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)

Leukocyte trafficking in normal and diseased skin appears to be initially governed by endothelial surface glycoproteins that promote adhesive interactions with circulating leukocytes. In a separate study, we have demonstrated that one of these glycoproteins, endothelial-leukocyte adhesion molecule-1 (ELAM-1), is rapidly induced on postcapillary dermal venules as a direct consequence of experimentally-elicited degranulation of adjacent mast cells (Proc Natl Acad Sci USA 86:8972-8976, 1989). A principle endogenous mediator of mast cell degranulation is the neuropeptide substance P. In this study, we exposed organ cultures of neonatal human foreskins for 45 min to substance P or to a substance P analogue (D-pro4, D-trp7,9)SP(4-11) that binds to the identical mast cell surface receptor but which does not provoke histamine release. Dermal mast cells were uniformly degranulated only in explants exposed to substance P, as judged by ultrastructural analysis. After subsequent culture in medium alone for 6 h, superficial venules of explants exposed to substance P showed evidence of ELAM-1 induction, as documented histochemically using H4/18 monoclonal antibody. ELAM-1 was not induced by substance P analogue. Furthermore, preincubation of explants with analogue or with the mast cell inhibitor, cromolyn sodium, abrogated the ability of substance P to induce ELAM-1. From these results we suggest that substance P endogenously released by dermal nerve fibers upon physiologic or electrical stimulation may be important in the regulation of endothelial-leukocyte interactions in vivo. This concept provides further evidence for a neurogenic and psychogenic modulation of the immune response, and may be relevant to the course of naturally occurring dermatoses (e.g., psoriasis) that are commonly exacerbated by emotional stress.
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PMID:Substance P induces the expression of an endothelial-leukocyte adhesion molecule by microvascular endothelium. 169 Feb 49

In the present study, we characterized specific binding of bombesin (BBS)/gastrin-releasing peptide (GRP) to mouse colon cancer (MC-26) cells. MC-26 cells were inoculated into male BALB/c mice subdermally, and tumors were harvested from mice 21-28 days postinoculation. Tumor membranes were analyzed for binding to GRP-related peptides, using either 125I-GRP or 125I-tyrosine4-BBS. Under optimal binding assay conditions, BBS displaced specific binding of both 125I-GRP and 125I-tyrosine4-BBS in a dose-dependent manner, and a curvilinear displacement resulted. Specific binding data, analyzed by either a Scatchard or a Lineweaver-Burk plot, demonstrated presence of 2 classes of specific binding sites, arbitrarily named type I and type II sites. Type I sites had a high binding affinity [Kd 0.45 +/- 0.05 nM (SE)] and a relatively low capacity (226 +/- 27 fmol/mg membrane protein), whereas type II sites had a 10-20-fold lower binding affinity and approximately 6-7-fold higher capacity. BBS/GRP binding sites were specific for GRP-related peptides and demonstrated no significant binding affinity for all other unrelated peptides tested. Relative binding affinity of GRP analogues was in the order of GRP (14-27) greater than neuromedin C greater than or equal to BBS greater than or equal to GRP (1-27) greater than neuromedin B (for the later, P greater than 0.05 versus other peptides). Two BBS receptor antagonists, [D-Arg1,D-trp7,9,Leu11]-substance P (spantide) and [Leu13-psi-(CH2NH)Leu14]BBS also inhibited specific binding of 125I-GRP in a dose-dependent manner. Molecular weight of GRP/BBS binding proteins on tumor membranes was determined by cross-linking methods. A major molecular form (greater than 80-90%) (Mr approximately 75,000) and a minor Mr approximately 180,000 band were evident, both under reducing and nonreducing conditions. BBS (0.5-50 nM) demonstrated a significant dose-dependent growth effect on MC-26 cells in vitro, in terms of [3H]thymidine and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide uptake; these studies indicate that the BBS/GRP binding sites on MC-26 cells may serve as functional receptors and mediate the growth effects of BBS on MC-26 cells.
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PMID:Specific binding and growth effects of bombesin-related peptides on mouse colon cancer cells in vitro. 220 41

