits this breakdown.
Westfall
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Department of Physiology and Pharmacology, University of Strathclyde, Royal College, Glasgow, UK.
Kennedy
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Sneddon
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D000109:Acetylcholine / Q000494:pharmacology; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D004347:Drug Interactions; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D058910:Purinergic P2 Receptor Agonists; D013268:Stimulation, Chemical; D009435:Synaptic Transmission / Q000187:drug effects*; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation / Q000502:physiology
C092431:6-N,N-diethyl-beta,gamma-dibromomethylene-D-ATP; D004791:Enzyme Inhibitors; D058910:Purinergic P2 Receptor Agonists; D006632:Histamine; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C027201:ectoATPase; D000109:Acetylcholine