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)

Mast cells have been studied extensively for their involvement in allergic reactions, where they secrete numerous powerful mediators in response to immunoglobulin E and specific antigens. However, they are also triggered by neuropeptides, they have been found in close contact with neurons, and they are activated in diseases such as angioedema, interstitial cystitis and irritable bowel disease, the prevalence of which is much higher in women. When tested on purified rat peritoneal mast cells, 17 beta-estradiol augmented secretion of histamine and serotonin, starting at 1 microM and in a dose-dependent manner, whether stimulated by the mast cell secretagogue compound 48/80 or the neuropeptide substance P. However, 17 beta-estradiol did not augment mast cell secretion stimulated by immunoglobulin E and specific antiserum indicating that immunologic stimulation is under different regulation. Testosterone inhibited secretion induced by compound 48/80. Tamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, inhibited serotonin and histamine release from purified rat peritoneal mast cells triggered by compound 48/80 or substance P. Tamoxifen also inhibited the increase in intracellular free Ca2+ originating from an influx of extracellular Ca2+ in response to compound 48/80. Moreover, tamoxifen antagonized the synergistic effect of phorbol myristate and the cation ionophore A23187 on mast cell secretion, suggesting that tamoxifen's inhibition may be due to regulation of protein kinase C activity. Tamoxifen may, therefore, have a beneficial effect in other neuroimmunoendocrine disorders both through estrogen receptor blockade and inhibition of mast cell secretion.
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PMID:Estradiol augments while tamoxifen inhibits rat mast cell secretion. 138 69

1. The effect of an acetly-coA lysolecithin acyltransferase inhibitor, thimerosal, on the release of endothelium-derived relaxing factor (EDRF) was examined in the greyhound isolated coronary artery. 2. Thimerosal (1-10 microM) relaxed fully, ring segments of coronary artery which were contracted with the thromboxane A2-mimetic, U46619 (30 nM). The response was endothelium-dependent, slow in both onset and time to reach maximum. The maximum relaxation to the highest concentration of thimerosal (10 microM) was maintained for 10-20 min before the tissue slowly regained active force (1-2 h) to the same or higher level as that prior to the addition of thimerosal. At this time the endothelium-dependent relaxation responses to acetylcholine (ACh), substance P (SP), bradykinin (BK) and the calcium ionophores, ionomycin and A23187 were abolished. The endothelium-dependent contractions to the nitric oxide synthase inhibitors, NG-nitro-L-arginine (L-NNA; 10-100 microM) and NG-monomethyl-L-arginine (L-NMMA: 10-100 microM), however, were unaffected. 3. Thimerosal (10 microM) did not affect the relaxation curve to sodium nitroprusside (SNP) nor the contraction curve to the thromboxane A2-mimetic, U46619. 4. Both the relaxation response to thimerosal and the selective block of the relaxation responses to stimulated EDRF release were unaffected by either indomethacin (10 microM) or superoxide dismutase (150 u ml-1). 5. L-NNA (100 microM) significantly blocked the relaxation curves to thimerosal and A23187 but not that to SNP.6. Abolition of stimulated EDRF-mediated responses with thimerosal was unlikely to result from maximal and maintained stimulation of EDRF release even when active U46619-induced force had returned to pre-thimerosal levels, since the relaxation curves to glyceryl trinitrate (GTN) and SNP were markedly attenuated in the presence of SNP and GTN respectively when active force was restored with endothelin-1 (ET-1).7. Melittin (1 microM), ionomycin (1 microM) and A23187 (1 microM) each had selective effects on stimulated but not basal EDRF responses, similar to those of thimerosal.8. We propose that stimulated but not 'basal' release of EDRF is dependent on the release of arachidonic acid or one of its non-cyclo-oxygenase metabolites, possibly by Ca2'-dependent activation of phospholipase A2.
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PMID:Thimerosal blocks stimulated but not basal release of endothelium-derived relaxing factor (EDRF) in dog isolated coronary artery. 138 15

