Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Castrol-oil induced diarrhea in rats was potently prevented by compounds SR 140333 and SR 48968, the first a tachykinin NK1- and the second a NK2-receptor antagonist. SR 48968 was more effective and also reduced fecal water content.
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PMID:The non-peptide tachykinin NK1- and NK2-receptor antagonists SR 140333 and SR 48968 prevent castor-oil induced diarrhea in rats. 921 3

Substance P (SP), vasoactive intestinal polypeptide (VIP), and somatostatin content in rectal mucosa were determined by radioimmunoassay (RIA) in 38 diabetic patients (12 with normal bowel function, 13 with diabetic diarrhea, and 13 with constipation) and in 10 nondiabetic controls with normal bowel function. SP content (picograms per milligram) in the rectal mucosa of diabetics with normal bowel function was significantly higher than that of nondiabetic controls (P < .05). SP content in the rectal mucosa of diabetics with diabetic diarrhea and constipation was significantly lower than in diabetics with normal bowel habits and nondiabetic controls (P < .05). No differences were found in the rectal mucosa content of VIP and somatostatin between the different groups of diabetics and controls. Diabetic diarrhea is a condition with an intermittent nature and frequently alternates with constipation. Our findings showing low levels of rectal mucosa SP in both conditions suggest a possible common role of SP in the pathogenesis of diabetic diarrhea and constipation.
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PMID:Decreased substance P content in the rectal mucosa of diabetics with diarrhea and constipation. 922 23

Opioids have long been known to inhibit intestinal fluid and electrolyte secretion. They act locally on central and peripheral opiate receptors where they are rapidly degraded by neuropeptidases, the major one being enkephalinase (EC 3.4.24.11). A number of studies have shown that, when the problem of degradation can be overcome, enkephalins have potent antisecretory properties. In 1980, an enkephalinase inhibitor was described which increased the functional availability of enkephalins. More recently an orally active enkephalinase inhibitor, acetorphan, has been shown to inhibit infectious and chemically induced diarrhoea. Acetorphan does not appear to affect gastrointestinal motility and, although it also inhibits the breakdown of a range of other neuropeptides, such as substance P and neuropeptide Y, it is a promising agent with therapeutic potential.
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PMID:Enkephalins and enkephalinase inhibitors in intestinal fluid and electrolyte transport. 935 86

(R)-3-(1-[2-(4-benzoyl-2-(3,4-difluorophenyl)-morpholin-2-yl)- ethyl]-4-phenylpiperidin-4-yl)-1-dimethylurea (SR 144190) is a new non-peptide antagonist of tachykinin NK2 receptors. SR 144190 potently and selectively inhibited neurokinin A binding to NK2 receptors from various species, including humans. In in vitro functional assays, it was a potent, selective and competitive antagonist of NK2 receptors with apparent affinities (pA2 values) between 9.08 and 10.10. In vivo, SR 144190 blocked [Nle10]neurokinin A-(4-10)-induced bronchoconstriction in guinea pigs (ID50 = 21 micrograms kg-1 i.v. and 250 micrograms kg-1 i.d.) and [beta Ala8]neurokinin A-(4-10)-induced urinary bladder contraction in rats (ID50 = 11 micrograms kg-1 i.v. and 190 micrograms kg-1 i.d.). It prevented citric acid-induced cough and airway hyperresponsiveness to acetylcholine in guinea pigs (1 mg kg-1 i.p.) as well as castor oil-induced diarrhoea in rats (0.01-10 micrograms kg-1 s.c. or p.o). Finally, it blocked the turning behaviour induced by intrastriatal injections of [Nle10]neurokinin A-(4-10) in mice (ID50 = 3 micrograms kg-1 i.v. and 16 micrograms kg-1 p.o.).
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PMID:Biochemical and pharmacological activities of SR 144190, a new potent non-peptide tachykinin NK2 receptor antagonist. 941 22

Toxin A, a 308,000-Mr enterotoxin from Clostridium difficile, mediates antibiotic-associated diarrhea and colitis in humans. Injection of toxin A into animal intestine triggers an acute inflammatory response characterized by activation of sensory neurons and immune cells of the intestinal lamina propria, including mast cells and macrophages, and migration of circulating neutrophils in the involved intestinal segment. In this study we show that mice genetically deficient in the neurokinin-1 receptor are protected from the secretory and inflammatory changes as well as from epithelial cell damage induced by toxin A. The protective effect of neurokinin-1R deletion correlates with diminished intestinal levels of the cytokine TNF-alpha and its mRNA and the leukocyte enzyme myeloperoxidase. These results demonstrate a major requirement for substance P receptors in the pathogenesis of acute inflammatory diarrhea.
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PMID:Neurokinin-1 (NK-1) receptor is required in Clostridium difficile- induced enteritis. 954 82

