NITRIC OXIDE-SENSITIVE GUANYLYL CYCLASE INHIBITS ACETYLCHOLINE-RELEASE AND EXCITATORY MOTOR TRANSMISSION IN THE GUINEA-PIG ILEUM

This study examined the mechanism through which nitric oxide inhibits the release of acetylcholine and excitatory motor neurotransmission in the guinea-pig ileum. The selective inhibitor of nitric oxide-sensiti ve guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) , concentration-dependently enhanced both basal release (-log EC50: 6. 8) and electrically (10 Hz) -evoked release (-log EC50: 6.0) of [H-3]a cetylcholine from longitudinal muscle-myenteric plexus preparations pr eincubated with [H-3]choline. The increase by ODQ of basal release app eared to be exocytotic since it was prevented by tetrodotoxin (300 nM) and absence of calcium from the superfusion medium. In addition, ODQ (1 mu M) increased the electrically-evoked tachykininergic and choline rgic muscle contractions as measured in the presence of scopolamine (1 00 nM) or of the neurokinin-1 receptor antagonist CP 99994 (100 nM), r espectively. The nitric oxide synthase inhibitor L-N-G-nitro-arginine (100 mu M) behaved similar to ODQ and increased cholinergic and tachyk ininergic motor neurotransmission. The nitric oxide-independent activa tor of soluble guanylyl cyclase, 3-(5'-hydroxymethyl-2'-furyl)-1-benzy l indazole, concentration-dependently inhibited the electrically evoke d acetylcholine release (-log EC50: 6.0) and longitudinal muscle contr actions (-log EC50: 5.7). ODQ (10 mu M) antagonized the effects of 3-( 5'-hydroxymethyl-2'-furyl)-1-benzyl indazole. The results suggest that endogenous nitric oxide tonically activates soluble guanylyl cyclase in myenteric neurons which leads to inhibition of the release of the e xcitatory transmitters acetylcholine and substance P. ODQ prevents the effects of nitric oxide and thus facilitates cholinergic and tachykin inergic motor neurotransmission in the guinea-pig ileum. (C) 1997 IBRO . Published by Elsevier Science Ltd.