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)

The distribution in the bowel wall of vasoactive intestinal polypeptide-, neuropeptide Y-, and substance P-containing nerve cell bodies and nerve fibers has been described in human sigmoid colon by immunohistochemical examination. In patients with chronic idiopathic constipation, diverticular disease, and in controls (of tissue taken from patients with carcinoma, from a site distant from the tumor that appeared macroscopically normal), the concentrations of vasoactive intestinal polypeptide, neuropeptide Y, and substance P have been measured by immunoassay in the following preparations of sigmoid colon: mucosa, whole colonic wall with mucosa dissected away, circular muscle, and taenia coli. In idiopathic constipation, the vasoactive intestinal polypeptide content of the whole wall minus mucosa was reduced when compared with controls (P less than 0.05) but was unaltered in the mucosa, circular muscle, and taenia coli. In diverticular disease, the vasoactive intestinal polypeptide content of the mucosa and whole wall minus the mucosal layer was increased when compared with control tissue (P less than 0.05 and P less than 0.02, respectively) but was unaltered in the circular muscle and taenia coli. Substance P and neuropeptide Y levels in all layers of colonic wall were unaltered in these two diseases. The disturbances in the normal neural content of vasoactive intestinal polypeptide in the bowel wall in idiopathic constipation and diverticular disease may initiate or contribute to the functional changes seen in these disorders.
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PMID:Vasoactive intestinal polypeptide levels in sigmoid colon in idiopathic constipation and diverticular disease. 169 28

The characteristics of [(125)I]Bolton-Hunter[Sar(9),Met(O(2))(11)]substance P ([(125)I]BH-SarSP) binding were investigated in membranes of human ascending, transverse, distal, and sigmoid colon circular muscle. Binding of [(125)I]BH-SarSP was of high affinity (K(D) = 68 nM) and low capacity (B(max) = 0.31 fmol/mg of wet weight tissue), and showed no regional differences. [(125)I]BH-SarSP binding was inhibited by SP approximately equal to [Pro(9)]SP > or = (2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP99994) >> neurokinin (NK) A > or = neuropeptide gamma > [Lys(5),MeLeu(9),Nle(10)]-NKA(4-10) approximately (S)-N-methyl-N[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl) butyl]benzamide (SR48968) >> senktide, suggesting binding to NK-1 sites. Most agonists seemed to bind to two sites. In autoradiographic studies, dense binding for [(125)I]BH-SarSP was associated with submucosal and longitudinal muscle blood vessels, and the submucosal margin of circular muscle (corresponding to interstitial cells of Cajal), with moderate binding over most of the circular muscle. In normal colon circular muscle strips, [Pro(9)]SP was almost ineffective, and SP caused contractions with pD(2) values of 5.3 to 5.7. No regional differences were observed in potency or efficacy. Responses to SP were inhibited by the NK-2 receptor antagonist SR48968, but not by NK-1 antagonist CP99994, indicating the involvement of NK-2 rather than NK-1 receptors. Atropine significantly inhibited contractions induced by SP, indicating a minor cholinergic component. Contractile responses to SP were considerably reduced in preparations from patients with diverticular disease, and marginally reduced in ulcerative colitis compared with control. This study clearly demonstrates an NK-1 binding site on human colon circular muscle, but its role in this tissue remains unclear and may not involve contractile mechanisms. The attenuated contractility in specimens with diverticular disease may reflect disease-related alterations of the tachykinin receptor system.
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PMID:Roles of substance P receptors in human colon circular muscle: alterations in diverticular disease. 1213 Jul 25

Diverticulosis is largely asymptomatic but recent evidence suggests that episodes of acute diverticulitis double the risk of subsequently suffering from recurrent noninflammatory pain. Numerous animal models demonstrate how inflammation is followed by circular muscle hypertrophy, abnormalities of innervation, and increased sensitivity to cholinergic agents. There is also an impairment of norepinephrine and acetylcholine release and damage to nitrergic neurons. These changes are also associated with visceral hypersensitivity. Many of the features, including visceral hypersensitivity are also seen in symptomatic patients with diverticulosis. The trinitrobenzene sulfonic acid colitis model demonstrates that inflammation is followed by long lasting increases in tachykinin and other neuropeptide immunoreactivity. These changes occur both in the mucosa and myenteric plexus and parallel changes seen in resections and mucosal biopsies in diverticular patients. These neural abnormalities may be responsible for the visceral hypersensitivity, which explains why symptoms correlate poorly with objective abnormalities such as intraluminal pressure or motor patterns. Treatment of visceral hypersensitivity might be more effective than current therapies that often leave pain unaltered.
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PMID:How inflammation changes neuromuscular function and its relevance to symptoms in diverticular disease. 1688 93

