The role of constitutive and inducible nitric oxide synthase in senna- and cascara-induced diarrhoea in the rat (original) (raw)
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Inhibitors of nitric oxide synthetase prevent castor-oil-induced diarrhoea in the rat
British Journal of Pharmacology, 1993
1 Castor oil (2 ml orally) produced copious diarrhoea in rats 3 h after its administration. 2 Pretreatment (intraperitoneal, i.p.) of rats with the NO synthesis inhibitors Na-nitro-L-arginine methyl ester (L-NAME, 1-25 mg kg-') and NG-monomethyl-L-arginine (L-NMMA, 2.5-100mg kg-') inhibited or prevented castor-oil-induced diarrhoea. L-Arginine (150-600 mg kg-', i.p.) administered to rats pretreated with L-NAME 10 mg kg-', drastically reduced the antidiarrhoeal activity of L-NAME in a dose-related manner. D-Arginine (900 mg kg-') did not modify the protection by L-NAME. 3 Pretreatment (i.p.) of rats with L-NAME (2.5-25 mg kg-') decreased the intestinal fluid accumulation and Na+ secretion induced by castor oil. L-Arginine (600 mg kg-') but not D-arginine (900 mg kg-') counteracted the inhibitory effect of L-NAME (10mg kg-'). 4 L-NAME (10 and 25 mg kg-) had no significant effect on the intestinal transit in normal rats or those given castor oil. 5 These results provide evidence that nitric oxide (NO) could play an important role in castor-oilinduced diarrhoea.
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.
European Journal of Pharmacology, 1993
The effects of N~-nitro-L-arglnine methyl ester (L-NAME) and N°-monomethyl-L-argmine (L-NMMA), inhibitors of mtrlc oxide (NO) synthase, were studied on ricinoleic acid-evoked contractions in rat isolated ileum. Rlcinoleic acid (10 -5 to 10 -4 M) caused a concentration-dependent contraction. Addition of L-NAME (30-300/zM) or L-NMMA (30-300/xM) to the Tyrode's solution increased in a concentration-dependent fashion the amplitude of the ricinolelc acid-evoked responses. L-Arginine (900 /zM), a natural substrate of NO synthase, but not D-arginine (900 /zM), counteracted the effect of L-NAME (300 /xM). The potentiating effect of L-NAME was also prevented by sodium nitroprusside (0.1-1 /zM), a generator of NO. These results provide evidence that endogenous NO may modulate the contraction of rat deum induced by ricinolelc acid. As the contraction induced by ncinoleic acid is not blocked by tetrodotoxin (0.6 and 6.0/zM) the contractile effect of ricinoleic acid results mainly from a direct action on the smooth muscle.
Sennosides do not kill myenteric neurons in the colon of the rat or mouse
Neuroscience, 1989
Effects of senna on the myenteric plexus of the colon were investigated in view of earlier reports that this anthraquinone cathartic depletes the plexus of its intrinsic neurons. Rats and mice were given purgative doses of sennosides in their drinking water for 4 and 5 months, respectively. Body growth was reduced, and the weight of the colon with its contents was increased relative to the weight of the whole body in the treated animals. The latter change was attributed to depressed propulsive motility of the large intestine. Total numbers of myenteric neurons were determined from whole-mount preparations stained with Cuprolinic Blue-magnesium chloride, which selectively coloured the neuronal somata. The number of neurons in the rat's colon was unaffected by treatment with senna, but the colons of the treated mice contained significantly more neurons than those of their controls.
Is Senna Laxative Use Associated to Cathartic Colon, Genotoxicity, or Carcinogenicity?
Journal of Toxicology, 2009
Due to their natural origin, apparent low oral toxicity, effectiveness, and accessibility without a medical prescription, the anthranoid laxatives are a popular remedy for constipation and are frequently used abusively. Therefore, it is important to characterize its harmful and/or toxic effects. The sennosides, main active metabolites of senna, exhibit a very low toxicity in rats, and its genotoxic activity in bacterial strains as well as mammal cells was classified as weak in those cases where it was shown to be significant. The toxicological and mutagenic status of the crude extract of senna, however, is not as well characterized, and it is necessary to do so since it is frequently, and at the same time incorrectly, believed that the chronic use of anthranoid laxatives is a risk factor for the development of colorectal cancer. The objective of this article was to review the information that arises in various scientific medical databases using key words such as senna, sen,Senna ale...
Journal of neurogastroenterology and motility, 2018
The aim of present study is to estimate the effects of L. (MO) on visceral hypersensitivity (VH), defecation pattern and biochemical factors in 2 experimental models of irritable bowel syndrome (IBS) and the possible role of nitric oxide. Two individual models of IBS were induced in male Wistar-albino rats. In the acetic acid model, the animals were exposed to rectal distension and abdominal withdrawal reflex, and the defecation patterns were determined. In the restraint stress model, the colons of rats were removed and the levels of TNF-α, myeloperoxidase, lipid peroxidation, and antioxidant powers were determined. Rats had been treated with MO, L-NG-nitroarginine methyl ester (L-NAME), aminoguanidine (AG), MO + AG, or MO + L-NAME in the mentioned experimental models. Hypersensitive response to rectal distension and more stool defecation in control rats have been observed in comparison to shams. MO-300 significantly reduced VH and defecation frequency in comparison to controls. VH ...
