Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the type of neurokinin (NK) receptor involved in the epithelium-dependent substance P (SP)-induced relaxation of rat trachea precontracted with serotonin (5-HT). We first compared the relaxant effects of different agonists to the three NK receptors on rat trachea in the presence (E+) and absence (E-) of the epithelium. The three agonists to the NK-1 receptor, SP, SP-O-methylester and [beta Ala4, Sar9, Met(O2)] SP(4-11), at a concentration of 1 microM induced a relaxation of 40 +/- 5, 33 +/- 4 and 31 +/- 6%, respectively in E+ segments. They had weak and nonsignificant effects in E- segments. In addition, (+/-)CP-96,345 (1 microM), the NK-1-selective non-peptide antagonist, inhibited the SP-induced relaxation by 45%. Conversely, the three NK-2 receptor agonists, NKA, NKA(4-10) and [Nle10]NKA(4-10), and the two NK-3 receptor agonists, neurokinin B (NKB) and [MePhe7]NKB(4-10), had no effect on E+ or E- tracheal segments. The N-terminal SP fragment SP(1-9) was also inactive. These results suggest that SP-induced relaxation is mediated through activation of epithelial NK-1 receptors. Preincubation with the cyclooxygenase inhibitor, indomethacin (2.8 microM), abrogated the relaxant effect of the three NK-1 receptor agonists on E+ tracheas. We measured in additional experiments prostaglandin E2 (PGE2), PGF2 alpha, 6-keto PGF1 alpha and thromboxane B2. SP (1 microM) induced a 6.1-fold increase in PGE2 production (from 13 pg after 5-HT to 78 pg) in E+ segments, whereas only a 1.5-fold increase occurred in E- preparations.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Activation of an epithelial neurokinin NK-1 receptor induces relaxation of rat trachea through release of prostaglandin E2. 127 60

Tachykinin receptors mediating substance P-induced secretion were examined in muscle-stripped segments of guinea-pig ileum set up in flux chambers. Changes in the short-circuit current (Isc) served as an index of active, electrogenic ion transport. Substance P evoked a transient increase in Isc which was concentration-dependent. The maximal change in Isc occurred at 1 microM concentration. [Sar9,Met(O2)11]-substance P, a neurokinin 1 (NK-1) receptor agonist, evoked a similar concentration-dependent increase in Isc. [Nle10]NKA(4-10) (1 microM) or [Pro7]NKB (1 microM), selective NK2 and NK3 agonists, respectively, had minimal effects on Isc. CP-96,345 (5 microM), a nonpeptide NK-1 antagonist, and the peptide NK-1 antagonist, GR82334 (1 microM), reduced the secretory response to substance P (50 nM) in the presence and absence of tetrodotoxin (0.2 microM). The NK2 antagonist, [Tyr5,D-Trp6,8,9,Arg10]NKA(4-10) MEN 10207 had no effect on the substance P response. Tetrodotoxin (0.2 microM) significantly reduced, but did not abolish the Isc response to substance P (1 microM) and [Sar9,Met(O2)11]substance P (1 microM). The substance P response was unaltered by 5 microM atropine and 50 microM mecamylamine. Piroxicam (10 microM) or pyrilamine (10 microM) or a combination of both had no effect on the tetrodotoxin-resistant substance P response. Electrical field stimulation evoked a biphasic increase in Isc which was significantly reduced by 0.2 microM tetrodotoxin. Atropine (5 microM) reduced the first peak of the biphasic response and mecamylamine (50 microM) had no effect. Similarly, 5 microM CP-96,345 and 1 microM GR82334 did not alter the EFS-induced change Isc. The results suggest that substance P-evoked secretory responses are independent of histamine or prostaglandins. Substance P responses are mediated by an NK-1 receptor type on enteric neurons and possibly epithelial cells.
 ...
PMID:Neurokinin 1 receptors mediate substance P-induced changes in ion transport in guinea-pig ileum. 127 53

