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)

1. The present study was undertaken to determine the mechanism of action of endothelin-1 (ET-1)-induced contraction of the guinea-pig isolated trachea. 2. ET-1 (1 nM-0.3 microM) produces a concentration-dependent contraction of guinea-pig trachea with an EC50 of approximately 25 nM. The combination of the peptidoleukotriene receptor antagonist, SK&F 104353 (10 microM) and the H1-histamine receptor antagonist, mepyramine (10 microM), which abolishes antigen-induced contraction in guinea-pig trachea, was without effect on ET-1 concentration-response curves. Furthermore, the platelet-activating factor (PAF) receptor antagonist, WEB 2086, (1 or 10 microM) did not inhibit ET-induced contraction. 3. ET-1 (0.3 microM) did not stimulate histamine or immunoreactive peptidoleukotriene release from guinea-pig isolated trachea. 4. The release of various prostanoids from guinea-pig trachea was increased significantly by ET-1 (0.3 microM); the profile of release was prostaglandin D2 (PGD2) = PGE2 = 6-keto PGF1 alpha (PGI2 metabolite) > thromboxane B2 = PGF2 alpha >> 9 alpha, 11 beta PGF2 (PGD2 metabolite). ET-1-induced release of prostaglandins, which was about 30% of that elicited by antigen in sensitized tissues, was not affected by epithelium removal and was observed in tissues from which the smooth muscle had been removed. Previous studies in our laboratory indicated that indomethacin potentiated contraction produced by high concentrations of ET-1, whereas a thromboxane receptor antagonist was without appreciable effect on ET-1 concentration-response curves. 5. Pretreatment of tissues for 1 h with capsaicin (10 microM), which depletes different sensory neurones, produced a small, but significant, inhibitory effect on ET-1 concentration-response curves in the presence but not the absence of the epithelium. The combination of the NK1 tachykinin receptor antagonist,CP-96,345 (0.1 microM), and the NK2 tachykinin receptor antagonist, SR 48968 (0.1 microM), was without effect on ET-l concentration-response curves but substantially antagonized capsaicin-induced contraction.6. The present data suggest that in guinea-pig isolated trachea, ET- 1 produces contraction predominantly via a direct mechanism: there is no significant contribution of the release of histamine,leukotrienes, PAF, or tachykinins (acting on NK1 or NK2 receptors). Although ET-1 evokes the release of an array of prostanoids from the trachea they do not appear to have a major influence on the contractile response.
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PMID:Relative contributions of direct and indirect mechanisms mediating endothelin-induced contraction of guinea-pig trachea. 750 80

Prostaglandins are known to enhance the inflammatory and nociceptive actions of other chemical mediators of inflammation such as bradykinin. One possible mechanism for this sensitizing action is that prostanoids augment the release of neuroactive substances from sensory neurons. To initially test this hypothesis, we examined whether selected prostaglandins could enhance the resting or bradykinin-evoked release of immunoreactive substance P (iSP) and/or immunoreactive calcitonin gene-related peptide (iCGRP) from sensory neurons in culture. Bradykinin alone causes a concentration-dependent increase in the release of iSP and iCGRP from isolated sensory neurons, and this action is abolished in the absence of extracellular calcium. Pretreating the neurons with PGE2 (10 nM to 1 microM) potentiates the bradykinin-evoked release of both iSP and iCGRP by approximately two-to fourfold. At these concentrations, PGE2 alone did not significantly alter peptide release. Exposing the cultures to 1 microM PGF2 alpha is ineffective in altering either resting or bradykinin-evoked peptide release. Sensory neurons in culture contain cyclooxygenase-like immunoreactivity suggesting that the enzyme that converts arachidonic acid to prostaglandins is present. In addition, pretreating cultures with 14C-arachidonic acid yields radiolabeled eicosanoids that cochromatograph with known prostaglandin standards. Preexposing cultures to indomethacin abolishes the production of prostaglandins and attenuates the bradykinin-stimulated release of iSP and iCGRP. This implies that the synthesis of prostaglandins contributes to the bradykinin-evoked release of peptides. The augmentation of bradykinin-induced release of iSP and iCGRP by PGE2 may be one mechanism to account for the inflammatory and hyperalgesic actions of this eicosanoid.
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PMID:Prostaglandin E2 enhances bradykinin-stimulated release of neuropeptides from rat sensory neurons in culture. 751 58