The nonpeptide substance P receptor antagonist CP-96,345 was found to displace binding to Ca2+ channel binding sites labelled with either [3H]desmethoxyverapamil or [3H]diltiazem and to enhance [3H]nitrendipine binding. Unlike the substance P receptor antagonist activity of CP-96,345, these effects on Ca2+ channel binding sites were neither stereoselective nor species-dependent. It is concluded that CP-96,345 may act as an antagonist of L-type Ca2+ channels in addition to being a potent NK1 receptor (substance P) antagonist.
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PMID:The substance P receptor antagonist CP-96,345 interacts with Ca2+ channels. 138 77

AE0047, a new dihydropyridine-type Ca2+ entry blocker, significantly inhibited the contractions induced by transmural electrical stimulation and norepinephrine in dog mesenteric artery strips. The inhibition was greater in the case of the response to nerve stimulation. The 3H-overflow ratio evoked by electrical stimulation from strips previously soaked in [3H]norepinephrine was significantly reduced by AE0047 but not by nicardipine in a concentration sufficient to attenuate the response to norepinephrine. In aorta homogenate preparations, [3H]bunazosin binding was not replaced by AE0047 but by phentolamine. In strips treated with indomethacin, the endothelium-dependent relaxation caused by substance P and bradykinin was attenuated by treatment with AE0047 but not with nicardipine. The nitric oxide (NO)-induced relaxation was not influenced by AE0047. Cyclic GMP levels in the artery strips increased in response to substance P; the increase was markedly suppressed by AE0047 but not by nicardipine. In contrast to nicardipine, AE0047 appeared to inhibit the release of norepinephrine from adrenergic nerves and of NO from endothelial cells. The inhibition may be associated with the decreased transmembrane influx of Ca2+ in these tissues.
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PMID:AE0047, a new dihydropyridine Ca2+ entry blocker, inhibits the responses to adrenergic nerve stimulation and substance P in dog mesenteric arteries. 138 79

Xerostomia, the subjective feeling of dry mouth, affects millions of people particularly the elderly. It is invariably associated with hypofunction of the salivary glands. The amount, rate of secretion, and composition of saliva are regulated by both sympathetic and parasympathetic receptor systems whose stimulation transmits signals through intracellular messengers (cations, nucleotides, phospholipid derivatives) to structures and enzymes within the cell. Salivary glands express a variety of cell-surface receptors including adrenergic (alpha and beta), muscarinic-cholinergic, substance P, vasoactive intestinal peptide hormone, and ATP receptors. Ascorbate which is present in salivary acinar cells in relatively high concentrations, is closely involved in many cellular functions including the metabolism of pyrimidines, intracellular calcium, the catecholamines and other neurotransmitters which regulate salivary gland exocytosis. Ascorbate-dependent carboxyl-terminal peptide alpha-amidation enzyme similar to the pituitary peptidyl-glycine alpha-amidating monooxygase, is also present in salivary glands. It is therefore not fortuitous that the seemingly unrelated numerous factors like aging, drug ingestion, pregnancy, smoking, ionizing radiation, stress, and various pathological states such as cancer, autoimmune disorders, diabetes mellitus, and hypertension often implicated in the causation of xerostomia, all promote increased tissue requirement for and/or depletion of ascorbate.
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PMID:Ascorbate status and xerostomia. 143 93

