Intestinal motor depression by 7-nitroindazole through an action unrelatedto nitric oxide synthase inhibition

Nitric oxide (NO) is a cotransmitter of inhibitory motor neurons of the ent eric nervous system. This study examined the effect of 7-nitroindazole (7-N I), an inhibitor of neuronal NO synthase (NOS), on intestinal peristalsis a nd muscle activity and compared 7-NI with N-G-nitro-L-arginine methyl ester (L-NAME), a nonselective inhibitor of NOS isoforms. Peristalsis in isolate d segments of the guinea pig small intestine was triggered by a perfusion-i nduced rise of the intraluminal pressure. While L-NAME (10-300 mu mol/l) lo wered the peristaltic pressure threshold (PPT) at which propulsive muscle c ontractions were elicited, 7-NI (10-300 mu mol/l) caused a concentration-re lated increase in PPT. L-Arginine (1-3 mmol/l) failed to reverse peristalti c motor depression evoked by 7-NI but annulled the L-NAME-evoked stimulatio n of peristalsis. Drugs which stimulated peristalsis, such as L-NAME, nalox one, apamin and suramin plus pyridoxal phosphate-6-azophenyl-2'-4'-disulpho nic acid counteracted the inhibitory effect of submaximally effective conce ntrations of 7-NI on peristalsis. 7-NI (100-300 mu mol/l) inhibited circula r muscle contractions evoked by cholecystokinin octapeptide, the NK1 recept or agonist GR-73,632 and indomethacin whereas L-NAME (100-300 mu mol/l) fai led to inhibit any drug-evoked contraction. These data show that 7-NI, unli ke L-NAME, inhibits circular muscle contractions of the gut and depresses i ntestinal peristalsis. It is concluded that the inhibitory motor action of 7-NI is unrelated to inhibition of neuronal NOS and arises from depression of smooth muscle activity. Copyright (C) 1999 S.Karger AG, Basel.