The release of PGF2 alpha and PGE2, progesterone, androgens and oestradiol in vitro, and the aromatase activity in the brain of the male lizard Podarcis sicula sicula during three different phases of the reproductive period were evaluated. In addition, the effects of salmon GnRH, substance P, salmon GnRH antagonist, substance P antagonist, PGF2 alpha, PGE2 and acetylsalicylic acid on the release of prostaglandins and sex steroids and on aromatase activity in the brain were evaluated during the same three phases. PGF2 alpha, oestradiol and aromatase activity were higher during the refractory phase, androgens during the fighting phase, and progesterone during the mating phase, while PGE2 was lower during the refractory phase. Treatment with salmon GnRH increased PGF2 alpha, oestradiol and aromatase activity, but decreased the amount of androgens released. Substance P decreased PGF2 alpha, oestradiol and aromatase activity, but increased the amount of androgens released. PGF2 alpha increased oestradiol and aromatase activity, but decreased the amount of androgens released. Acetylsalicylic acid decreased PGF2 alpha, oestradiol and aromatase activity, but increased the amount of androgens released. These data suggest that salmon GnRH and substance P have different roles in reproductive processes, with opposite mechanisms, in the central nervous system of this male lizard: salmon GnRH seems to be involved in regulating the refractory phase, while substance P plays a role in regulating the fighting phase.
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PMID:Relationships among GnRH, substance P, prostaglandins, sex steroids and aromatase activity in the brain of the male lizard Podarcis sicula sicula during reproduction. 752 52

A marked decrease in zinc concentration was observed in plasma (P < 0.001), hindpaw skin (P < 0.01), and dorsal skin (P < 0.01) in zinc-deficient rats (rats fed a zinc-deficient diet for 3 wk), compared with the control rats fed the same zinc-deficient diet supplemented with ZnCO3 (50 mg/kg diet). The threshold intensity needed to elicit vasodilatation in the hindpaw skin of the zinc-deficient rats on electrical stimulation of the saphenous nerve in a peripheral direction was markedly lower (P < 0.01) than that in the control rats. No difference was observed between control (n = 5) and zinc-deficient rats (n = 5) in the magnitude of the plasma extravasation evoked by either histamine or substance P. There was no difference between control and zinc-deficient rats in terms of the dose-response curve for release of histamine by substance P. Prostaglandin E2 (PGE2) concentration in the hindpaw skin of the zinc-deficient rats was nearly fourfold higher (P < 0.01) than that of the control rats, whereas no difference in the leukotriene B4 level in the hindpaw skin was observed between control and zinc-deficient rats. From the present study, it seems likely that an increased level of PGE2 in the vicinity of the nociceptive C-fiber terminals in the hindpaw skin of zinc-deficient rats may sensitize the terminals of the nociceptive C-fibers of the saphenous afferent nerve in the hindpaw and thus facilitate the production of antidromic vasodilatation.
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PMID:Sensitization of nociceptive C-fibers in zinc-deficient rats. 754 64

Prostaglandins sensitize sensory neurons to activation by mechanical, thermal and chemical stimuli. This sensitization also results in an increase in the stimulus-evoked release of the neuroactive peptides, substance P and calcitonin gene-related peptide from sensory neurons. The cellular transduction cascade underlying the prostaglandin-induced augmentation of peptide release is not known. Therefore, we examined whether the sensitizing action of prostaglandins on peptide release from sensory neurons grown in culture is mediated by the second messenger, adenosine 3', 5' cyclic monophosphate (cAMP). Prostaglandin E2 and carba prostacyclin (a stable analog of prostaglandin I2) significantly increase the content of cAMP-like immunoreactive substance (icAMP) in the sensory neuron cultures at concentrations that also augment the bradykinin- or capsaicin-evoked release of peptides. Furthermore, pretreating sensory neurons with agents that increase intracellular cAMP mimics the sensitizing action of prostaglandins. Exposing cultures to either forskolin (0.1-10 microM), cholera toxin (1.5 micrograms), or 8-bromo-cAMP (100 microM) results in a significant enhancement of the bradykinin- or capsaicin-stimulated release of both substance P-like and calcitonin gene-related peptide-like immunoreactive substances. Pretreating sensory neurons with the adenylyl cyclase inhibitor, 9-tetrahydro-2-furyl adenine (5 mM), abolishes the prostaglandin-induced increases in icAMP content and attenuates the prostaglandin E2 or carba prostacyclin enhancement of the evoked release of calcitonin gene-related peptide-like immunoreactive substance. These results demonstrate that the cAMP transduction cascade mediates the sensitizing actions of prostaglandins on peptide release from sensory neurons.
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PMID:Prostaglandins facilitate peptide release from rat sensory neurons by activating the adenosine 3',5'-cyclic monophosphate transduction cascade. 762 63