Recent studies suggest endothelium to be involved in the vasorelaxation of calcium antagonists of the 1,4-dihydropyridine type, which may at least in part be mediated by endothelium-derived relaxing factor (EDRF = NO). To study this effect further, the influence of L-NG-nitro arginine (L-NNA), a specific inhibitor of EDRF-synthesis, on nitrendipine-induced vasorelaxation was examined in different isolated porcine arteries. Coronary, basilary, and tail arteries were bathed in Krebs-Henseleit solution and endothelial function was verified by means of substance P, an EDRF releasing neuropeptide. Vasorelaxation of nitrendipine in PGF2 alpha-precontracted arteries was studied in the presence and absence of L-NNA. Nitrendipine-induced vasorelaxation was markedly reduced by the addition of L-NNA in all vessels studied. Tachyphylactic effects of nitrendipine could be excluded. The obtained results may be explained by an enhancement of nitrendipine action by basally released EDRF, alternatively, by an increased EDRF-release induced by this calcium antagonist. Therefore, in a second series of experiments the release of EDRF was studied in isolated coronary arteries under cumulative application of nitrendipine. Using the nitric oxide scavenging properties of oxyhemoglobin, EDRF release was measured spectrophotometrically by means of methemoglobin formation. The application of nitrendipine resulted in a concentration-dependent increase in the extinction rate, indicating an increased release of NO which could be inhibited by preincubation with L-NNA. It may be concluded that, in functionally intact vessels, vasorelaxation induced by nitrendipine may additionally be mediated by an increased release of EDRF.
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PMID:Nitric oxide (EDRF) enhances the vasorelaxing effect of nitrendipine in various isolated arteries. 146 29

Spontaneous oscillations in intracellular Ca2+ concentration ([Ca2+]i) and membrane potential were used to monitor rhythmicity in freshly dispersed and cultured interstitial cells (IC) from the canine colon. The frequency of oscillations and responses to a number of channel blockers, agonists, ionic substitutions, and temperature were similar in freshly dispersed and cultured cells. An increase in the amplitude of Ca2+ oscillations after 3-6 days in culture and an increase in the rate of decline of [Ca2+]i in cultured IC were two differences noted between freshly dispersed and cultured cells. The frequency and amplitude of oscillations were a function of extracellular Ca2+ concentrations, and oscillations were abolished when the transmembrane flux of Ca2+ was reduced by nicardipine, La3+, or removal of Ca2+ from the extracellular medium. Oscillations persisted in the presence of ryanodine and ouabain. Lowered temperatures or a reduction in the concentration of Ca2+ in the medium reduced the frequency of spontaneous oscillations. Carbachol and substance P caused a transient increase in [Ca2+]i. Substance P then abolished spontaneous events. ATP and calcitonin gene-related peptide increased the frequency of spontaneous activity. Vasoactive intestinal peptide caused a temporary delay in spontaneous oscillations when added to the medium. Results indicate that freshly dispersed and cultured IC may be useful in studies of the mechanisms of rhythmicity in the gastrointestinal system.
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PMID:Calcium oscillations in freshly dispersed and cultured interstitial cells from canine colon. 155 Feb 5

The synthetic hexapeptide, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP, Growth Hormone-Releasing Peptide), has no structural similarities with any of the GH-releasing peptides known and its action in releasing GH is by a complementary but yet not clearly defined action on the pituitary as well as hypothalamus. Therefore, in vitro studies have been performed to demonstrate and characterize GHRP binding sites on peripheral membranes of both porcine pituitary and hypothalamus. The membrane binding sites were specific, reversible, saturable and time, temperature, pH and concentration dependent under optimum binding assay conditions. The maximum specific binding was observed between pH 5.0 and 6.0. In the presence of Ca2+ and Mg2+ ions, with or without chelating agents there was a significant reduction in the specific binding. Scatchard analysis of these binding sites using increasing doses of unlabeled GHRP revealed a single low affinity site with a 2.1 x 10(-5) M and 1.7 x 10(-5) M and a maximum number of sites of 10 nmol/mg protein and 5 nmol/mg protein for pituitary and hypothalamus, respectively. It is also observed that (D-Lys3)-GHRP, substance P antagonists and growth hormone-releasing factor analog were potent inhibitors of GHRP binding in both tissues.
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PMID:Growth hormone-releasing peptide (GHRP) binding to porcine anterior pituitary and hypothalamic membranes. 155 31

