Mediators of Nicotine‐induced Relaxations of the Rat Gastric Fundus

Abstract

1. Relaxations of strips of rat gastric fundus were elicited with nicotine (100 mumol/L), nitric oxide (NO; 30 mumol/L), sodium nitroprusside (SNP; 100 nmol/L) and vasoactive intestinal polypeptide (VIP; 1 nmol/L). 2. Methylene blue (30 mumol/L), an inhibitor of soluble guanylate cyclase, reduced relaxations elicited by NO and nicotine, but not those elicited by VIP. 3. Chymotrypsin (1 U/mL) abolished VIP-induced relaxations and reduced nicotine-induced relaxations, but had no effect on SNP-induced relaxations. 4. NG-nitro-L-arginine methyl ester (L-NAME; 100 mumol/L), an inhibitor of NO synthase, reduced relaxations elicited by nicotine, but not those elicited by SNP or VIP. 5. When nicotine-induced relaxations had been reduced by either L-NAME or chymotrypsin, the addition of the other agent produced a greater reduction. However, the relaxations were not abolished. 6. Nicotine-induced relaxations were abolished by tetrodotoxin (1 mumol/L) or hexamethonium (100 mumol/L), indicating that they were due to activation of neuronal nicotinic receptors. Their reduction by methylene blue and L-NAME indicates that an NO-like mediator was involved. Their reduction by chymotrypsin indicates that a VIP-like peptide was involved. However, since they were not abolished by a combination of L-NAME and chymotrypsin, it appears that at least one more as yet unidentified mediator may be involved.

Gastrointestinal Function Regulation by Nitrergic Efferent Nerves

“…Neurogenic relaxation and IJP were reportedly mediated by the neurotransmitter NO in the gastric fundus and pyloric sphincters from the rat (Boeckxstaens et al, 1991a;McLaren et al, 1993;Jenkinson et al, 1995;Curro et al, 1996;Curro and Preziosi, 1998;De Man et al, 1998;Lefebvre, 1998), guinea pig (Kojima et al, 1993), dog (Bayguinov et al, 1999), pig (Colpaert and Lefebvre, 2000), mouse (Selemidis and Cocks, 2000;Suzuki et al, 2000;Ergun and Ogulener, 2001), Japanese monkey (N. Toda, K. Ayajiki, and T. Okamura, unpublished data), and human (Tomita et al, 1999;Tonini et al, 2000). Typical responses to nitrergic nerve stimulation of the isolated monkey pyloric sphincter are shown in Fig.…”

“…However, in GI smooth muscles, the NO-induced relaxation is mediated by the guanylyl cyclase-cyclic GMP pathway and also by membrane hyperpolarization. In GI smooth muscles from animals (Desai et al, 1991;McLaren et al, 1993;Olgart and Iversen, 1999) or humans (Bartho et al, 2002), involvement of cyclic GMP in NO-induced relaxation has been derived from studies using the soluble guanylyl cyclase inhibitors methylene blue and ODQ or the cyclic NITRERGIC INNERVATION IN GI TRACT GMP phosphodiesterase inhibitor zaprinast or measuring directly the cyclic GMP contents . Ward et al (1992) suggested that inhibitory junction potentials mediated by neurogenic NO are presumably coupled with the enhanced production of cyclic GMP.…”

“…Nicotine Kojima et al, 1993;McLaren et al, 1993;Mozhorkova et al, 1994), DMPP (Boeckxstaens et al, 1993a;Takeuchi et al, 1996), K ϩ , 5-HT (Boeckxstaens et al, 1990b;Bogers et al, 1991), ATP, and GABA (Boeckxstaens et al, 1991b) reportedly stimulate nitrergic nerves and release NO or a NO analog in the GI tract. Nerve action potentials appear to contribute to the inhibitory response to these chemical stimuli because the induced relaxation is susceptible to tetrodotoxin.…”

Reversal of the Gastric Effects of Nicotine by Nitric Oxide Donor Treatment

“…Under most conditions, NO originates only from eNOS and nNOS. McLaren et al [32]demonstrated that nicotine could modulate NO release from nNOS. Although NO release from nNOS does influence gastric motility, the involvement of gastric motility in ethanol-induced gastric mucosal damage appears to be limited.…”

Subtilisin Increases Macromolecular Efflux from the Oral Mucosa

“…Nonetheless, the knowledge of increased mucosal permeability in response to topical exposure to subtilisin is important. Specifically, the accumulation of various smokeless-tobacco-associated chemical carcinogens or viral genetic material from viruses such as the human papillomavirus requires access to the proliferative zone of the oral mucosa to promote malignant changes (12,15,19,23,28,34,37). Subtilisin may facilitate this process by increasing oral mucosa permeability.…”