Nitric oxide mediates intestinal hyperaemic responses to intraluminal bile-oleate (original) (raw)
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Bile acid induced colonic irritation stimulates intracolonic nitric oxide release in humans
Gut, 1996
Aim-To measure the intracolonic release of nitric oxide end products (nitrates plus nitrites) and eicosanoids in response to intraluminal irritation with deoxycholic acid (DCA). Patients-Seven patients with irritable bowel syndrome. Methods-The left colon was perfused with a solution with or without 3 mM deoxycholic acid. Aspirates were assayed for eicosanoids by specific radioimmunoassay, and for nitrates plus nitrites by the Griess reaction. To confirm that stimulated colonic mucosa can produce nitric oxide (NO), ancillary studies were performed in vitro using samples of normal mucosa obtained from five surgically resected colons. Samples were incubated for 30 minutes in Kreb's solution, 3 mM DCA or DCA with 1 mM L-nitro-argininemethyl-ester (L-NAME) to inhibit the NO synthase. Finally, NO synthase activity was measured in five samples ofhuman colonic mucosa.
Acta Physiologica Scandinavica, 2004
Aim: Experiments were performed in anaesthetized rats to clarify the role of nitric oxide (NO) in the control of colonic permeability. Methods: Colonic luminal pressure, the transmucosal potential difference (PD) and the clearance of [ 3 H] mannitol and [ 14 C] urea from blood to lumen were measured. NO synthesis was blocked with N x -nitro-l-arginine (l-NNA) i.v. and mucosal permeability was increased by deoxycholic acid (DCA, 4 mm). The involvement of histamine in the response was studied by giving the histamine H 1 receptor blocker pyrilamine. Results: In proximal colon, l-NNA per se increased luminal pressure and PD but had no significant effect on clearance. DCA per se increased luminal pressure, had no significant effect on PD, but increased mannitol and urea clearance and the clearance ratio. l-NNA and pyrilamine both blocked the luminal pressure effect of DCA but l-NNA had no significant effect on the clearance response to DCA. In distal colon, l-NNA per se had no significant effect on pressure and clearance, but increased PD like in proximal colon. DCA had no significant effect on luminal pressure, but markedly reduced PD and increased both clearance and clearance ratio. In this segment, l-NNA significantly potentiated the clearance response to DCA, and further increased clearance ratio to a value not significantly different from unity (1.00 AE 0.05). Conclusion: The data suggest that in vivo, moderate concentrations of bile acids increase colonic permeability in rats via a mechanism that is inhibited by NO in distal but not in proximal colon. In distal colon, NO may contribute to the maintenance of epithelial barrier function.
The Journal of Physiology, 2003
Nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) interact in the regulation of neuromuscular function in the gut. They are also potent intestinal secretogogues that coexist in the enteric nervous system. The aims of this study were: (1) to investigate the interaction between NO and VIP in inducing fluid secretion in the rat jejunum, and (2) to determine whether the NO effect on intestinal fluid movement is neurally mediated. The single pass perfusion technique was used to study fluid movement in a 25 cm segment of rat jejunum in vivo. A solution containing 20 mM L-arginine, a NO precursor, was perfused into the segment. The effect of the NO synthase inhibitors (L-NAME and L-nitroindazole (L-NI)) and the VIP antagonist ([4Cl-D-Phe 6 ,Leu 17 ]VIP (VIPa)) on L-arginine-induced changes in fluid movement, expressed as ml min _1 (g dry intestinal weight) _1 , was determined. In addition, the effect of neuronal blockade by tetrodotoxin (TTX) and ablation of the myenteric plexus by benzalkonium chloride (BAC) was studied. In parallel groups of rats, the effect of L-NAME and L-NI on VIP-induced intestinal fluid secretion was also examined. Basal fluid absorption in control rats was (median (interquartile range)) 65 (45-78). L-Arginine induced a significant fluid secretion (_14 (_20 to _5); P < 0.01). This effect was reversed completely by L-NAME (60 (36-65); P < 0.01) and L-NI (46 (39-75); P < 0.01) and partially by VIPa (37 (14-47); P < 0.01). TTX and BAC partially inhibited the effect of L-arginine (22 (15-32) and 15 (10-26), respectively; P < 0.05). The effect of VIP on fluid movement (_23 (_26 to _14)) was partially reversed by L-NAME (24 (8.4-35.5); P < 0.01) and L-NI (29 (4-44); P < 0.01). The inhibition of VIP or NO synthase prevented L-arginine-and VIP-induced intestinal fluid secretion through a neural mechanism. The data suggest that NO enhances the release of VIP from nerve terminals and vice versa. Subsequently, each potentiates the other's effect in inducing intestinal fluid secretion.
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.
Acid-sensing pathways of rat duodenum
American Journal of Physiology-Gastrointestinal and Liver Physiology, 1999
We tested the hypothesis that the duodenal hyperemic response to acid occurs through activation of capsaicin-sensitive afferent nerves with subsequent release of vasodilatory substances such as calcitonin gene-related peptide (CGRP) and nitric oxide (NO). Laser-Doppler flowmetry was used to measure duodenal blood flow in urethan-anesthetized rats. Duodenal mucosa was superfused with pH 7.0 buffer with capsaicin or bradykinin or was acid challenged with pH 2.2 solution, with or without vanilloid receptor antagonists, a CGRP receptor antagonist, an NO synthase (NOS) inhibitor, or a cyclooxygenase inhibitor. The selective vanilloid receptor antagonist capsazepine (CPZ) dose dependently inhibited the hyperemic response to acid and capsaicin but did not affect bradykinin-induced hyperemia. Ruthenium red was less inhibitory than capsazepine. Selective ablation of capsaicin-sensitive nerves, CGRP-(8—37), and N G-nitro-l-arginine methyl ester inhibited acid-induced hyperemia, but indomethac...
