DIFFERENTIAL-EFFECTS OF NITRIC-OXIDE DONORS ON BASAL AND ELECTRICALLY-EVOKED RELEASE OF ACETYLCHOLINE FROM GUINEA-PIG MYENTERIC NEURONS

1 The effects of the nitric oxide (NO) donors, 3-morpholino-sydnonimin e (SIN-1), S-nitroso-N-acetylpenicillamine (SNAP) and sodium nitroprus side on basal and electrically evoked release of [H-3]-acetylcholine w ere studied in myenteric plexus longitudinal muscle preparations of th e guinea-pig small intestine preincubated with [H-3]-choline. 2 The NO donors concentration-dependently increased basal release of [H-3]-ace tylcholine. The increase in release was calcium-dependent and was prev ented in the presence of tetrodotoxin. Superoxide dismutase (150 u ml( -1)) potentiated the effect of SIN-1. The selective inhibitor of solub le guanylyl cyclase, H-1-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ, 0.01-1 mu M), antagonized the facilitatory effect of SNAP. 8-Bro mo cyclic GMP and the cyclic GMP-specific phosphodiesterase inhibitor, zaprinast (both 0.1-1 mM), also enhanced basal [H-3]-acetylcholine re lease. The effect of 10 mu M SNAP was significantly enhanced in the pr esence of zaprinast. 3 The NO donors concentration-dependently inhibit ed the electrically evoked release of [H-3]-acetylcholine, whereas 8-b romo cyclic GMP and zaprinast enhanced the evoked release. The inhibit ion of acetylcholine release by SNAP was not affected by ODQ (0.01-1 m u M). 4 It is concluded that NO stimulates basal acetylcholine release from myenteric neurones through activation of guanylyl cyclase. In ad dition, NO inhibits the depolarization evoked release of acetylcholine by a presynaptic mechanism unrelated to cyclic GMP. The data imply th at NO is not only an inhibitory transmitter to intestinal smooth muscl es but also a modulator of cholinergic neurotransmission in the myente ric plexus.