A series of tachykinin antagonists has been synthetized by substituting the amino acids of eight naturally occurring tachykinins into the general antagonist [pro4, trp7,9, Phe 11]tachykinin-(4-11). Five decapeptide antagonists were also synthetized. These antagonists were tested on four smooth muscle preparations, the rabbit mesenteric vein, the guinea-pig ileum, the guinea-pig trachea and the rat urinary bladder. On all tissues, except the rat urinary bladder, antagonists that had amino acids other than Gln5 Gln6 found in the substance P molecule were inactive as antagonists, and some had marked intrinsic activity on the guinea-pig ileum and the guinea-pig trachea. The inhibitory activity of these antagonists on the rat urinary bladder, however, was quite marked. The activities of these antagonists on the rat urinary bladder can be summarized as follows: (a) In general decapeptide antagonists were of low affinity. (b) Octapeptide antagonists showed variable affinities against the various tachykinins and some were selective. The only two antagonists which were fairly active against all tachykinins were [pro4, trp7,9, Phe11]SP-(4-11) and [pro4, trp7,9, Phe11] UPE-(4-11). (c) Physalaemin was frequently antagonized in a non-surmountable manner. (d) Eledoisin and kassinin were each inhibited by only one antagonist, and the antagonist was different for each tachykinin. Some tachykinin receptors on smooth muscle have a binding site which is highly selective for Gln5 Gln6, especially if the affinity of antagonists is considered. Another tissue, the rat urinary bladder, does not exhibit this selectivity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tachykinin antagonists: substitutions in positions 5 and 6 with amino acids from the primary sequence of substance P homologues. 241 54

The presence of a substance P-like peptide in intestinal and body wall tissues, ventral nerve fiber and seminal vesicles of the earthworm Lumbricus terrestris has been demonstrated by means of a radioimmunoassay technique. The greatest substance P-like immunoreactivity was measured in intestinal tissues where it stimulates the rate of spontaneous contraction. This effect is inhibited by the substance P antagonist (D-pro2, D-trp7,9)-SP suggesting a possible involvement of receptor mechanisms. Dual localization of substance P-like immunoreactivity in earthworm intestinal and nerve tissues follows the pattern observed of peptidal hormones in vertebrates which are common to both endocrine and non-endocrine tissues.
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PMID:Immunochemical evidence for substance P-like peptide in tissues of the earthworm Lumbricus terrestris: action on intestinal contraction. 242 89

The irritative response to Nd:YAG laser capsulotomy was studied in unanaesthetized rabbits. Posterior lens capsulotomy with a total energy of 100 mJ had no effect on the pupil size but increased the intraocular pressure by 5-10 mmHg and caused a breakdown of the blood-aqueous barrier. Anterior lens capsulotomy with a total energy of 20, 60 or 100 mJ caused constriction of the pupil, and an increase in intraocular pressure in a dose-dependent manner, and a breakdown of the blood-aqueous barrier. Indomethacin attenuated all the component parts of the irritative response and (D-arg1, D-pro2, D-trp7,9, leu11)-SP attenuated the miotic response. A combination of indomethacin and the substance P antagonist almost completely abolished the irritative response. This indicates that the acute YAG-laser-induced irritation in the rabbit eye is dependent both on a release of prostaglandins and on substance P, the former probably releasing the latter from sensory nerves.
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PMID:A study of the mechanism of ocular irritation following YAG laser capsulotomy in rabbits. 243 20

Polymorphonuclear leukocytes (PMNL) are a component of the inflammatory response to neurogenic mediators. Using the micropore filter approach, the authors studied the chemoattracting properties of tachykinins, including substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), and that of calcitonin gene-related peptide (CGRP) for human PMNL in vitro and now show that SP in near nanomolar concentrations stimulates locomotion of human PMNL. Locomotion of PMNL is induced by SP, aminoterminal SP (1-9) and the SP receptor antagonist [D-pro2, D-trp7,9]-SP (DPDT) but not by carboxyterminal SP (3-11), NKA, NKB, or CGRP suggesting that the aminoterminal amino acids arginine and proline are essential residues of SP in activation of PMNL locomotion. In contrast, the migratory effect of SP on monocytes resides in the carboxyterminal SP amino acid sequence, which is in agreement with carboxyterminal, SP receptor-mediated chemotaxis of human monocytes previously shown by others. From the known structure-activity relationships for SP receptors it is concluded that induction of PMNL migration by SP does not involve neurokinin-1 (NK-1), NK-2 or NK-3 receptors. "Checkerboard" analysis reveals that PMNL locomotion by SP is not dependent on concentration gradients and thus represents chemokinesis, which is enhancement of speed and/or frequency of locomotion. One cannot exclude that this action of SP on PMNL is mediated by the aminoterminal sequence via yet unknown SP "receptors".(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro human polymorphonuclear leukocyte chemokinesis and human monocyte chemotaxis are different activities of aminoterminal and carboxyterminal substance P. 247 93

[pro4,trp7,9,Leu11]SP-(4-11), a substance P (SP) antagonist, selectively antagonized contractions produced by either capsaicin or SP on the rat isolated urinary bladder. These experiments provide direct evidence indicating that the motor effects of capsaicin on rat urinary bladder are attributable, at least in part, to the release of endogenous SP.
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PMID:Evidence for the involvement of endogenous substance P in the motor effects of capsaicin on the rat urinary bladder. 258 73