Capsaicin stimulates cyclic GMP production via nitric oxide (NO) (or another nitrosyl factor) in dorsal root ganglion (DRG) neurons maintained in culture. The purpose of the present study was to characterize further capsaicin stimulation of cyclic GMP production in DRG cells maintained in culture, investigate other algesic and/or inflammatory agents for effects on cyclic GMP production, and examine cells responsible for NO production and cyclic GMP production. Capsaicin stimulation of cyclic GMP production in DRG cells was dose dependent, receptor mediated, and attenuated by hemoglobin. Prostaglandin E2, substance P, and calcitonin gene-related peptide did not affect basal, capsaicin-stimulated, or bradykinin-stimulated cyclic GMP production. Other inflammatory or algesic agents, including serotonin, histamine, ATP, glutamate, aspartate, and NMDA, did not affect cyclic GMP production. Pretreatment of DRG cells with lipopolysaccharide increased basal cyclic GMP production in neuronal but not in nonneuronal cultures and facilitated stimulation of cyclic GMP production by L-arginine. Capsaicin pretreatment of neuronal DRG cultures, which destroys capsaicin-sensitive (small diameter) afferent neurons, attenuated capsaicin- and bradykinin-stimulated cyclic GMP production but did not affect basal or sodium nitroprusside-stimulated cyclic GMP production. These results indicate that capsaicin elicits production of a nitrosyl factor via capsaicin-sensitive (small diameter) neurons. Capsaicin evoked cyclic GMP production in nonneuronal DRG cultures in the presence but not in the absence of apposed neuronal DRG cultures. Overall, these findings suggest that specific exogenous (or endogenous) substances may stimulate production of a nitrosyl factor(s) by a subset of DRG neurons, and nitrosyl factors produced by these neurons may affect cyclic GMP production in neighboring neuronal or non-neuronal cells.
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PMID:Stimulation of cyclic GMP production via a nitrosyl factor in sensory neuronal cultures by algesic or inflammatory agents. 779 Aug 81

Using an isolated loop of the proximal duodenum of conscious rats, the role of vasoactive intestinal peptide (VIP) in the duodenal HCO3- response to HCl was examined, especially interactions with participating cholinoceptor mechanisms and prostaglandins. A 5-min perfusion with 150 mmol/liter HCl increased luminal VIP during 3 hr, with a peak output during and immediately after the acid challenge. The HCl-stimulated output was unaffected by atropine and hexamethonium, but was augmented by indomethacin from 13.6 (9.5-17.8) to 39 (20-85) fmol/cm/min. The HCO3- secretion in response to graded doses of intravenous VIP (0.00625-6 nmol/kg/30 min) was dose-dependent to maximally 33.5 +/- 10.5 mumol/cm/hr. The HCO3- secretion during a single intravenous infusion of VIP (12 nmol/kg/hr), 13.9 +/- 4.2 mumol/cm/hr, was unchanged by atropine, reduced to 10.0 +/- 3.5 mumol/cm/hr by hexamethonium, and augmented to 18.9 +/- 4.7 mumol/cm/hr by indomethacin. Exogenous VIP did not change the basal luminal output of PGE2; neither did exogenous PGE2 nor indomethacin affect the basal luminal output of VIP. HCl-induced increases in luminal outputs of VIP, substance P, and neurokinin A (the two latter with unknown roles) were differentially affected by atropine, hexamethonium, and indomethacin, indicating that the acid challenge released the peptides through controlled mechanisms. In conclusion, in the duodenal HCO3- response to luminal HCl, VIP may have a stimulatory role, which partially depends on nicotinic, but not on muscarinic cholinoceptor mechanisms, and which is negatively modulated by prostaglandins.
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PMID:HCl-stimulated duodenal HCO3- secretion in conscious rat. Interactions among VIP, nicotinic receptor mechanisms, and prostaglandins. 792 32