Neurokinin A (NKA) is an important spasmogen in human colon. We examined inflammatory disease-related changes in the tachykinin NK(2) receptor system in human sigmoid colon circular muscle, using functional, radioligand binding, and quantitative reverse transcription-polymerase chain reaction methods. In circular muscle strips, indomethacin enhanced contractile responses to NKA (p < 0.01) and to the NK(2) receptor-selective agonist [Lys(5),MeLeu(9),Nle(10)]-NKA(4-10) (p < 0.05) in both normal and acute diverticular disease (DD) specimens, indicating NK(2) receptor-mediated release of relaxant prostanoids. Contractile responses to both tachykinins were reduced in strips from DD (p < 0.001) and ulcerative colitis (UC) (p < 0.05) specimens. Responses to acetylcholine were no different in other strips from the same disease patients, demonstrating that the change in responsiveness to tachykinins in disease is specifically mediated by the NK(2) receptor. In membranes from UC specimens, receptor affinity for (125)I-NKA (median K(D) 0.91 nM, n = 16) was lower (p < 0.01) than that in age-matched control specimens (K(D) 0.55 nM, n = 40), whereas K(D) (0.65 nM, n = 28) in DD was no different from control. No disease-related changes in receptor number (B(max)) were found (mean, 2.0-2.5 fmol/mg of wet weight tissue), suggesting that the reduced contractile responses in disease are not due to a loss of receptor number. Different mechanisms may account for the reduced contractility in DD compared with UC. A gender-related difference in receptor density was seen in controls, with B(max) lower in females (1.77 fmol/mg, n = 15) than in males (2.60 fmol/mg, n = 25, p = 0.01). In contrast, no gender-related differences were seen in NK(2) receptor mRNA in control colonic muscle, indicating that the gender difference is a post-translational event.
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PMID:Tachykinin NK2 receptor and functional mechanisms in human colon: changes with indomethacin and in diverticular disease and ulcerative colitis. 1795 48

Some patients with colonic diverticula suffer recurrent abdominal pain and exhibit visceral hypersensitivity, though the mechanism is unclear. Prior diverticulitis increases the risk of being symptomatic while experimental colitis in animals increases expression of neuropeptides within the enteric nervous system (ENS) which may mediate visceral hypersensitivity. Our aim was to determine the expression of neuropeptides within the ENS in diverticulitis (study 1) and in patients with symptomatic disease (study 2). Study 1 - Nerves in colonic resection specimens with either acute diverticulitis (AD, n = 16) or chronic diverticulitis (CD, n = 16) were assessed for neuropeptide expression recording % area staining with protein gene product (PGP9.5), substance P (SP), neuropeptide K (NPK), pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP) and galanin. Study 2 - Seventeen symptomatic and 15 asymptomatic patients with colonic diverticula underwent flexible sigmoidoscopy and multiple peridiverticular mucosal biopsies. Study 1- Neural tissue, as assessed by PGP staining was increased to a similar degree in circular muscle in both AD and CD. The CD specimens showed significant increases in the immunoreactivity of SP, NPK and galanin in both mucosal and circular muscle layer compared with controls. Study 2 - Mucosal histology was normal and PGP9.5 staining was similar between groups however patients with symptomatic diverticular disease demonstrated significantly higher levels of SP, NPK, VIP, PACAP and galanin within the mucosal plexus. Patients with symptomatic diverticular disease exhibit increased neuropeptides in mucosal biopsies which may reflect resolved prior inflammation, as it parallels the changes seen in acute and chronic diverticulitis.
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PMID:Post inflammatory damage to the enteric nervous system in diverticular disease and its relationship to symptoms. 1945 15

Otilonium bromide (OB) is a spasmolytic compound of the family of quaternary ammonium derivatives and has been successfully used in the treatment of patients with irritable bowel syndrome (IBS) due to its specific pharmacodynamic effects on motility patterns in the human colon and the contractility of colonic smooth muscle cells. This article examines how. OB inhibits the main patterns of human sigmoid motility in vitro, which are spontaneous rhythmic phasic contractions, smooth muscle tone, contractions induced by stimulation of excitatory motor neurons and contractions induced by direct effect of excitatory neurotransmitters. It does this mainly by blocking calcium influx through L-type calcium channels and interfering with mobilization of cellular calcium required for smooth muscle contraction, thereby limiting excessive intestinal contractility and abdominal cramping. OB also inhibits T-type calcium channels and muscarinic responses. Finally, OB inhibits tachykinin receptors on smooth muscle and primary afferent neurons which may have the joint effect of reducing motility and abdominal pain. All these mechanisms mediate the therapeutic effects of OB in patients with IBS and might be useful in patients with other spastic colonic motility disorders such as diverticular disease.
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PMID:Colonic smooth muscle cells and colonic motility patterns as a target for irritable bowel syndrome therapy: mechanisms of action of otilonium bromide. 2505 96