Potential excitatory role of nitric oxide on 2-deoxy-d-glucose-induced gastric motility in rats (original) (raw)
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British Journal of Pharmacology, 1992
The influence of the nitric oxide (NO) biosynthesis inhibitor N0-nitro-L-arginine methyl ester (L-NAME) on the gastric relaxation induced by peripheral vagal stimulation was investigated in the anaesthetized rat. 2 Peripheral vagal stimulation (10 Hz, 10 V, 1 ms for 20 s) induced a reproducible biphasic response: a short-lasting increase followed by a more pronounced decrease in intragastric pressure. This response also occurred in reserpinized animals (5mg kg-, i.p., 24 h before the experiment) while atropine (1 mg kg1, i.v.) abolished the initial increase in intragastric pressure. 3 L-NAME (1-30mg kg-',i.v.) induced an increase in arterial blood pressure. L-NAME (1 mg kgi.v.) had no influence on the vagally induced gastric response while L-NAME (10 and 30mgkg-' i.v.) significantly changed it: the initial increase in intragastric pressure was enhanced while the decrease in intragastric pressure was reduced or abolished. N0-nitro-L-arginine (L-NNA, l0 mg kg-%, i.v.) had the same effect. 4 An i.v. infusion of phenylephrine (10pgkg-lmin-1) inducing a pressor response similar to that produced by L-NAME (30mgkg-1, i.v.) did not influence the vagal gastric response. Infusion of L-arginine (300mgkg-' bolus, then lOOmgkg-lh-') starting 30min beforehand, reduced the pressor effect and prevented the influence of L-NAME (lOmgkg-, i.v.) on the vagal gastric response. After injection of both atropine (lmgkg-', i.v.) and L-NAME (30mgkg-', i.v.), the vagally induced decrease in intragastric pressure was similar to that obtained under control conditions. 5 These results are consistent with NO being released and inducing gastric relaxation during peripheral vagal stimulation. In addition to NO, another inhibitory non-adrenergic non-cholinergic neurotransmitter is released.
Role of NO in vagally-mediated relaxations of guinea-pig stomach
Naunyn-Schmiedeberg's Archives of Pharmacology, 1993
Vagal stimulation of the stomach induces a relaxation mediated via non-adrenergic, non-cholinergic (NANC) nerves. The neurotransmitter which is responsible for this relaxation is still unknown. To determine whether nitric oxide (NO) or a NO related substance mediates this relaxation, an intact guinea-pig stomach was mounted in an organ bath, with electrodes surrounding the vagal nerves.
Nitric Oxide: From Gastric Motility to Gastric Dysmotility
International Journal of Molecular Sciences, 2021
It is known that nitric oxide (NO) plays a key physiological role in the control of gastrointestinal (GI) motor phenomena. In this respect, NO is considered as the main non-adrenergic, non-cholinergic (NANC) inhibitory neurotransmitter responsible for smooth muscle relaxation. Moreover, many substances (including hormones) have been reported to modulate NO production leading to changes in motor responses, further underlying the importance of this molecule in the control of GI motility. An impaired NO production/release has indeed been reported to be implicated in some GI dysmotility. In this article we wanted to focus on the influence of NO on gastric motility by summarizing knowledge regarding its role in both physiological and pathological conditions. The main role of NO on regulating gastric smooth muscle motor responses, with particular reference to NO synthases expression and signaling pathways, is discussed. A deeper knowledge of nitrergic mechanisms is important for a better ...
Neuronal nitric oxide in the gut
Journal of Gastroenterology and Hepatology, 1993
Motility of the gastrointestinal tract is directly controlled by enteric inhibitory and excitatory motor neurons that innervate the layers of smooth muscle. Inhibitory motor neurons mediate receptive and accommodative relaxations and control the opening of sphincters, thus playing an important role in normal gut motility, Recent studies have demonstrated that nitric oxide (NO) is an important neurotransmitter released by inhibitory motor neurons in animal and human gut. Antagonists of nitric oxide synthase (NOS), the synthetic enzyme for NO, reduce the effectiveness of transmission from inhibitory motor neurons. Exogenous NO mimics inhibitory nerve activation, and a variety of compounds that affect the availability of endogenously produced NO modulate relaxations of gastrointestinal smooth muscle. It is clear, however, that NO is unlikely to be the only transmitter released by enteric inhibitory motor neurons: several other substances such as vasoactive intestinal polypeptide (VIP), or related peptides, and adenosine triphosphate (ATP) are also likely to contribute to nerve-mediated inhibition. The identification of NO as a major inhibitory neurotransmitter to gastrointestinal smooth muscle fills an important gap in our understanding of the physiological control of motility and opens up a wide range of new experimental possibilities. It may eventually lead. to the development of new drugs for motility disorders. It should be noted, however, that NO is important in the brain, in cardiovascular control, in blood cell function and in many other organ systems, suggesting that it may be difficult to achieve specific pharmacological intervention targeted on inhibitory neurotransmission in the gut, without undesirable side effects.
