Modulation by nitric oxide of spontaneous motility of the rat isolated duodenum: Role of tachykinins

Abstract

1 Incubation of proximal segments of the rat isolated duodenum with N(G)-nitro-L-arginine (L-NOARG; 3-100 μM) produced a concentration-dependent increase in both resting tone and the amplitude of the spontaneous contractions. These effects were attenuated by concurrent incubation with L-arginine (1 mM) but not D-arginine (1 mM). 2 These changes in resting tone and motility induced by L-NOARG (30 μM) were substantially reduced by concurrent incubation with tetrodotoxin (1 μM) or hexamethonium (10 μM), implicating the involvement of a local neuronal response. 3 The L-NOARG-induced increase in duodenal motility was not, however, inhibited by atropine (1 μM), guanethidine (6.4 μM) phentolamine (1 μM), or indomethacin (10 μM), indicating a noncholinergic, non-adrenergic and non-prostanoid-mediated contractile response. 4 The NK1/NK2 tachykinin receptor antagonist, (D-Pro2, D-Trp7,9 substance P, 1-10 μM), and the NK2-receptor antagonists, MEN 10,207 and MEN 10,376 (1-5 μM), concentration-dependently reduced the effect of L-NOARG (30 μM) on spontaneous duodenal motility. 5 The resting tone and amplitude of the spontaneous contractions was likewise increased by incubation with N(G)-monomethyl-L-arginine (L-NMMA; 100-1000 μM). However, incubation with L-NMMA (100 μM) attenuated the actions of more potent L-NOARG (30 μM) on resting motility. 6 Administration of E.coli endotoxin (3 mg kg-1, i.v.) to the rat 5 h prior to tissue removal, at a time of known induction of NO synthase, reduced the amplitude of spontaneous contractions of the isolated duodenum, an effect inhibited by pretreatment of the rats with dexamethasone (1 mg kg-1) 2 h prior to endotoxin challenge. 7 These findings indicate a role of endogenous NO in the modulation of spontaneous tone and motility in the rat duodenum. Induction of NO synthase may result in a reduction in spontaneous motility of the tissue. By contrast, inhibition of constitutive NO biosynthesis unmasks a contractile response that is neuronally mediated and involves tachykinin NK2 receptors.