Using a sensitive in vitro microperfusion method, the effects of selective and potent agonists of NK1, NK2, and NK3 tachykinin receptors ([Pro9]SP, ([Lys5,MeLeu9,Nle10]NKA-(4-10), and [Pro7]NKB, respectively) on the presynaptic control of dopamine release were investigated in striosomal-enriched (area rich in [3H]naloxone binding sites) and matrix-enriched areas of the rat striatum. Marked differences could be demonstrated as follows: (i) when used at 0.1 microM, the NK1 agonist stimulated the release of [3H]dopamine continuously synthesized from [3H]tyrosine in both compartments, while the NK2 and NK3 agonists enhanced the release of [3H]dopamine only in the matrix; (ii) the stimulatory effect of the NK3 agonist was less pronounced than those of the NK1 and NK2 agonists; (iii) the NK1 agonist-evoked responses were tetrodotoxin (1 microM) sensitive, while those of the NK2 and NK3 agonists were, respectively, partially and totally tetrodotoxin resistant; (iv) specific receptors are involved in these responses since the stimulatory effects of the NK1 and NK2 agonists were, respectively, blocked by potent antagonists of NK1 (RP-67580; 1 microM) and NK2 (SR-48968; 1 microM) receptors, while these antagonists did not affect the NK3 agonist-evoked response; (v) the indirect stimulatory effect of the NK1 agonist was partially reduced under local blockade of cholinergic transmission in the matrix but not in the striosomal-enriched area. Interestingly, this study also revealed mismatches between autoradiographic data and receptor-mediated responses, since NK2 binding sites could not be observed in the striatum while NK3 but not NK1 binding sites were visualized in the striosomal-enriched area.
 ...
PMID:Distinct presynaptic control of dopamine release in striosomal- and matrix-enriched areas of the rat striatum by selective agonists of NK1, NK2, and NK3 tachykinin receptors. 128 Aug 22

The neural ganglion of ascidians exhibits a novel and rapid pattern of regeneration whereby within approximately 28-35 days of total ablation an entirely new neural complex is formed. In normal adults, neuronal cell bodies expressing substance P- (SP-Li), neurokinin A-(NKA-Li), CCK/gastrin- (CCK-Li), and insulin-like immunoreactivity exhibit a clearly defined pattern of localization in the cortical rind of the ganglion with characteristic long processes arising from the perikarya running throughout the neuropile. CCK-Li cell bodies are particularly concentrated close to the points of exit of the main nerve trunks. We have used antisera raised against these peptides to monitor the process of regeneration up to postoperative (pa) day 35. Only SP and CCK antisera produced positive staining in the regenerating tissue. Immunoreactive cell bodies first appear following 14 days pa. At this time CCK-Li neurons are more abundant than SP-Li neurons and in contrast to the pattern found in the normal adult ganglion, immunoreactive cell bodies are located both peripherally and centrally in the core of the ganglion and processes were rarely seen. Later stages exhibited an increasing number of SP-Li neurons and at 35 days pa SP-Li cell bodies clearly predominate. CCK-Li neurons typically become clustered close to the points of emergence of the anterior nerve roots. The early expression of CCK-Li and SP-Li molecules during regeneration is considered in terms of their potential role in development and cell proliferation in the newly forming ganglion.
 ...
PMID:Pattern of substance P- and cholecystokinin-like immunoreactivity during regeneration of the neural complex in the ascidian Ciona intestinalis. 128 44

1. We have estimated potencies of tachykinin receptor agonist and antagonist analogues in order to determine the recognition characteristics of tachykinin receptors mediating phasic contractile responses of the rat isolated urinary bladder in vitro. 2. The NK1-selective synthetic agonists, substance P methyl ester and GR73632, the synthetic NK2-selective agonists [beta-Ala8]-NKA(4-10) and GR64349, and the mammalian tachykinins, neurokinin A and neurokinin B, were assayed relative to substance P and were found to be approximately equipotent. The NK3-selective agonist, senktide, was inactive (10 microM). 3. Potencies of all these agonists were not significantly different (P > 0.05) when experiments were carried out in the presence of the neutral endopeptidase inhibitor, phosphoramidon, and the kininase II inhibitor, enalaprilat (both 1 microM). 4. The NK1-selective antagonist, GR82334, inhibited responses to substance P methyl ester in a competitive manner in the rat urinary bladder and the rat ileum, and also in the guinea-pig ileum. Markedly different pKB estimates were obtained in the rat bladder (6.38) and rat ileum (6.56) compared to the guinea-pig ileum (7.42). GR82334 (3 microM) was inactive against responses of the rat bladder to [beta-Ala8]-NKA(4-10). 5. The NK1-selective antagonist (+/-)-CP-96,345 also inhibited responses of the rat bladder and guinea-pig ileum to substance P methyl ester; however, in the rat bladder at 1 microM, this antagonist reversibly inhibited responses both to the NK2-selective agonist [beta-Ala8]-NKA(4-10) and to the muscarinic agonist carbachol (P < or = 0.01), thus showing evidence of some non-selective depressant actions. 6. The NK2-selective antagonists, MEN10207 and L-659,874, competitively inhibited responses of the rat bladder to the NK2-selective agonist [P-Ala5]-NKA(4-10) giving pKB estimates of 5.75 and 6.68,respectively. Both antagonists (1O microM) were inactive against responses to the NKI-selective agonist substance P methyl ester.7. These results support the proposal of a mixed population of NKI and NK2 receptors mediating contraction of the rat isolated urinary bladder. The NK2 receptor is characterized by a relatively low affinity for the NK2-selective antagonist MEN10207 but a high affinity for L-659,874. The NKImediated responses are inhibited by (+/-)-CP-96,345: this compound however, has non-specific depressant effects in the rat bladder at high concentration (1 microM). In contrast, the NK,-receptor peptide antagonist GR82334, did not have non-specific depressant effects and competitively inhibited NK, responses in the rat bladder and rat ileum with an affinity significantly lower than at the NK,-receptors in the guinea-pigileum.
 ...
PMID:A pharmacological study of NK1 and NK2 tachykinin receptor characteristics in the rat isolated urinary bladder. 128 72

