Substance P-induced Histamine Release Research Articles

Substance P-mediated cardiac mast cell activation: An in vitro study

The neuropeptide substance P can induce degranulation of cardiac mast cells at high concentrations. Herein, we seek to further understand substance P activation of cardiac mast cells in the context of other neuropeptides as well as modulation by non-neuropeptides. This is important given the increasingly recognized role of both cardiac mast cells and substance P in adverse cardiac remodeling. To address this, we isolated cardiac mast cells and compared their response to substance P as well as other members from the tachykinin family of peptides, including neurokinin A and hemokinin-1. We also tested the ability of other factors to manipulate the cardiac mast cell response to substance P. We found that while neurokinin A did not induce cardiac mast cell degranulation, both substance P and hemokinin-1 induced a concentration-dependent release of histamine; the maximal response to hemokinin-1 was greater than to substance P. Neurokinin-1 receptor blockade prevented substance P-induced histamine release, while only partially attenuating hemokinin-1-induced histamine release. The antioxidant N-acetylcysteine attenuated histamine release in response to hemokinin-1 and had no effect on substance P-induced histamine release. Selective PPAR-γ agonists attenuated histamine release in response to substance P. These data indicate that substance P activates cardiac mast cells via the neurokinin-1 receptor, and that the activation response is different to other tachykinins. That the response to substance P is receptor mediated and can be modulated by activation of other receptors (PPAR-γ), argues that substance P activation of cardiac mast cells has potential biological significance.

Inhibition of substance P-induced histamine release from rat peritoneal mast cells by ultraviolet light B irradiation: decreased intracellular calcium as a partial mechanism

Inhibition of substance P-induced histamine release from rat peritoneal mast cells by ultraviolet light B irradiation: decreased intracellular calcium as a partial mechanism

８‐メトキシソラレンと長波長紫外線（ＵＶＡ）併用（ＰＵＶＡ）によるサブスタンスＰ刺激ラット腹腔肥満細胞からのヒスタミン遊離抑制

８‐メトキシソラレンと長波長紫外線（ＵＶＡ）併用（ＰＵＶＡ）によるサブスタンスＰ刺激ラット腹腔肥満細胞からのヒスタミン遊離抑制

Substance P Activates the Release of Histamine from Human Skin Mast Cells through a Pertussis Toxin-Sensitive and Protein Kinase C-Dependent Mechanism

Using pharmacologic agents, we explored the mechanism by which a potent neuropeptide, substance P, induces the secretion of histamine from human skin mast cells and compared their effects on substance P-induced histamine release to the secretion activated by anti-IgE. Histamine release from human cutaneous mast cells induced by substance P was inhibited by the Ge-protein inhibitor pertussis toxin that, in turn, did not affect the IgE-mediated secretion. Similarly to anti-IgE, two activators of protein kinase C, tetradecanoylphorbol acetate (TPA) and bryostatin 1, significantly inhibited the substance P-induced response. In contrast, drugs that enhance intracellular levels of cAMP, an inhibitor of protein kinases, genistein, and a protease inhibitor, AEBSF, did not affect substance P-induced histamine secretion, whereas these compounds significantly reduced the response initiated by anti-IgE. Our data demonstrate that substance P activates human cutaneous mast cells by acting on G proteins and protein kinase C. Our results also suggest that the biochemical pathways underlying mast cell activation by substance P and anti-IgE are to a great extent unrelated.

155 Inhibition of substance P-induced histamine release from rat peritoneal mast cells by 8-methoxypsoralen plus long-wave ultraviolet irradiation in parallel with the suppression of intracellular calcium ion level

155 Inhibition of substance P-induced histamine release from rat peritoneal mast cells by 8-methoxypsoralen plus long-wave ultraviolet irradiation in parallel with the suppression of intracellular calcium ion level

37 Inhibition of substance P-induced histamine release from rat peritoneal mast cells by ultraviolet B irradiation and 8-methoxypsoralen plus long-wave ultraviolet irradiation

37 Inhibition of substance P-induced histamine release from rat peritoneal mast cells by ultraviolet B irradiation and 8-methoxypsoralen plus long-wave ultraviolet irradiation

072 Inhibition of substance P-induced histamine release from rat peritoneal mast cells by ultraviolet B irradiation: Suppressed intracellular calcium ion level as a possible mechanism

072 Inhibition of substance P-induced histamine release from rat peritoneal mast cells by ultraviolet B irradiation: Suppressed intracellular calcium ion level as a possible mechanism

Substance P-induced histamine release in tracheally perfused guinea pig lungs.