Electrical field stimulation (EFS; 5-10 V, 1 ms, 20 Hz for 1 min) of isolated guinea pig trachea resulted in a rapid increase in tone that is blocked by either atropine or tetrodotoxin (TTX). EFS of tracheal spirals also caused large increases in the release of certain prostanoids with release of prostaglandin (PG)D2, PGE2 and PGF2 alpha (16.5-, 3.0- and 4.1-fold, respectively). In contrast to the smooth muscle response, however, EFS-induced release of prostanoids was not significantly altered in the presence of TTX. Removal of the epithelium reduced the amount of prostanoids released by EFS. Thus, EFS-induced production of PGD2, PGE2 and PGF2 alpha was significantly reduced by about 30%, 70% and 80% in epithelium-denuded tissues, respectively. Direct vagal stimulation caused a rapid contraction of the trachealis but failed to elicit increases in the release of histamine or arachidonic acid metabolites. Furthermore, the selective stimulant of C-type sensory fibers capsaicin (3 microM) or exogenously applied substance P (1 microM) or neurokinin A (1 microM) failed to induce histamine, leukotriene or prostanoid release from guinea pig tracheal rings. Although, the mechanism involved in stimulation of arachidonic acid metabolism by EFS is unclear, this effect in part involves the epithelium but apparently is not mediated by airway elements sensitive to TTX, direct vagal stimulation or tachykinins.
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PMID:Release of inflammatory mediators from guinea pig trachea by electrical field stimulation: lack of neuronal involvement. 793 67

Dietary deficiency of magnesium (Mg) in rodents results in cardiomyopathic lesion formation. In our rat model, these lesions develop after 3 weeks on the Mg-deficient diet; significant elevation of several cytokines, IL-1, IL-6 and TNF alpha also occurs. In probing the mechanisms of lesion formation, we obtained data supporting the participation of free radicals (Freedman AM et al.: Bioch Biophys Res Commun 1990; 170: 1102). Recently, we identified an early elevation of circulating substance P and proposed a role of neurogenic peptides during Mg-deficiency (Weglicki WB, Phillips TM: AM J Phys 1992;262:R734). The present study was designed to evaluate the contribution of neurogenic peptides to the pathogenesis of Mg-deficiency. In the blood, substance-P and calcitonin gene related peptide (CGRP) are elevated during the first week on the diet. During the second week, circulating histamine, PGE2 and TBAR-materials were elevated and red cell glutathione was reduced, all prior to the elevation of the inflammatory cytokines during the third week. When the rats were treated with the substance P-receptor blocker [CP-96,345], the levels of substance P and CGRP remained elevated; however, increases in histamine, PGE2, TBAR-materials, and the decrease in red cell glutathione were inhibited; also, the development of cardiac lesions was inhibited significantly. These data support a central role for neurogenic peptides, especially substance P, in the development of cardiomyopathic lesions during Mg-deficiency.
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PMID:Neurogenic peptides and the cardiomyopathy of magnesium-deficiency: effects of substance P-receptor inhibition. 802 89

Short chain fatty acids stimulate Cl secretion in rat descending colon in vitro via an enteric reflex involving mucosa and cholinergic nerves. We used the short circuit current as the measure of Cl secretion caused by Na propionate (NaP) (0.5 mM) in luminal bath fluid and studied the mechanism of the response. The NaP response was decreased 81% by atropine and 76% by lidocaine. It was unaffected by tetrodotoxin, omega-conotoxin or by tachyphylaxis to capsaicin, CGRP, substance P, histamine or PGE2. It was not reduced by inhibitors of 5-HT2 or 5HT3 receptors or by partial tachyphylaxis to 5-HT. However, superficial mucosal injury with hypertonic Na sulfate (2 M) or xylose (4.5 M) reduced the NaP response by 90% and 86%, respectively, and mucosal concanavalin A (1 mg/ml) reduced it by 73%. Neither piroxicam (10 microM) nor nordihydroguaretic acid (10 microM) affected the NaP response. We hypothesize that NaP stimulates the superficial epithelium to release an unidentified agonist that depolarizes predominantly cholinergic nerve terminals and causes colonic secretion.
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PMID:Mechanisms of the secretory response to luminal propionate in rat descending colon in vitro. 836 52


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