Previous evidence suggests that nonadrenergic, noncholinergic (NANC) inhibitory neurotransmission in visceral muscles may be mediated by nitric oxide (NO). We have demonstrated that NO and the NO carrier S-nitrosocysteine can mimic the hyperpolarization in colonic muscle caused by nerve stimulation. The finding that S-nitrosocysteine breaks down fast enough to cause inhibitory junction potential (IJP)-like hyperpolarizations suggests that NO could be stored as a nitrosothiol in secretory vesicles in nerve terminals. Oxyhemoglobin blocked hyperpolarization responses to NO and S-nitrosocysteine and NANC IJPs. These findings suggest that NO is a biologically active transmitter substance in NANC inhibitory neurotransmission. NO enhanced the open probability of Ca(2+)-activated K+ channels in isolated colonic muscle cells. These channels may mediate the hyperpolarization response to NANC neurotransmission in colonic muscles.
1 Nitric oxide (NO) may serve as a non-adrenergic, non-cholinergic (NANC) neurotransmitter released from enteric inhibitory nerves in the gastrointestinal tract. We tested whether guanosine 3':5'-cyclic monophosphate (cyclic GMP) may serve as a second messenger in transducing the NO signal into inhibitory junction potentials (ij.ps) and relaxation in the canine proximal colon. 2 The membrane permeable analogue of cyclic GMP, 8-bromo cyclic GMP mimicked the effects of NO by hyperpolarizing cells near the myenteric border of the circular muscle layer and shortening slow waves in cells near the submucosal surface of the circular muscle layer. 8-Br-cGMP also inhibited spontaneous phasic contractions. 3 The specific cyclic GMP phosphodiesterase inhibitor, M&B 22948, hyperpolarized cells near the myenteric border and prolonged the duration of ij.ps. M&B 22948 also inhibited phasic contractile activity. 4 Methylene blue failed to reduce significantly the amplitude and duration of ij.ps and had variable effects on contractions. 5 Cyclic GMP levels were assayed in unstimulated muscles and in muscles exposed to exogenous NO and electrical field stimulation. Both stimuli hyperpolarized membrane potential, inhibited contractions, and elevated cyclic GMP levels.6 Treatment of muscles with L-NW-nitroarginine methyl ester (L-NAME) increased spontaneous contractile activity and lowered cyclic GMP levels. The inhibitory effect of M&B 22948 on contractions was greatly reduced after muscles were treated with L-NAME. 7 These data support the concept that the effects of NANC nerve stimulation and NO (which may be one of the enteric inhibitory transmitters) may be mediated by cyclic GMP.
Nonadrenergic, noncholinergic (NANC) nerves regulate slow waves along the submucosal border of the canine proximal colon. Experiments were performed to determine the role of nitric oxide (NO) in NANC responses. NANC responses are characterized by hyperpolarization and reduction in slow-wave amplitude and duration during the period of stimulation. This is followed by a "rebound" excitation (increase in amplitude and duration) of the slow wave immediately after the stimulus. These responses were blocked by L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase and by tetrodotoxin (TTX). Exogenous NO mimicked NANC responses, including the poststimulus rebound excitation. Responses to NO were unaffected by L-NAME or TTX. Responses to NANC nerve stimulation and NO were blocked by oxyhemoglobin but not by methemoglobin. Rebound excitation was reduced by pretreatment with indomethacin, suggesting that an eicosanoid may mediate this phase of NANC responses. Taken together, these data suggest that NO mediates NANC nerve responses in the proximal colon. NO appears to directly cause the inhibitory response, but the rebound response may depend on release of an eicosanoid.
Experiments were performed to determine the involvement of nitric oxide synthase in the generation of nonadrenergic, noncholinergic (NANC) inhibitory junction potentials (IJPs) in the canine proximal colon. Smooth muscle cells were impaled near the myenteric border between the circular and longitudinal layers. Cells exhibited rhythmic myenteric potential oscillations. IJPs were evoked with electrical field stimulation in the presence of drugs to block adrenergic and cholinergic neurotransmission. N omega-nitro-L-arginine, methyl ester (L-NAME), a nitric oxide synthase inhibitor, progressively reduced the amplitude of IJPs. The effect of L-NAME was reversed by L-Arg but not by the stereoisomer D-Arg. IJPs disrupt the regular pattern of myenteric potential oscillations. This effect was also blocked by L-NAME and reversed by L-Arg. These experiments suggest that a product of the nitric oxide synthetic pathway is involved in NANC neurotransmission in the canine proximal colon.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.