The capacity of substance P (SP) and endogenously released tachykinins to liberate histamine was examined in isolated tracheally perfused guinea pig lungs. Increasing doses of tracheally injected SP were associated with the recovery of increasing amounts of histamine from lung effluent. The mechanism of SP-induced histamine liberation was explored in studies with neurokinin-(NK) receptor agonists and antagonists. Tracheal injection of either the NK1 agonist [Sar9,Met(O2)11]SP or the NK2 agonist [beta-Ala8]-neurokinin A-(4-10) was associated with a significant increase in histamine recovery from lung effluent. In addition, both the NK1 antagonist CP-99994 and the NK2 antagonist SR-48968 significantly inhibited SP-induced histamine release. These findings support the hypothesis that SP can liberate histamine from guinea pigs lungs by a mechanism that depends predominantly on NK1- and NK2-receptor activation. The liberation of endogenous tachykinins by acute tracheal injection of capsaicin was also associated with augmented histamine recovery, which was inhibited by combined NK1- and NK2-receptor blockade. Tracheal injection of SP was associated with an increase in the percentage of airway mast cells exhibiting histological evidence of degranulation. This study demonstrates that exogenous SP, as well as endogenous tachykinins released from capsaicin-sensitive neurons, can liberate histamine, most likely from airway mast cells, by a mechanism that depends predominantly on the activation of NK1 and NK2 receptors.

The use of cutaneous microdialysis to measure substance P-induced histamine release in intact human skin in vivo

Background: The purpose of this study was to introduce a microdialysis technique, which makes it possible to measure the release of small inflammatory mediators into the extracellular water space in intact human skin in vivo. Using this technique, we have studied the histamine releasing properties of substance P, a putative skin mast cell releasing agent.Methods: Small hollow fibers were inserted into the upper dermis of nine healthy subjects. Each fiber was perfused with Kreb's Ringer bicarbonate buffer at a rate of 3.0 μl/min. After establishment of a baseline, each fiber was challenged intracutaneously with substance P (0 to 4 μmol/L). Samples were collected at 2-minute intervals for 18 minutes. Histamine was measured by a fluorometric method, which correlated with an enzyme immunoassay (r = 0.96).Results: Baseline dialysate histamine concentration was 1.7 ± 0.3 ng/ml. Peak histamine release after injection of vehicle, 0.5, 1, 2, and 4 μmol/L substance P was 0.0, 1.0, 6.0, 44.5, and 88.5 ng/ml, respectively (p = 0.00002). Statistically significant histamine release was demonstrated with 1.0 μmol/L substance P and greater. Most peak values were seen 2 to 4 minutes after injection. The histamine elimination showed a monoexponential decline; dialysate histamine half-life was 3.81 ± 0.28 minutes.Conclusions: This study showed that substance P releases histamine in a dose-dependent manner from intact human skin in normal subjects. We suggest that microdialysis may be a promising technique for the evaluation of mediator levels in intact human skin after intradermal injection of an inflammatory or allergenic stimulus.

Eosinophil granule proteins inhibit substance P-induced histamine release from human skin mast cells

We have investigated the activity of the four principal cationic proteins of the eosinophil granules, major basic protein (MBP), eosinophil peroxidase (EPO), eosinophil-derived neurotoxin, and eosinophil cationic protein on histamine release from human skin mast cells. These four cationic proteins, over the concentration range of 10 to 200 μg/ml, did not induce significant histamine release, nor did they prime anti-IgE-induced histamine release from human skin mast cells significantly. However, a brief incubation (15 minutes) of two of the four principal eosinophil granule proteins, MBP and EPO, at concentrations of 50 to 200 μg/ml, caused a significant concentration-related inhibition of histamine release induced by 30 μmol/L substance P. The concentrations producing 50% inhibition for MBP and EPO on substance P-induced histamine release were 30 μg/ml and 100 μg/ml, respectively. This inhibitory effect appears to be a direct effect of these proteins on skin mast cells because purified (78% to 85%) skin mast cells displayed a similar response to MBP and EPO ( n = 4). Also, when skin mast cells were incubated with 100 μg/ml MBP and EPO for 15 minutes and washed twice before activation by substance P, the inhibitory effect was not altered. These two proteins also inhibited histamine release induced by 10 μg/ml compound 48 80 . These results suggest that MBP and EPO affect the same binding site(s) on skin mast cells as those of substance P.

Sulphasalazine and balsalazide have membrane-stabilizing effects and cytoprotective action on ethanol-treated rat rectocolon

Sulphasalazine (SASP) and balsalazide (BSZ) inhibited 48/80 or substance P-induced histamine release from rat peritoneal mast cells and rat erythrocyte lysis induced by heat, phospholipase C (PLC) or deoxycholic acid (DA). In thein situ ethanol-perfused rat rectocolon, SASP or BSZ (administered via the colonic lumen) reduced ethanol-induced release of histamine and lactate dehydrogenase (LDH), tissue oedema and myeloperoxidase (MPO) activity. These results suggest that the drugs are membranestabilizing, cytoprotective and anti-inflammatory. The inhibition of rat erythrocyte lysis by SASP and BSZ was reduced more by pre-treatment of the erythrocytes with trinitrobenzene sulphonic acid (TNBS), which denatures proteins, than by PLC or DA, indicating that the cell membrane-stabilizing action of SASP and BSZ may be more related to cell membrane proteins than lipids.

