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)

To elucidate the possible role of substance P in the pathogenesis of acute gastric mucosal damage, rats were treated intragastrically with 1.0 mL 96% ethanol, 0.6N HCl, or 25% NaCl, with or without IP coadministration of substance P, senktide, or septide (1 mumol/L per 100 g). All three peptides were found to double the mean lesion area when compared with that induced by ethanol, whereas substance P antagonist (1 mumol/L per 100 g) prevented the expansion of damage extent. The increased damage was associated with increased gastric mucosal levels of platelet activating factor, leukotriene B4, and leukotriene C4. Substance P antagonists also reduced by half the extent of the gastric damage induced by ethanol when administered by itself. WEB 2086 (platelet-activating factor antagonist; Boehringer Ingelheim KG, Germany), hydroxyzine (H1 blocker), and cimetidine (H2 blocker) reduced lesion area by 50%, but only in rats treated with both substance P and ethanol. Ketotifen (mast-cell stabilizer) (100 micrograms/100 g), administered orally 30 minutes before damage induction, totally abolished the extent of the damage induced by either ethanol or the coadministration of ethanol and peptides in the surface epithelium of the entire mucosa. The protective effect of ketotifen was accompanied by significant reduction in mucosal generation of platelet-activating factor, leukotriene C4, and leukotriene B4. Similar mucosal protection was afforded by ketotifen against damage induced by 0.6N HCl, 25% NaCl, or indomethacin. Therefore, it is suggested that substance P is involved in the pathogenesis of acute ethanol-induced gastric mucosal damage. The effective mucosal protection provided by ketotifen indicates the important role of mast cells and their mediators in the pathogenesis of acute gastric mucosal damage and may have therapeutic implications.
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PMID:Gastric mucosal damage by ethanol is mediated by substance P and prevented by ketotifen, a mast cell stabilizer. 170 83

The mammalian tachykinins substance P (SP) and neurokinin A (NKA) are known to be present in sensory airway nerves of animals and humans. We studied the effect of mammalian and nonmammalian tachykinins on the conducting airways of anesthetized, mechanically ventilated Fisher 344 rats. Dose-dependent increases in lung resistance and decreases in dynamic compliance occurred after the intravenous administration of eledoisin (E), kassinin (K), NKA, and SP. E, K, and NKA were more potent bronchoconstrictors than was SP. Neurokinin B (NKB) caused a similar decrease in dynamic compliance, but had no effect on lung resistance. This order of potency suggests a predominance of NK-2 receptors in the rat airways. Both atropine and the 5-hydroxytryptamine antagonist methysergide largely reduced the bronchoconstriction induced by E and SP. Vagotomy did not change this reaction, whereas pretreatment with the ganglion blocker hexamethonium slightly enhanced the bronchoconstrictor action of E and SP. Sodium cromoglycate and nedocromil sodium, 2 drugs that can inhibit mediator release from inflammatory cells, significantly reduced the bronchoconstrictor action of NKA. Ketotifen, an antihistamine with mast-cell-stabilizing properties, significantly reduced the bronchoconstriction induced by E, whereas the H1-receptor antagonist clemastine had no effect. We conclude that tachykinins cause bronchoconstriction in rats largely by an indirect mechanism, involving both acetylcholine and 5-hydroxytryptamine. We suggest that tachykinins cause bronchoconstriction by stimulation of postganglionic vagal nerve endings and mast cells.
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PMID:The mechanism of tachykinin-induced bronchoconstriction in the rat. 246 68

To elucidate the possible role of vasoactive intestinal peptide (VIP) in the pathogenesis of acute gastric mucosal damage, rats were treated intragastrically with 1.0 ml 96% ethanol with or without intravenous or intraperitoneal coadministration of VIP (1 nmol/liter to 1 mumol/liter/100 g). VIP was found to double the mean lesion area when compared with that induced by ethanol alone (P < 0.05), an effect that was prevented by VIP antagonist (1 mumol/liter/100 g). A substance P antagonist (1 mumol/liter/100 g) also reduced the extent of gastric damage induced by coadministration of VIP and ethanol. VIP antagonist or substance P antagonist significantly reduced ethanol-induced gastric mucosal damage. Gastric mucosal levels of LTB4, LTC4, VIP, and substance P were significantly increased in ethanol-treated rats as compared with saline-treated animals (P < 0.05). The augmentation of ethanol-induced damage by VIP was associated with increased gastric mucosal levels of LTB4. In VIP-treated rats, gastric mucosal levels of substance P were found to be significantly increased compared with control rats (P < 0.05). Administration of VIP to pyloric-ligated rats significantly increased gastric acid output and blood pepsinogen A levels as compared with saline treated rats (P < 0.05). Ketotifen, a mast cell stabilizer (100 micrograms/100 g), administered orally 30 min before damage induction by ethanol, with or without VIP, totally abolished the damage of the surface epithelium of the entire gastric mucosa and significantly reduced the mucosal levels of LTC4 and LTB4 (P < 0.05). It is suggested that VIP is involved in the pathogenesis of acute ethanol-induced gastric mucosal damage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of vasoactive intestinal peptide (VIP) in pathogenesis of ethanol-induced gastric mucosal damage in rats. 768 41