The role of nitric oxide in intestinal fluid and electrolyte secretion depends upon whether the conditions under study are physiological or pathophysiological. In physiological conditions, endogenous nitric oxide seems to be a proabsorptive molecule, based on the findings that nitric oxide synthase inhibitors reverse net fluid absorption to net secretion in mice, rats, guinea pigs, rabbits, and dogs. This proabsorptive mode involves the enteric nervous system, the suppression of prostaglandin formation, and the opening of basolateral K+ channels. However, in some pathophysiological states nitric oxide synthase may be produced at higher concentrations that are capable of evoking net secretion. Thus nitric oxide synthase contributes to the diarrheal response in trinitrobenzene sulfonic acid-induced ileitis in guinea pigs and is the mediator of the laxative action of several intestinal secretagogues including castor oil, phenolphthalein, bisacodyl, magnesium sulfate, bile salts, senna, and cascara in the rat. Corresponding with the in vivo results, nitric oxide-donating compounds or nitric oxide itself stimulate chloride secretion in the guinea pig and rat intestine in vitro. Exceptions are the diarrhea produced by bacterial enterotoxins in the rat, in which nitric oxide seems to have a proabsorptive role, and the mouse ileum in vitro, in which nitric oxide-donating compounds produce a net proabsorptive effect on basal ion transport. Several endogenous secretagogues (substance P, 5-hydroxytryptamine, interleukin-1beta), which are important mediators of the inflammatory bowel diseases, act, at least in part, through the liberation of nitric oxide. Clinical studies have shown that nitric oxide is elevated in several inflammatory bowel diseases and other secretory conditions including ulcerative colitis, Crohn's disease, toxic megacolon, diverticulitis, infectious gastroenteritis, and infantile methemoglobinemia. However, the determination of nitric oxide in secretory diarrhea per se does not give conclusive information on the nitric oxide contribution to clinical secretory diarrhea.
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PMID:Nitric oxide as a modulator of intestinal water and electrolyte transport. 972 40

Membrane metalloendopeptidase EC 3.4.24.11 (Enkephalinase, neutral endopeptidase, NEP) is a cellular ectoenzyme, immunophenotypically identified as the leukocyte cluster of differentiation CD10 or CALLA (common acute lymphoblastic leukemia antigen). Immunological, biochemical and molecular biology techniques have identified tis cell membrane feature in various organs: brain, cardiovascular system, lung, placenta, kidney etc. The CD10 immunophenotype is a common feature of lymphoblasts in acute lymphoid leukemia not expressing the T- or B-markers. The enzymatic activity of CD10/NEP possibly influences normal lymphocyte ontogeny by proteolytic cleavage of the regulatory peptides. The substrates of CD10/NEP in the kidneys are (see the list of abbreviations) ANP, adrenomedullin and PAMP; in the brain, the substrates are enkephalins and oxytocin; in the lung, bombesin, BLP, GRP, neuromedin C, substance P and neurokinin A; in the cardiovascular system, angiotenisin II, bradykinin and CGRP; in the gut, VIP; on the neutrophil membrane, fMLP etc. Some substrates are not strictly tissue-specific, e.g. substance P. Preclinical and clinical trials explore possibilities of therapeutic application of the inhibitors of neutral endopeptidase, such as thiorphan in the management of pain, diarrhoea, depression, arterial hypertension and asthma. Other possibilities of application include the treatment of hyalinomembranous disease and prevention of neurotoxicosis in tetanus and botulism.
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PMID:[Membrane metalloendopeptidase (CD10/CALLA): distribution, physiologic and pathophysiologic functions and its inhibitors]. 974 92

Nearly 30% of patients treated with metformin experience gastrointestinal side effects. Since release of 5-hydroxytryptamine (5-HT) from the intestine is associated with nausea, vomiting, and diarrhea, we examined whether metformin induces 5-HT release from the intestinal mucosa. In 40% of tissue biopsy specimens of human duodenal mucosa, metformin (1, 10, and 30 microM) caused an increase in 5-HT outflow by 35, 70, and 98%, respectively. Peak increases in 5-HT outflow were observed after 10-15 min exposure to metformin, returning to baseline levels after 25 min. Tetrodotoxin (1 microM) reduced by about 50% the metformin-evoked increase in 5-HT outflow (P<0.05). Metformin-evoked release was not affected by scopolamine + hexamethonium, propranolol, the 5-HT3 receptor antagonist dolasetron, naloxone, or the NK1 receptor antagonist L703606. In the presence of tetrodotoxin (1 microM), somatostatin (1 microM) further reduced metformin-induced 5-HT release by 15-20%. In view of the 5-HT releasing effects of selective 5-HT3 receptor agonists to which metformin (N-N-dimethylbiguanide) is structurally related, we investigated whether metformin directly interacts with 5-HT3 receptors. Receptor binding (inhibition of [3H]-GR65630 binding) and agonist effects (stimulation of [14C]-guanidinium influx) at 5-HT3 receptors were studied in murine neuroblastoma N1E-115 cells, which express functional 5-HT3 receptors. Metformin up to 0.3 mM failed to inhibit [3H]-GR65630 binding and to modify displacement of [3H]-GR65630 binding induced by 5-HT. 5-HT (3 microM) stimulated the influx of [14C]-guanidinium in intact N1E-115 cells. Metformin up to 1 mM failed to modify basal influx, 5-HT-induced influx, and 5-HT+ substance P-induced influx of [14C]-guanidinium. Our results indicate that metformin induces 5-HT3 receptor-independent release of 5-HT from human duodenal mucosa via neuronal and non-neuronal mechanisms. Part of the gastrointestinal side effects observed during treatment with metformin could, thus, be produced by the release of 5-HT and other neurotransmitter substances within the duodenal mucosa.
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PMID:Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors. 1065 Nov 52

