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 inte stine were secured in a three chambered organ bath so that different p arts of the reflex pathways could be independently exposed to drug-con taining solutions. Reflexes were evoked by distension or compression o f the mucosa in two adjacent chambers and reflex responses were record ed from the circular muscle with intracellular microelectrodes in the third chamber. Thus, the actions of drugs at connections between senso ry neurones and interneurones, between interneurones and other interne urones 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 th e central stimulation chamber or the recording chamber. 4 In contrast, L-NMMA (100 mu M) enhanced the descending inhibitory reflex when adde d to the chamber in which stimuli were applied. This effect was preven ted by prior exposure to L-arginine (100 mu M), which had no effect by itself. Conduction of reflexes between the stimulus chamber and the r ecording chamber was unaffected by the presence of L-NMMA in an interv ening chamber. 5 L-NMMA (100 mu M) added to the recording chamber depr essed the descending inhibitory reflex, an effect that was prevented b y previous exposure to L-arginine. 6 The nitric oxide donor, sodium ni troprusside (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, r eleased from the cell bodies of descending interneurones, suppresses t ransmission from synaptic connections made with them by enteric sensor y neurones.