A series of ten octa- and five undecapeptide antagonists of SP have been tested in four isolated smooth muscle preparations in order to characterise the receptors mediating the SP-induced contractions of the guinea pig ileum (G.P.I.), the guinea pig trachea (G.P.T.) and the rabbit mesenteric vein (R.M.V.) and the relaxation of the dog carotid artery (D.C.A.). It has been shown that: (a) Indirect effects by substance P and related peptides, mediated by acetylcholine or prostaglandins reduce the affinity of [pro4,trp7,9,10]SP (4-11) (an SP-antagonist) only in the G.P.I. (b) Octapeptide antagonists are specific for SP, have no agonistic activities and exert a competitive antagonism against SP, its homologues and fragments. (c) Undecapeptide antagonists are weaker than the octapeptides in the G.P.I. and G.P.T. and slightly stronger in the D.C.A. and R.M.V. However these compounds still have variable degrees of agonistic activity in some tissues. Affinity of octapeptide antagonists bearing the basic structure [pro4,trp7,9]SP-(4-11) is increased by the additional replacement of Leu10 with trp, Met11 with Leu, Nle or Phe, but it is slightly reduced by substituting Phe8 with Val. Antagonists containing aliphatic residues at the C-terminal end, for instance [pro4,trp7,9,Nle11]SP-(4-11) are more potent than others in the R.M.V., while those with aromatic residues, for instance [pro4,trp7,9,10]SP-(4-11) are weak on the R.M.V. but fairly active on the G.P.T. These antagonists do not show any selectivity on the G.P.I. and the D.C.A. Comparison of antagonists affinities for receptor characterisation suggest the existence of three different functional sites for SP-related peptides. The site of the G.P.I. and D.C.A., which accepts both the antagonists containing aromatic or aliphatic groups at the C-terminal end; the site of the G.P.T. which prefers the aromatic and that of the R.M.V. which shows high affinity for aliphatic residues. The receptor classification emerging from data obtained with antagonists is compared with the classifications of the literature and with those based on the order of potencies of SP homologues and fragments.
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PMID:Receptors for substance P. III. Classification by competitive antagonists. 620 Mar 37

A dose-dependent contractile effect of substance P (SP) on the isolated, everted rat portal vein was competitively inhibited by two selective SP antagonists (pro2, phe7, trp9)-SP and (pro4, trp7,9)-SP 4-11. Phentolamine, atropine, methysergide, mepyramine, cimetidine, Sar1, Ile8-angiotensin II, Leu8, des-Arg9-bradykinin and indomethacin did not block the action of SP. However, some of these antagonists differentially reduced SP responses, but such inhibitory effects were shown to be nonspecific. The results suggest that the SP-induced contractions of the rat portal vein were directly mediated by specific receptors localized on the smooth muscle cells. In addition, the response to SP appeared to be independent of prostaglandin biosynthesis.
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PMID:Postjunctional localization of substance P receptors on the rat portal vein. 620 Aug 90

Various attempts to developing antagonists for substance P (SP) and related peptides, based on our past experience with angiotensin, kinins, and neurotensin, were unsuccessful. The particular features of SP, namely the high activity of C-terminal partial sequences in some pharmacological tests were used to develop one hexa and several octapeptide antagonists. Weak antagonists were obtained with a single modification, namely the replacement of Leu10 with trp in the sequences SP (6-11), SP (4-11) and SP (1-11). The affinity of octa and undecapeptide antagonists could be increased by using two (in positions 7 and 9 or 7 and 10) or 3 (in position 7, 9 and 10) substitutions of the natural residues with trp. Affinity of antagonists was further increased by replacing Met11 with either Nle or Phe. These new compounds showed some selectivity, [pro4, trp7 ,9, Nle11 ]-SP (4-11) being more potent in the rabbit mesenteric vein than all other octapeptides described in the present study; on the other hand, [pro4, trp7 ,9,10,Phe11]-SP (4-11) was found to be the most potent antagonist of SP and related peptides in the guinea pig ileum and the guinea pig trachea. Both compounds were similarly active in the dog carotid artery. Undecapeptide antagonists, bearing the same structural modifications as the octapeptides, were found to be stimulant in the guinea pig trachea and relaxant in the dog carotid artery. The agonistic property was eliminated by repeated applications of the compounds in guinea pig tracheae, and therefore the compounds could be tested as antagonists. The undecapeptides were found to be much more active antagonists against kasinin and eledoisin than against SP and physalaemin. The data obtained with the octa and undecapeptide antagonists of SP have been used for identification and characterization of SP receptors in various smooth muscles. It appears that SP and related peptides may exert their numerous pharmacological effects by activating more than one receptor type.
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PMID:Substance P--structure-activity studies and the development of antagonists. 620 30


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