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)

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

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

We synthesized a novel ligand [4,5-3H-Leu9]-Neurokinin A (3H-NKA, S.A 117-144 Ci/mmol), and evaluated its binding to hamster urinary bladder membranes (HUBM). The ligand bound to HUBM in a highly-specific (94 +/- 4%) and protein-dependent manner. Binding was rapid (k1 = 0.037 nM-1*min-1) and saturable (Bmax = 1210 +/- 177 fmol/mg protein), to a single population of high-affinity sites (KD = 2.41 +/- 0.15 nM, nH = 0.99 +/- 0.02). Binding was inhibited by non-hydrolyzable GTP analogs. Competition experiments with HUBM demonstrated the following rank order of potency: NKA > Kassinin > [beta-Ala8]-NKA(4-10) > [Nle10]-NKA(4-10) = Eledoisin = NKB > Physaelamin > Substance P. The selective NK-1 and NK-3 ligands, [Sar9-Met (O2)11]-SP, (+/-) CP96,345 and Senktide respectively, did not inhibit binding at 10 microM, whereas, the selective NK-2 antagonists: (+/-) SR-48,968 >> L-659,877 > R396 >> MEN-10,207 > MEN-10,376, inhibited binding in a competitive manner. In contrast, the low specific binding (< 30%) detected in guinea pig lung membranes, was not inhibited by selective NK-2 ligands. Over 30 ligands (0.1-10 microM) from other receptor classes, were not inhibitory. The data suggest that this new ligand binds with high-affinity and selectivity to homogeneous population of NK-2 receptors on HUBM but not on lung membranes, and is a suitable ligand to study NK-2 receptors.
 ...
PMID:Pharmacologic characterization of the novel ligand [4,5-3H-Leu9]neurokinin-A binding to NK-2 receptors on hamster urinary bladder membranes. 133 74

Neuronal hypertrophy occurs in a subpopulation of neurons in the infundibular nucleus of post-menopausal women. The hypertrophied neurons contain NKB, SP and estrogen receptor gene transcripts. Although associated with reproductive aging, post-menopausal neuronal hypertrophy is not a sign of central nervous system degeneration. Quite the opposite, because the hypertrophy is accompanied by marked increases in tachykinin gene expression, reflecting increased neuronal activity. We have proposed that infundibular neurons containing NKB, SP and estrogen receptor mRNAs participate in the hypothalamic circuitry regulating estrogen negative feedback on gonadotropin release in the human. In addition, there is evidence to suggest that the hypertrophied tachykinin neurons may be involved in the initiation of menopausal flushes. Because menopause affects a well characterized system, and has consistent and substantial changes in hormone levels, we have had the rare opportunity to correlate changes in hormone secretion with structural and neurochemical changes in the human hypothalamus. We suspect that future studies of the hypothalami of post-menopausal women will continue to be a fruitful avenue for investigating neuroendocrine regulation in the human.
 ...
PMID:Hormonal influences on morphology and neuropeptide gene expression in the infundibular nucleus of postmenopausal women. 133 3

In the rat parotid gland, substance P has been shown to induce a phosphatidylinositol bisphosphate breakdown resulting in an inositol trisphosphate production. These data suggested that substance P activated a phospholipase C and thus mediated its effects through the calcium-phospholipid pathway. To determine which neurokinin (NK) receptor was involved in the substance P response, we have used selective agonists of the different NK receptors and examined their effects on both inositol trisphosphate production and calcium movements. A selective NK-1 receptor agonist, [Sar9Met(O2)11]-substance P, evoked an [3H]inositol trisphosphate production and a rapid and transient 45Ca2+ efflux. On the other hand, selective NK-2 and NK-3 receptor agonists, [beta-Ala8]-NKA(4-10) and [MePhe7]-NKB, respectively, were without effect. We conclude that, in the rat parotid glands, only the NK-1 receptors are coupled to the calcium-phospholipid pathway. The C-terminal part of substance P appeared to be sufficient to stimulate this route because the C-terminal octapeptide, substance P(4-11), mimicked substance P effects on both inositol trisphosphate production and calcium movements. The NK-2 and NK-3 receptors, if present in the rat parotid glands, are not associated with the calcium-phospholipid pathway.
 ...
PMID:The NK-1 receptor and a calcium-phospholipid pathway: inositol trisphosphate production and calcium movements induced by selective agonists of neurokinin receptors in rat parotid glands. 137 20