The development of newer, more potent, nonsedating H1-receptor antagonists has led to a reappraisal of the potential of this class of drugs in the treatment of asthma. Studies conducted in Japan have examined the pharmacologic profile and clinical efficacy of one of these newer agents, terfenadine. In vitro, terfenadine inhibited the release of histamine from rat peritoneal mast cells and guinea pig lung tissue and conjunctiva in response to such stimuli as compound 48/80, concanavalin A, substance P, A-23187, and the partial peptide of eosinophil major basic protein. Ketotifen had similar, though less potent, antiallergic activity in these models. Mechanisms that appear to be involved in the mediation of this inhibitory effect include the prevention of intracellular calcium ion release and calcium uptake, the inhibition of protein kinase C translocation, and the activation of adenylate cyclase and the resulting accumulation of cyclic AMP (cAMP). A multicenter, double-blind, controlled clinical trial compared the efficacy of ketotifen, 2 mg bid, with that of terfenadine, given at doses of 120 or 240 mg bid (two or four times the US recommended dose, respectively) in the treatment of mild to moderate atopic and mixed-type asthma in adults. Physician assessment of overall improvement and patient evaluation of response were somewhat better with terfenadine, particularly the 120-mg bid dose. As in other comparative studies of these two drugs, terfenadine produced less drowsiness than ketotifen.
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PMID:The Japanese perspective: effects of terfenadine in bronchial asthma: in vitro and in vivo research. 769 May 27

In guinea pig airways, electrical field stimulation (50 V, 0.5 msec, 8 Hz for 20 seconds) produces a rapid contraction, which is followed by a long-lasting contraction, at least in the lower part of the trachea and in the bronchi. The latter contraction is due to the release of neuropeptides from airway sensory nerves. Ketotifen fumarate has been demonstrated to inhibit the noncholinergic contraction in guinea pig airways in vitro, but no attempt has been made to identify the receptor type. Therefore we have performed an in vitro study to investigate which receptor is responsible for the inhibitory effects of ketotifen on noncholinergic contraction in guinea pig airways. Ketotifen (3 to 100 mumol/L) produced a concentration-dependent inhibition of the noncholinergic contraction, with a maximum inhibition of 74% +/- 7% at 8 Hz stimulation (p < 0.001; n = 5). Pretreatment of the tissues with either cimetidine (10 mumol/L) or thioperamide (10 mumol/L) or phentolamine (10 mumol/L) did not prevent the inhibitory effect of ketotifen (10 mumol/L). Cetirizine (10 mumol/L), on the other hand, produced no inhibition of the noncholinergic contraction at all. Metitepine (0.1 mumol/L) and methysergide (1 mumol/L), both 5-HT1 antagonists, attenuated the inhibitory effect of ketotifen (10 mumol/L). Ketanserin (a 5-HT2 antagonist, 10 mumol/L) and tropisetron (a 5-HT3 antagonist, 1 mumol/L) had no effect. Ketoifen (100 mumol/L) did not affect the cumulative dose-response relationship to exogenous substance P (0.01 mumol/L to 10 mmol/L).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ketotifen modulates noncholinergic contraction in guinea pig airways in vitro by a prejunctional nonhistamine receptor. 806 73

We assessed the effects of KW-4679 on bronchoconstriction, airway hyperresponsiveness and infiltration of inflammatory cells into the bronchoalveolar lavage (BAL) fluid induced by platelet-activating factor (PAF) in guinea pigs. (1) KW-4679 (1, 10 mg/kg, p.o.) significantly inhibited PAF-induced bronchoconstriction in anesthetized, ventilated guinea pigs. Ketotifen (1, 10 mg/kg, p.o.) also significantly inhibited that reaction. (2) Intravenous administration of PAF (600 ng/kg/hr) to ventilated anesthetized guinea pigs induced bronchial hyperresponsiveness to histamine or substance P. PAF-induced bronchial hyperresponsiveness was significantly attenuated by pretreatment with KW-4679 (3 mg/kg, i.v.). (3) Exposure of guinea pigs to an aerosol of PAF induced an increase in the numbers of total leukocytes, eosinophils, neutrophils and lymphocytes in BAL fluid at 24 hr. KW-4679 (10 mg/kg, p.o.) reduced the increase in eosinophils in BAL fluid. Ketotifen (10 mg/kg, p.o.) partially reduced the increase in eosinophils in BAL fluid. (4) KW-4679 did not inhibit PAF-induced rabbit platelet aggregation. These observations indicate that KW-4679 attenuates the PAF-induced pulmonary reactions in guinea pigs and that these actions may be beneficial for the treatment of allergic bronchial asthma.
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PMID:[Effect of KW-4679, a novel antiallergic drug, on platelet-activating factor (PAF)-induced bronchoconstriction, airway hyperresponsiveness and pulmonary cell accumulation in guinea pigs]. 856 11

Calcitonin gene-related peptide (CGRP) released from sensory neurons, which are closely apposed to mast cells and blood vessels, mediates gastric hyperemia in response to acid challenge of the damaged mucosa. Substance P (SP) is coreleased with CGRP from sensory neurons, but the role of this peptide in gastric blood flow regulation is largely unknown. Chambered rat stomachs were exposed to 1.5 M NaCl and acidic saline after treatment with SP, aprotinin (serine protease inhibitor), and the mast cell stabilizers ketotifen and sodium cromoglycate (SCG). Gastric hyperemia (measured with a laser Doppler flow velocimeter) after hypertonic injury and acid challenge was nearly abolished by SP. Aprotinin infused together with SP and pretreatment with ketotifen and SCG before SP restored the gastric hyperemia. Ketotifen and SCG inhibited mast cell degranulation in SP-treated rats. Preservation of gastric hyperemia was correlated with improved mucosal repair. These data suggest that impaired hyperemia by SP during acid challenge of the gastric mucosa may be mediated by a mast cell-dependent mechanism involving the release of proteases from mast cells.
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PMID:Substance P may attenuate gastric hyperemia by a mast cell-dependent mechanism in the damaged gastric mucosa. 1056 13