1. In our search for compounds that inhibit the binding of [3H]-substance P (SP) to guinea-pig lung membranes, the dipeptide SP antagonist, FK888, was developed by chemical modification of the parent compound, (D-Pro4, D-Trp7,9,10, Phe11)SP4-11. 2. In a [3H]-SP binding assay using guinea-pig lung membranes and rat brain cortical synaptic membranes, FK888 displaced [3H]-SP binding with a Ki value of 0.69 +/- 0.13 nM and 0.45 +/- 0.17 microM, respectively, in a competitive manner. 3. FK888 inhibited the contraction of guinea-pig isolated ileum induced by SP in the presence of atropine and indomethacin (a NK1 receptor bioassay) with a pA2 value of 9.29 (8.60-9.98). 4. FK888 inhibited contractions of rat vas deferens by NKA (a NK2 receptor bioassay) and of rat portal vein by NKB (a NK3 receptor bioassay) at concentrations at least 10,000 times greater than that required to inhibit contractions of guinea-pig ileum. 5. FK888 also inhibited SP-induced airway oedema in guinea-pig after both intravenous and oral administration. 6. These data demonstrate that FK888 is a potent and selective NK1 antagonist which is active both in vitro and in vivo.
 ...
PMID:Pharmacological profile of a high affinity dipeptide NK1 receptor antagonist, FK888. 128 73

We describe the effects of RP 67580, a new non-peptide substance P (SP) antagonist, on tachykinin-induced contractions of guinea-pig ileum, trachea and urinary bladder, rabbit pulmonary artery and rat portal vein. All NK1 agonists tested (SP, Septide, SPOMe and [Pro9]SP) contracted guinea-pig ileum, trachea and urinary bladder (pD2 = 7.5 to 9.1), but they had no effect on rabbit pulmonary artery or rat portal vein (pD2 < 6). RP 67580 inhibited these effects: guinea-pig ileum, pA2 = 7.1 to 7.6; guinea-pig trachea and urinary bladder, pKB = 6.3 to 6.8. The difference in RP 67580 activity in these tissues might be due to the existence of subtypes of NK1 receptors. RP 67580 (1 microns) did not affect the contractions induced by the two NK2 agonists, NKA and [Lys5, MeLeu9, Nle10]NKA(4-10) (pA2 < 6), except in guinea-pig ileum (pA2 = 7.3-7.5) where these two NK2 agonists interact apparently with NK1 receptors. In the tissue preparations used, RP 67580 (1 micron) was without effect on contractions induced by the NK3 agonists: NKB and senktide. These results indicate the high selectivity for NK1 receptors of RP 67580. In all cases, similar results were obtained with another non-peptide SP antagonist, (+/-) CP-96,345. The present work provides further evidence that RP 67580 and (+/-) CP-96,345 exert in vitro a potent, selective and competitive antagonistic action on NK1 receptors and suggests the existence of at least two distinct NK1 receptor subtypes in some guinea-pig peripheral organs.
 ...
PMID:Comparison in different tissue preparations of the in vitro pharmacological profile of RP 67580, a new non-peptide substance P antagonist. 128 22