Enhancement of Histamine Release from Rat Peritoneal Mast Cells Exposed to Formaldehyde

AbstractWhile formaldehyde is an indoor and outdoor pollutant, little is known about the effect of formaldehyde exposure on induction of allergic and inflammatory reactions. To examine the effects of in vitro exposure to formaldehyde on rat mast cell functions, purified peritoneal mast cells (PMC) were exposed to 1, 5, 10, and 50 ppm formaldehyde for 30 min and then incubated with secretagogues. Histamine release from PMC stimulated with A23787 or anti-rat IgE was significantly enhanced at 5 ppm formaldehyde. Substance P-induced histamine release was affected at 10 and 50 ppm formaldehyde; however, no enhancement of substance P-induced histamine release was seen below 5 ppm. The effects of modulators of mediator release on enhanced histamine release from formaldehyde-exposed PMC induced by immunological and nonim-munological stimulation were also examined. Pretreatment with cholera toxin or dexa-methasone did not prevent the formaldehyde-induced enhancement in histamine release. Howevec pretreatment with ...

Substance P-induced histamine release from rat peritoneal mast cells and its inhibition by antiallergic agents and calmodulin inhibitors

Substance P-induced histamine release and Ca2+ release from the intracellular Ca store of rat peritoneal mast cells were inhibited by both antiallergic drugs and microtubule inhibiting agents. It was found that in the case of antiallergic compounds, histamine release inhibition may be intimately related to the inhibition of Ca2+ release from the intracellular store in which the microtubules play an important role. When mast cells were pretreated with either theophylline or dibutyryl cAMP, the inhibition of histamine release was closely related to the inhibition of Ca2+ release from the intracellular Ca store. Calmodulin inhibitors were also effective in inhibiting histamine release from mast cells induced by substance P. The inhibitory potencies of calmodulin inhibitors on histamine release from mast cells were closely correlated with those exerted on calmodulin activity.

Effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on substance P-induced histamine release from rat peritoneal mast cells

12-O-tetradecanoylphorbol-13-acetate (TPA, 1 to 30 ng/ml) produced a dose-related inhibition of substance P (SP)-induced histamine release from rat peritoneal mast cells. TPA itself induced some histamine release over this concentration range (maximum release about 20% of total). Maximum inhibition of SP-induced release by TPA required preincubation with TPA for at least 10 min. The inhibitory action of TPA was observed in the absence as well as in the presence of extracellular calcium (0.4 mM). Inhibition of diacylglycerol kinase by R 59022 or of diacylglycerol lipase by RHC 80267 reduced SP-induced histamine release. Oleolylacetylglycerol (OAG, 50 microM) inhibited histamine release induced by SP but was less potent than TPA. It is concluded that protein kinase C activation in rat peritoneal mast cells is associated with inhibition of SP-induced histamine release.

Substance P-Induced Histamine Release from Human Basophils, Skin and Lung Fragments: Effect of Nedocromil Sodium and Theophylline

We compared histamine release induced by substance P with those obtained with classical secretagogues on human basophils, lung and skin fragments. We also tested the capacity of nedocromil sodium and theophylline to inhibit histamine release in these 3 experimental models. Substance P (10(-4) M) caused a noncytotoxic histamine release (about 10% of total) from basophils, lung and skin fragments. Substance P-induced histamine release was always smaller than that obtained with optimal doses of anti-IgE, formyl-methionine phenylalanine or compound 48/80. Nedocromil sodium did not prevent secretagogue-induced histamine release from basophils or sliced skin. In contrast, it significantly inhibited anti-IgE- or substance P-induced histamine release from human lung. Theophylline caused a dose-related inhibition on these 3 models. We conclude that substance P is a modest secretagogue for human basophils and mast cells, and that skin and lung mast cells are heterogeneous with respect to their response to nedocromil sodium.

Substance P induced hydrolysis of inositol phospholipids in rat skin in an in vivo model of inflammation

The present study was undertaken to study the ability of substance P (SP) to induce inositol phospholipid (IP) hydrolysis measured as inositol mono-phosphate (IP1) accumulation, in an in vivo blister model of neurogenic inflammation in the rat hind footpad. SP was found to induce IP1 accumulation in a concentration dependent manner. The use of SP analogues (SP 5–11 and SP 1–7) indicated that the response is mainly mediated by the C-terminal sequence of the peptide. The response was significantly reduced by the SP antagonist spantide, suggesting that the response is mostly due to activation of the SP receptor on small diameter vessels. Capsaicin pretreatment did not have an effect on the ability of SP to induce the response. Experiments with mepyramine suggest that the response is also partly mediated by SP induced histamine release from mast cells. This is the first study to provide direct evidence for phosphoinositide mediated SP effects in the skin.