Intralipid-induced gastric relaxation is mediated via NO
Neurogastroenterology & Motility, 1995
In vitro, nitric oxide (NO) has been shown to be the neurotransmitter responsible for gastric relaxation. In vivo gastric relaxations can be controlled via reflex pathways originating in the duodenum. The aim of this study was to determine whether NO was involved in gastric relaxation in !viva in conscious dogs induced by intraduodenal administration of intralipid.
Delayed gastric emptying induced by inhibitors of nitric oxide synthase in rats
European Journal of Pharmacology, 1994
The effect of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester, on gastric emptying of a non-nutrient solution was investigated in conscious rats. NG-Monomethyl-e-arginine (10 mg/kg i.v.) and NG-nitro-e-arginine methyl ester (3 or 10 mg/kg i.v.) inhibited the 20-min rate of gastric emptying of liquids by 34%, 69% and 84% respectively, whereas the 0.3 mg/kg of NG-nitro-L-arginine methyl ester or 3 mg/kg of N°-monomethyl-e-arginine had no effect. The inhibitory effect of NG-nitro-e-arginine methyl ester (3 mg/kg) was prevented by L-arginine (300 mg/kg i.v.), but not by o-arginine (300 mg/kg i.v.). NG-Nitro-L-arginine methyl ester (0.3-10 mg/kg) induced a dose-related increase in mean blood pressure up to 161 + 10 mm Hg. Spontaneous hypertensive rats with a mean blood pressure of 180 + 5 mm Hg had a gastric emptying rate of 51.9 + 6.1%. These data indicate that NO synthase inhibitors given i.v. at doses that inhibit NO synthase, delay gastric emptying through mechanisms which are unrelated to changes in arterial blood pressure.
Nitroxergic nerves mediate vagally induced relaxation in the isolated stomach of the guinea pig
Proceedings of the National Academy of Sciences, 1991
Here we show that the relaxation induced by stimulation of the vagus nerve in the presence of cholinergic (muscarinic) and adrenergic blockade in the isolated stomach of the guinea pig is mediated by nitric oxide (NO). This is substantiated by inhibition of vagal relaxation by NGmonomethyl-L-arginine, an inhibitor of NO synthesis. The effect of NG-monomethyl-L-arginine was partially reversed by coincubation with L-anine but not with D-arginne. NO activates soluble guanylate cyclase, and relaxation of the stomach induced by vagal stimulation was prevented by an inhibitor of soluble guanylate cyclase, methylene blue, further supporting our conclusions. The relaxant effect of vagal stimulation was also ablated by hexamethonium, an inhibitor of ganglionic nicotinic receptors, thereby showing that gangionic transmission did not rely on NO, through its release from pr onic neurons. However, hexamethonium did not inhibit the gastric relaxation brought about by increasing the inragastric pressure, which is also mediated by NO as previously described by us. The selective inhibition by hexamethonum of only the vagafly mediated relaxation but not of the pressure-induced relaxation of the stomach indicates the existence of at least two separate neuronal pathways able to generate NO and bring about gastric accommodation of food or fluid.
British Journal of Pharmacology, 1994
Hammersmith Hospital, Du Cane Road, London W12 ONN 1 Nitric oxide synthase (NOS) was localized in the guinea pig stomach by immunocytochemistry. In vitro experiments were carried out on the isolated stomach of the guinea pig to study any possible links between nitric oxide (NO) and vasoactive intestinal peptide (VIP) in mediating relaxations induced by vagal stimulation. 2 NOS was localized to nerve cell bodies and nerve fibre varicosities of the myenteric plexus in wholemounts of the longitudinal muscle-myenteric plexus of the stomach fundus. The NOS-positive cells had a Dogiel type I morphology characteristic of motor neurones. 3 The cross-sections of the stomach wall showed NOS-positive neurones mainly in the myenteric plexus ganglia and NOS-positive nerve fibre varicosities in the circular muscle layer. 4 Relaxations induced by vagal stimulation were almost completely prevented by L-NAME with an IC50 value of 5.5 x 10-6M. This inhibition was reversed by L-arginine (2 mM). 5 VIP (100nM) induced reproducible relaxations of the stomach. These were unaffected by tetrodotoxin (2f1M) or Nw-nitro-L-arginine methyl ester (L-NAME, 100 AM). 6 Desensitization to the relaxant effect of VIP partially reduced relaxations induced by vagal stimulation, glyceryl trinitrate or sodium nitroprusside but not noradrenaline. 7 These results show that NO has a neuronal origin in the guinea pig stomach, and support NO, and not VIP, as the major neurotranmitter of vagally induced gastric relaxation in the guinea pig.