In competitive radioligand binding assays, the NK2 receptor antagonists [Tyr5,D-Trp6,8,9,Arg10]NKA(4-10) (MEN 10207) and [Tyr5,D-Trp6,8,9,Arg10]NKA(3-10) (MEN 10208) had high and low affinity, respectively, in bovine stomach membranes and SKLKB82#3 cells, a murine fibroblast cell line transfected with a cDNA encoding for the bovine NK2 receptor. These antagonists also had different affinities when inhibiting neurokinin A-induced polyphosphoinositide hydrolysis in SKLKB82#3 murine fibroblasts. Thus, the de novo protein expressed by the SKLKB82#3 murine fibroblasts may represent a distinct NK2 receptor subtype.
 ...
PMID:Demonstration of a neurokinin A receptor subtype in transfected fibroblasts. 131 43

The present study was undertaken to assess the activity of the neurokinin-2 (NK2) tachykinin receptor-selective antagonists MEN 10,376, L 659,877 and R 396 along with the NK2 receptor-selective ligand, MDL 28,564 on the isolated guinea pig gallbladder. None of the antagonists tested inhibited the response to the peptide CCK-8, although they competitively antagonized the contractile effect produced by NKA in the above tissue. The following rank order of potency was observed: MEN 10,376 (pKB = 6.77) greater than L 659,877 (pKB = 6.29) greater than R396 (pKB = 5.26). MEN 10,376 also antagonized the response to the NK3-selective agonist [MePhe7].NkB (10 microM), showing that the agonist activity of this peptide is due to NK2 receptor stimulation. On the other hand, MDL 28,564 had an agonist effect in the isolated gallbladder, its maximal effect approaching 58% of that to NKA. The results obtained using the above NK2 receptor-selective drugs in the guinea pig gallbladder was similar to that observed in other mammalian tissues bearing the NK2A receptor subtype, such as the endothelium-denuded rabbit pulmonary artery, the guinea pig bronchus and the circular muscle of the human colon and ileum. Therefore, we conclude that in the isolated guinea pig gallbladder tachykinins exert their contractile effect by activating NK2 receptors, which seem to belong to the NK2A receptor subtype.
 ...
PMID:Effect of newly developed tachykinin agonist and antagonists on the guinea pig isolated gallbladder. 131 68

Experiments were designed to characterize receptor(s) that mediate nonadrenergic, noncholinergic contractions of the guinea pig hilar bronchus using selective neurokinin (NK)1 (CP 96,345) and NK2 (R396 and MEN 10,376) tachykinin receptor antagonists. Left and right hilar bronchi were studied as pairs in the presence of atropine, propranolol, phentolamine; indomethacin and thiorphan. (2S, 3S)-cis-2-(diphenylmethyl)-N-(2-methoxyphe nyl)-1-azabicyclo[2,2,2]octan-3-amine (CP 96,345) selectively antagonized contractions of the bronchus to the NK1 agonist Ac-[Arg6,Sar9,Met(O2)11]-SP(6-11) with a -log molar KB value of about 8.0. Similarly, Ac-Leu-Asp-Gln-Trp-Phe-Gly-NH2 (R396) and [Tyr5, D-Trp6,8,9, Lys10]-NKA(4-10) (MEN 10,376) selectively antagonized contractions to the NK2 agonist [beta Ala8]-NKA(4-10) with -log molar KB values of about 5.5 and 6.7, respectively. CP 96,345 (3 x 10(-7) M) had no effect on contractions evoked by transmural electrical stimulation (TES). However, both R396 (1 x 10(-5) to 1 x 10(-4) M) and MEN 10,376 (1 x 10(-6) to 1 x 10(-5) M) caused blockade of responses to TES. CP 96,345 (3 x 10(-7) M) antagonized TES-induced contractions only when studied after substantial blockade by R396 or MEN 10,376. Contractions to TES were not abolished by R396, MEN 10,376 or a combination of these antagonists with CP 96,345. R396 (1 x 10(-6) M) increased the maximum contraction to TES and potentiated the frequency-response curve in bronchi treated with MEN 10,376 (1 x 10(-6) M).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Nonadrenergic, noncholinergic contractile responses of the guinea pig hilar bronchus involve the preferential activation of tachykinin neurokinin2 receptors. 132 30


1 2 3 4 5 6 7 8 9 10 Next >>