Various kinds of neuropeptides have been identified to be immunoreactive in the drainage angle of mammalian eyes. However, little is known about second messenger system involvement with these peptides. To determine whether some of these peptides are linked to a calcium signalling system in the trabecular meshwork (TM) cells, their effects on [Ca2+]i transients in fura-2 loaded cultured bovine TM cells were studied with a digital video-imaging system. The main findings of this study were: (1) The basal [Ca2+]i was 164.0 +/- 1.0 nM (mean +/- standard error of the mean, n = 668). (2) Of the neuropeptides examined, neuropeptide Y (NPY) (10(-6)M) is the most potent because it increased [Ca2+]i by about four-fold from the basal level. Other peptides--substance P, bombesin, calcitonin gene-related peptide, and vasoactive intestinal peptide induced smaller increases in [Ca2+]i. (3) We defined a response as positive if [Ca2+]i increased to a value that was 1.2-fold over the basal level. The majority of the TM cells reacted to NPY, whereas only 20-30% of the cells reacted to any of the other peptides. (4) The chelation of extracellular Ca2+ shortened the half-life of a NPY-induced response without affecting its latency. (5) NPY (10(-6)M) significantly increased the formation of inositol triphosphate following a 15 sec exposure. The same was the case for inositol monophosphate and inositol diphosphate. The results of this study suggest that in bovine TM cells, NPY stimulation is coupled to Ca2+ signalling through an increase in polyphosphoinositide turnover.
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PMID:Neuropeptide-induced [Ca2+]i transients in cultured bovine trabecular cells. 155 68

Low doses (0.2-0.8 microM) of capsaicin were used to achieve selective excitation of C-fibres and the consequent synaptic activation of dorsal horn neurons (laminae I-VI) in the spinal cord of the 12-20-day-old mouse, maintained in vitro. Most dorsal horn cells were activated by application of capsaicin to dorsal root ganglia. The response consisted of a long-lasting membrane depolarization with increased regenerative (synaptic) activity in 79% of the cells, and in a further 7% only an increased synaptic activity was evoked. These effects of capsaicin were completely blocked by removing extracellular calcium ions from the superfusate to the spinal cord, or by the addition of 1 microM tetrodotoxin, suggesting a presynaptic origin of the capsaicin action. Only 67% of cells excited by capsaicin were sensitive to exogenous substance P. The excitatory amino acid antagonists, kynurenic acid (50-100 microM) or (-)-2-amino-5-phosphonovaleric acid (10-20 microM) completely blocked the capsaicin-evoked response in deep dorsal horn cells, indicating the involvement of excitatory amino acid receptors in the synaptic pathway. However, in superficial dorsal horn neurons these antagonists attenuated, but never completely abolished, the capsaicin-evoked depolarization. The kynurenic acid-resistant component of the capsaicin-evoked excitation in superficial dorsal horn cells suggests the involvement of non-amino acid excitatory transmitters--possibly neuropeptides--in the synaptic transmission. Activation of primary afferents by high-intensity electrical stimulation of the dorsal roots induced a prolonged (0.5-3 s) postsynaptic excitation in the majority of deep dorsal horn cells. The duration of the synaptic response was significantly reduced by (-)-2-amino-5-phosphonovaleric acid. Following repeated application of capsaicin, desensitization of the capsaicin-evoked synaptic activation of dorsal horn cells occurred. This effect was paralleled with the loss of the prolonged (-)-2-amino-5-phosphonovaleric acid-sensitive phase of the excitatory postsynaptic potential evoked by the high-intensity electrical stimulation of dorsal roots. This observation suggested that activation of the N-methyl-D-aspartate receptors in the dorsal horn can be activated by small-calibre capsaicin-sensitive fibres. In summary, our data suggest that the selective activation of C-fibre afferents with capsaicin produces synaptic activity in the dorsal horn which has a strong excitatory amino acid component as well as a non-excitatory amino acid, possibly peptidergic, component.
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PMID:Synaptic activation of dorsal horn neurons by selective C-fibre excitation with capsaicin in the mouse spinal cord in vitro. 158 13


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