Experimental colitis is ameliorated by inhibition of nitric oxide synthase activity
Gut, 1995
Enhanced nitric oxide (NO) generation by stimulated NO synthase (NOS) activity may, through its oxidative metabolism contribute to tissue injury in experimental colitis. In this study the possible amelioration of experimental colitis by NG-nitro-Larginine methyl ester (L-NAME), an inhibitor of NOS activity, was evaluated. Colitis was induced in rats by intracolonic administration of 30 mg trinitrobenzene sulphonic acid (TNB) dissolved in 0.25 ml 50%/o ethanol or by flushing the colon of capsaicin pretreated rats with 2 ml of 50/0 acetic acid. In several experiments, L-NAME 0-1 mg/ml was added to the drinking water at the time of colitis induction with TNB or seven days before acetic acid treatment. Rats were killed at various time intervals after induction of colitis. A 10 cm distal colonic segment was isolated, weighed, lesion area measured, and explants organ cultured for 24 hours for determination of NO generation by the Greiss reaction. The rest of the mucosa was scraped for determination of myeloperoxidase and NOS activities and leukotriene generation. In TNB treated rats mean arterial pressure was also determined up to 72 hours after damage induction, with or without cotreatment with nitroprusside. L-NAME significantly decreased the extent of tissue injury in TNB treated rats. Seven days after TNB treatment lesion area was reduced by 55°/0, colonic weight by 37%, and myeloperoxidase and NOS activity by 590/o and 42%, respectively. Acetic acid induced colitis in capsaicin pretreated rats was also significantly decreased by L-NAME. Twenty four hours after acetic acid treatment lesion area was reduced by 61%/ colonic weight by 21%, and NOS activity by 39%. Mean (SEM) arterial blood pressure in TNB+L-NAME treated rats was 37.6 (8.1) mm Hg higher than in TNB treated rats, an effect that was only partially abolished by nitroprusside. These results show that inhibition of NO synthesis by an L-arginine analogue significantly ameliorates the extent of tissue injury in two models of experimental colitis, an effect that is not due only to its vasoconstrictor properties. Modulation of NO generation may be a novel therapeutic approach in inflammatory bowel disease. (Gut 1995; 37: 247-255)
Journal of Pediatric Gastroenterology and Nutrition, 2002
Background: Senna laxatives are used worldwide. However, their misuse can lead to chronic mucosal inflammation with the accumulation of pigment-laden leukocytes and may cause colon cells to undergo apoptosis. This study explores the mechanisms by which rhein, an active component of senna, acts on a human intestinal cell line to induce ion secretion, apoptosis, and indirect chemotaxis of polymorphonuclear leukocytes. Methods: Human colonic adenocarcinoma (CaCo-2) monolayer cells, in the presence or in the absence of rhein, were used to monitor the production of reactive nitrogen species using the Griess reaction. Modified Ussing chambers were used to study electrolyte secretion. The capacity to recruit human polymorphonuclear leukocytes was evaluated using masked well chemotaxis chambers. Rhein-induced apoptosis was investigated by counting apoptotic nuclei stained with Hoechst 33258 dye. Results: Rhein caused a dose-dependent increase in shortcircuit current that was abolished in chloride-free bathing buffer or by preincubating with 100 mol/L N G-nitro-L-arginine (L-NAME) methyl ester. The concentration that maximally stimulated intestinal secretion, 50 mol/L rhein, induced nitrate production. Supernatants obtained from CaCo-2 cultures after incubation with 50 mol/L rhein stimulated a timedependent polymorphonuclear leukocytes chemotaxis that was significantly decreased with 100 mol/L L-NAME, whereas rhein per se was not active. Neutralizing antibodies antiinterleukin-8 (IL-8) and anti-ENA78 also inhibited chemotaxis. Overnight rhein incubation produced an increased number of apoptotic cells in the culture supernatant that was significantly decreased by preincubation with 100 mol/L L-NAME. Lightdegraded rhein had no effects on CaCo-2 monolayers. Conclusions: The integrity of rhein is crucial to generating nitric oxide, which mediates, with different time courses, ion secretion, chemotaxis, and apoptosis of human-derived cells.
Role of Nitric Oxide in Physiology and Pathology of the Gastrointestinal Tract
Mini-Reviews in Medicinal Chemistry, 2008
In this paper the physiological role of NO and isoforms of NOS in the gastrointestinal tract and the involvement of NO in pathological processes of digestive tract as well as the perspective of therapeutic use of NO-donating drugs and selective inhibitors of phosphodiesterase in the treatment of gastric diseases were presented.
Nitric oxide: potential role for reducing gastro-enteropathy
InflammoPharmacology, 2003
The pathogenesis of non-steroidal anti-in ammatory drug (NSAID)-induced gastroenteropathy may involve a number of key events leading to increased intestinal permeability and in ammation (topical effect) and the development of ulcers (micro-vascular effects of COX-1 inhibition and prostaglandin de ciency). Many strategies have been employed in an attempt to reduce the toxic effects of NSAIDs and these have been targeted at the different pathogenic stages of lesion development. One of the latest in this long chain of damage limitation has been the development of nitric oxide (NO) sequestering NSAIDs (NO-NSAIDs). It is suggested that the NO, which is released as the compounds are broken down, may counteract the consequences of the NSAID-induced decrease in mucosal prostaglandins. Here we examine the proposed mechanisms for NSAID-induced gastrointestinal damage together with some of the methods employed to address these mechanisms. We also consider the physiologic roles of NO in the gut together with how it may be potentially employed as an agent for limiting the side effects of NSAIDs in the gastrointestinal tract.