Characterization of neuropeptide‐induced histamine release from human dispersed skin mast cells

1. Human skin mast cells, unlike other human mast cells so far studied, released histamine in a concentration-related manner in response to substance P, vasoactive intestinal peptide (VIP) and somatostatin (1 microM to 30 microM). In contrast, eledoisin, physalaemin, neurokinin A, neurokinin B, calcitonin gene-related peptide (CGRP), neurotensin, bradykinin and Lys-bradykinin induced negligible histamine release. 2. The low histamine releasing activity of physalaemin, eledoisin, neurokinin A and neurokinin B relative to substance P suggests that the human skin mast cell activation site is distinct from the tachykinin NK-1, NK-2 or NK-3 receptors described in smooth muscle. 3. The relative potencies of substance P and its fragments SP2-11, SP3-11, SP4-11 and SP1-4 in releasing histamine from human skin mast cells suggests that both the basic N-terminal amino acids and the lipophilic C-terminal portion of substance P are essential for activity. 4. Peptide-induced histamine release, like that induced by compound 48/80, morphine and poly-L-lysine, is rapid, reaching completion in 10-20 s, is largely independent of extracellular calcium but requires intact glycolysis and oxidative phosphorylation. 5. The substance P analogue, [D-Pro4,D-Trp7,9,10] SP4-11 (SPA), not only reduced substance P-induced histamine release in a concentration-related manner but also inhibited that induced by VIP, somatostatin, compound 48/80, poly-L-lysine and morphine but not anti-IgE. 6. The similar characteristics of histamine release induced by substance P, VIP, somatostatin, compound 48/80, poly-L-lysine and morphine suggest that they share a common pathway of activation-secretion coupling distinct from that of IgE-dependent activation. Furthermore, the ability of human skin mast cells to respond to basic non-immunological stimuli including neuropeptides may reflect a specialised function for these cells.

Effect of antianaphylactic agents on substance-P induced histamine release from rat peritoneal mast cells

Substance P is known to be a potent histamine liberator for mast cells. The influence of antianaphylactic agents, disodium cromoglycate (DSCG), ketotifen, and tranilast was studied on substance-P and compound 48/80-induced histamine release from rat peritoneal mast cells. Substance-P induced histamine release was inhibited by these agents, while compound 48/80-induced histamine release was not inhibited by tranilast. Our findings suggest that these antianaphylactic agents are assumed to be effective for cutaneous diseases which might be concerned with substance P and histamine.

Substance P-Induced Histamine Release in Human Cutaneous Mast Cells

Substance P is an undecapeptide found in multiple sites throughout the central and peripheral nervous systems including small unmyelinated (type C) cutaneous nerve fibers. Previous studies demonstrated that antidromic stimulation results in substance P (SP) release from nerve endings, SP stimulates histamine release (HR) from rat mast cells in vitro, and intradermal SP in humans produces wheals identical to those induced by histamine. These studies suggest a possible role for SP as a link between neurologic events and cutaneous mast cell-mediated reactions. We therefore investigated SP-induced HR in an in vitro preparation of human skin mast cells. Human foreskin sections were incubated with varying concentrations of SP. Histamine was assayed using automated fluorimetry and release was calculated as a percentage of total tissue histamine. Substance P caused dose-dependent HR over a range from 10(-5) M (1.3%) to 5 X 10(-4) M (25.1%). Histamine release was optimal at 3 mM calcium and was blocked by pretreatment with calcium chelation. Naloxone failed to block HR. These studies suggest that HR from skin mast cells by SP may play a role in neural modulation of poorly understood inflammatory skin conditions.

The inhibition of substance P-induced histamine release from mast cells by 6, 7-dihydro-6, 8, 8, 10-tetramethyl-8H-pyrano-[3, 2-g] chromone-2-carboxylic acid (EAA).

In the presence of extracellular Ca2+, 6,7-dihydro-6,8,8, 10-tetramethyl-8H-pyrano [3, 2-g] chromone-2-carboxylic acid (EAA) had an inhibitory effect on the substance P-induced histamine release from rat peritoneal mast cells. Not only Ca2+ but also Mg2+, Sr2+ and Ba2+ were effective in enhancing the activity of EAA. Marked tachyphylaxis to EAA developed irrespective of the presence or absence of extracellular Ca2+. Cross-tachyphylaxis was observed between EAA and disodium cromoglycate (DSCG). These results indicate that the mode of action of EAA is similar, but not identical, with that of DSCG.