British Journal of Pharmacology, 2000
The morphological pattern and motor correlates of nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) innervation in the human isolated gastric fundus was explored.By using the nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)-diaphorase and specific rabbit polyclonal NO-synthase (NOS) and VIP antisera, NOS- and VIP-containing varicose nerve fibres were identified throughout the muscle layer or wrapping ganglion cell bodies of the myenteric plexus. NOS-immunoreactive (IR) neural cell bodies were more abundant than those positive for VIP-IR. The majority of myenteric neurones containing VIP coexpressed NADPH-diaphorase.Electrical stimulation of fundus strips caused frequency-dependent NANC relaxations. NG-nitro-L-arginine (L-NOARG: 300 μM) enhanced the basal tone, abolished relaxations to 0.3–3 Hz (5 s) and those to 1 Hz (5 min), markedly reduced (∼50%) those elicited by 10–50 Hz, and unmasked or potentiated excitatory cholinergic responses at frequencies 1 Hz. L-NOARG-resistant relaxations were virtually abolished by VIP (100 nM) desensitization at all frequencies.Relaxations to graded low mechanical distension (1 g) were insensitive to tetrodotoxin (TTX: 1 μM) and L-NOARG (300 μM), while those to higher distensions (2 g) were slightly inhibited by both agents to the same extent (∼25%).In the human gastric fundus, NOS- and VIP immunoreactivities are colocalized in the majority of myenteric neurones. NO and VIP mediate electrically evoked relaxations: low frequency stimulation, irrespective of the duration, caused NO release only, whereas shortlasting stimulation at high frequencies induced NO and VIP release. Relaxations to graded mechanical distension were mostly due to passive viscoelastic properties, with a slight NO-mediated neurogenic component at 2 g distension. The difference between NO and VIP release suggests that in human fundus accommodation is initiated by NO.The morphological pattern and motor correlates of nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) innervation in the human isolated gastric fundus was explored.By using the nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)-diaphorase and specific rabbit polyclonal NO-synthase (NOS) and VIP antisera, NOS- and VIP-containing varicose nerve fibres were identified throughout the muscle layer or wrapping ganglion cell bodies of the myenteric plexus. NOS-immunoreactive (IR) neural cell bodies were more abundant than those positive for VIP-IR. The majority of myenteric neurones containing VIP coexpressed NADPH-diaphorase.Electrical stimulation of fundus strips caused frequency-dependent NANC relaxations. NG-nitro-L-arginine (L-NOARG: 300 μM) enhanced the basal tone, abolished relaxations to 0.3–3 Hz (5 s) and those to 1 Hz (5 min), markedly reduced (∼50%) those elicited by 10–50 Hz, and unmasked or potentiated excitatory cholinergic responses at frequencies 1 Hz. L-NOARG-resistant relaxations were virtually abolished by VIP (100 nM) desensitization at all frequencies.Relaxations to graded low mechanical distension (1 g) were insensitive to tetrodotoxin (TTX: 1 μM) and L-NOARG (300 μM), while those to higher distensions (2 g) were slightly inhibited by both agents to the same extent (∼25%).In the human gastric fundus, NOS- and VIP immunoreactivities are colocalized in the majority of myenteric neurones. NO and VIP mediate electrically evoked relaxations: low frequency stimulation, irrespective of the duration, caused NO release only, whereas shortlasting stimulation at high frequencies induced NO and VIP release. Relaxations to graded mechanical distension were mostly due to passive viscoelastic properties, with a slight NO-mediated neurogenic component at 2 g distension. The difference between NO and VIP release suggests that in human fundus accommodation is initiated by NO.British Journal of Pharmacology (2000) 129, 12–20; doi:10.1038/sj.bjp.0702977
New Issues about Nitric Oxide and its Effects on the Gastrointestinal Tract
Current Pharmaceutical Design, 2001
Over the last years the important role of nitric oxide (NO) as endogenous modulator of numerous physiological functions has been shown. NO is involved in the regulation of blood flow, maintenance of vascular tone, control of platelet aggregation, and modulation of the activity of the mastocytes. It also plays a key role as neurotransmitter in the central and peripheric nervous system (non adrenergic non colinergic, NANC, neurons), in the nervous control of the cerebral blood flow and in the neuroendocrine regulation or synaptic plasticity. However, NO shows a dual behavior: at physiological concentrations, released through the constitutive synthase (cNOS), it regulates house-keeping functions, whereas its overproduction by the inducible isoenzyme (iNOS) exhibits cytotoxic activity because interacting with reactive species producing peroxinitrites (ONOO • ) and other compounds, which are highly damaging for the tissues.