PHARMACOLOGICAL EVIDENCE THAT NITRIC-OXIDE MAY BE A RETROGRADE MESSENGER IN THE ENTERIC NERVOUS-SYSTEM

1 The effects of inhibition of nitric oxide synthase on neuro-neuronal and neuromuscular transmission during motility reflexes in the small intestine of the guinea-pig were examined. 2 Isolated segments of intestine were secured in a three chambered organ bath so that different parts of the reflex pathways could be independently exposed to drug-containing solutions. Reflexes were evoked by distension or compression of the mucosa in two adjacent chambers and reflex responses were recorded from the circular muscle with intracellular microelectrodes in the third chamber. Thus, the actions of drugs at connections between sensory neurones and interneurones, between interneurones and other interneurones and at motor neurones could be distinguished. 3 N-G-monomethyl-L-arginine (L-NMMA; 100 mu M), an inhibitor of nitric oxide synthase, did not affect the ascending excitatory reflex when added to either the central stimulation chamber or the recording chamber. 4 In contrast, L-NMMA (100 mu M) enhanced the descending inhibitory reflex when added to the chamber in which stimuli were applied. This effect was prevented by prior exposure to L-arginine (100 mu M), which had no effect by itself. Conduction of reflexes between the stimulus chamber and the recording chamber was unaffected by the presence of L-NMMA in an intervening chamber. 5 L-NMMA (100 mu M) added to the recording chamber depressed the descending inhibitory reflex, an effect that was prevented by previous exposure to L-arginine. 6 The nitric oxide donor, sodium nitroprusside (100 mu M), added to the stimulus chamber, depressed both ascending excitatory and descending inhibitory reflexes. When added to the middle chamber, sodium nitroprusside had no effect on conduction of reflexes through this chamber. 7 It is deduced that nitric oxide, released from the cell bodies of descending interneurones, suppresses transmission from synaptic connections made with them by enteric sensory neurones.