Sangre de grado is an Amazonian herbal medicine used to facilitate the healing of gastric ulcers and to treat gastritis, diarrhea, skin lesions, and insect stings. This study was designed to evaluate the gastrointestinal applications. Gastric ulcers were induced in rats by brief serosal exposure of the fundus to acetic acid (80%). Sangre de grado was administered in drinking water at 1:1,000 and 1:10,000 dilutions from the postoperative period to day 7. Guinea pig ileum secretory responses to capsaicin, electrical field stimulation, and the neurokinin-1 (NK-1) agonist [Sar(9),Met(O(2))(11)]substance P were examined in Ussing chambers. Sangre de grado facilitated the healing of experimental gastric ulcer, reducing myeloperoxidase activity, ulcer size, and bacterial content of the ulcer. The expression of proinflammatory genes tumor necrosis factor-alpha, inducible nitric oxide synthase (iNOS), interleukin (IL)-1beta, IL-6, and cyclooxygenase-2 was upregulated by ulcer induction but reduced by sangre de grado treatment, particularly iNOS and IL-6. In Ussing chambers, sangre de grado impaired the secretory response to capsaicin but not to electrical field stimulation or the NK-1 agonist. We conclude that sangre de grado is a potent, cost-effective treatment for gastrointestinal ulcers and distress via antimicrobial, anti-inflammatory, and sensory afferent-dependent actions.
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PMID:Treatment of gastric ulcers and diarrhea with the Amazonian herbal medicine sangre de grado. 1089 63

5-HT3-receptor antagonists are potent and highly selective competitive inhibitors of the 5-HT3-receptor with negligible affinity for other receptors. They are rapidly absorbed and penetrate the blood-brain barrier easily. 5-HT3-receptor antagonists are metabolized by diverse subtypes of the cytochrome P450-system, metabolites are excreted mainly in urine. Half-lifes in healthy subjects vary from 3-4 hours (ondansetron, granisetron) to 7-10 hours (tropisetron, hydrodolasetron). 5-HT3-receptor antagonists do not modify any aspect of normal behaviour in animals or induce remarkable changes of physiological functions in healthy subjects. They are well tolerated over wide dose ranges, most common side effects in clinical use are headache and obstipation. Clinical efficacy was first established in chemotherapy-induced emesis. In this indication, 5-HT3-receptor antagonists set a new standard regarding efficacy and tolerability. Further established indications are radiotherapy-induced and post-operative emesis. Antiemetic efficacy results from a simultaneous action at peripheral and central 5-HT3-receptors. Other peripheral actions include reduction of secretion and diarrhea caused by increased intestinal serotonin content (e.g. in carcinoid syndrome), a limited antiarrhythmic activity and a reduction of experimentally induced pain. CNS effects comprise anxiolysis, attenuation of age-associated memory impairment, reduction of alcohol consumption in moderate alcohol abuse and an antipsychotic effect in patients with parkinson psychosis. In migraine, 5-HT3-receptor antagonists show moderate efficacy, as well. Repeatedly demonstrated efficacy of 5-HT3-receptor antagonists in patients suffering from fibromyalgia raises the question for the mechanism of action involved. Ligand binding at the 5-HT3-receptor causes manifold effects on other neurotransmitter and neuropeptide systems. In particular, 5-HT3-receptor antagonists diminish serotonin-induced release of substance P from C-fibers and prevent unmasking of NK2-receptors in the presence of serotonin. These observations possibly provide an approach for the causal explanation of favourable treatment results with 5-HT3-receptor antagonists in fibromyalgia.
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PMID:Preclinical and clinical pharmacology of the 5-HT3 receptor antagonists. 1102 30


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