L-Arginine, nitric oxide, and intestinal secretion: studies in rat jejunum in vivo
Gut, 1996
Background-L-Arginine has been shown to induce fluid secretion in human jejunum. Nitric oxide, a derivative of L-arginne is thought to have an important role as an intestinal secretagogue. Aim-To determine the effect of Larginine and the nitric oxide synthase inhibitor, nitro L-arginine methyl ester (L-NAME), on fluid and electrolyte movement in rat jejunum. Methods-A 25 cm segment ofrat jejunum was perfused in situ with iso-osmotic solutions containing either (1) saline, (2) D-arginine 20, (3) L-arginine 20, (4) L-NAME 0-1, 1, or 20 mmol/l, or (5) a combination of L-arginine 20 and L-NAME 0.1, 1, or 20 mmol/l. In further groups the effect of a subcutaneous injection of L-NAME 100 mglkg was examined in rats pretreated with either Dor L-arginine 500 mg/kg. Results-L-Arginine, unlike D-arginine, induced fluid secretion despite being better absorbed (mean-7 3 v 17-0 ,l/min/ g; p<001). L-NAME at 0.1 mmol/l had no effect on basal fluid movement but reversed L-arginine induced secretion (7.8; p<005). L-NAME at 1 and 20 mmol/l induced fluid secretion (-15.4 and-28-4, respectively), which was enhanced by the addition of L-argilnlne (-30.0 and-41-0, respectively; both p<005). A subcutaneous injection of L-NAME resulted in marked fluid secretion (-39.9) and histological evidence of intestinal ischaemia. These changes were attenuated or reversed by pretreatment with subcutaneous L-but not D-arginine. Conclusions-L-Arginine induces intestinal fluid secretion through production of nitric oxide. There is a delicate balance between the effect of nitric oxide as a secretagogue and its effect on maintaining blood flow and thus preventing intestinal ischaemia.
British Journal of Pharmacology, 1990
The interactions between nitric oxide (NO), prostacyclin and sensory neuropeptides in the maintenance of gastric mucosal integrity have been investigated in the anaesthetized rat. 2 Administration of either NG-monomethyl-L-arginine (L-NMMA) to inhibit endothelium-derived NO formation, indomethacin to inhibit prostanoid biosynthesis or chronic capsaicin pretreatment to deplete sensory neuropeptides, did not induce acute mucosal injury. 3 In capsaicin-pretreated rats, however, L-NMMA (12.5-l100mgkg-1 i.v.) dose-dependently induced acute mucosal damage, characterized as vasocongestion and haemorrhagic necrosis. The enatiomer D-NMMA (100 mg kg-1 i.v.) did not induce any detectable mucosal damage. 4 This mucosal injury induced by L-NMMA was inhibited by concurrent administration of L-arginine (300mg kgi.v.). 5 In indomethacin (5mgkg-1 i.v.)-pretreated rats, L-NMMA also induced mucosal damage. Furthermore, following indomethacin administration in capsaicin-pretreated rats, L-NMMA induced widespread, severe haemorrhagic necrotic damage. 6 These findings suggest a role for endogenous NO formed from L-arginine, acting in concert with prostacyclin and sensory neuropeptides, in the modulation of gastric mucosal integrity.
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.
European Journal of Pharmacology, 2004
Changes in vascular responsiveness are proposed as the basis for some of the cardiovascular complications in cholestasis. Cholestasis is also associated with accumulation of endogenous opioid peptides and evidence of nitric oxide (NO) overproduction. On the other hand, it is well known that anandamide, an endogenous cannabinoid ligand, causes hypotension and a decrease in systemic vascular resistance. In the present study, the possible role of the cannabinoid system in cholestasis-induced mesenteric vascular bed responsiveness was investigated. Mesenteric arteries of bile duct-ligated and sham-operated rats receiving daily administrations of saline were used for evaluating phenylephrine or anandamide dose -response, acute effects of N G -nitro-L-arginine methyl ester (L-NAME, 100 AM), a non-selective inhibitor of NO synthase (NOS), or naltrexone, an opioid receptors antagonist (1 AM). The other groups of bile duct-ligated and sham-operated rats received daily intraperitoneal administration of L-NAME (20 mg/kg/day), aminoguanidine, a selective inducible NOS (iNOS) inhibitor (150 mg/kg/day) or naltrexone (10 mg/kg/day). After 7 days, the superior mesenteric artery was cannulated and the mesenteric vascular bed was perfused according to the McGregor method. Anandamide-induced relaxation was significantly potentiated in mesenteric vascular beds of bile duct-ligated rats. Chronic treatment of bile duct-ligated animals with L-NAME and aminoguanidine blocked this hyperresponsiveness while the hyperresponsiveness was potentiated at large doses of anandamide on chronic treatment of these animals with naltrexone. Although acute L-NAME treatment of mesenteric beds completely blocked the anandamide-induced vasorelaxation in sham-operated rats, this vasorelaxation still was present in bile duct-ligated animals. Anandamide-induced vasorelaxation remained unaffected after acute naltrexone treatment of mesenteric beds in both bile duct-ligated and sham-operated rats. Our results indicate that (1) there is enhanced anandamideinduced vasorelaxation in cholestatic rats, probably due to a defect in cannabinoid or vanilloid receptors and (2) NO overproduction may be involved in cholestasis-induced vascular hyperresponsiveness. D