Neurokinin (NK) peptides such as substance P (SP) may modulate epithelial ion transport in the small intestine. The present study was undertaken to examine the pharmacological mechanisms by which SP and its endogenous homologs NKA and NKB affect active electrolyte transport in the mucosa of porcine jejunum. Neurokinins and NK agonist analogs increased short circuit current, a measure of active ion transport, across sheets of jejunal mucosa-submucosa with the order of potency: SP greater than [beta-Ala8]NKA4-10 greater than or equal to [Sar9,Met(O2)11]SP greater than NKA = Arg-NKB greater than NKB after their addition to the serosal aspect of tissues (SP EC50 = 11 nM). Epithelial responses to SP or NKA underwent rapid autotachyphylaxis and unidirectional cross-tachyphylaxis after repeated peptide administration. The neuronal conduction blocker tetrodotoxin significantly reduced NK efficacy. SP activity was significantly reduced in tissues pretreated with the muscarinic cholinoceptor blocker atropine or the eicosanoid synthesis inhibitor eicosa-5,8,11,14-tetraynoic acid. NK peptides increased contractility in longitudinally oriented strips of jejunal smooth muscle with an order of potency: [Sar9,Met(O2)11]SP greater than SP greater than Arg-NKB = [beta-Ala8]NKA4-10 greater than or equal to NKB = NKA (SP EC50 = 11 nM). SP-induced contractions were reduced by 70 to 80% in tissues pretreated with atropine or the neuronal Ca++ channel blocker, omega-conotoxin. [125I]Bolton-Hunter-substance P (BHSP) bound specifically to a single population of sites in slide-mounted sections of mucosa-submucosa and smooth muscle with Kd = 0.3 and 0.1 nM and Bmax = 18 and 31 fmol/mg protein, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Neurokinin receptors and mucosal ion transport in porcine jejunum. 137 58

We have discovered a novel cyclopeptide substance P (SP) antagonist, FK 224 (N-[N2-[N-[N-[N-[2,3-didehydro-N-methyl-N-[N-[3-(2-pentylphenyl )- propionyl]-L-threonyl]tyrosyl-L-leucynyl]-D-phenylalanyl]-L-allo- threonyl]-L-asparaginyl]-L-serine-nu-lactone), which inhibited [3H]SP binding to guinea pig lung membranes in a dose-dependent manner. According to Rosenthal analysis, the inhibitory effect of FK 224 on [3H]SP binding appears to be competitive. In order to clarify the receptor subtype selectivity of FK 224, we have studied the interaction of FK 224 with three tachykinin receptors (NK1, NK2 and NK3) by using receptor binding techniques and in vitro bioassays, and have also compared FK 224 with the novel nonpeptide antagonist, (+/-)-CP-96,345. In binding experiments, FK 224 dose-dependently inhibited [3H]SP binding to rat cerebral cortical membranes (NK1) and [3H]neurokinin (NK) A (NKA) binding to rat duodenum smooth muscle membranes (NK2), but did not affect [3H]eledoisin binding to rat cerebral cortical membranes (NK3). In bioassay experiments, FK 224 inhibited SP-induced contraction of guinea pig ileum (NK1) and NKA-induced contraction of rat vas deferens (NK2) in a dose-dependent manner, but did not affect NKB-induced contraction of rat portal vein (NK3). In contrast, (+/-)-CP-96,345 inhibited SP-induced contraction of guinea pig ileum, but not NKA-induced contraction of rat vas deferens or NKB-induced contraction of rat portal vein. In the presence of FK 224, SP dose-response curves and NKA dose-response curves were shifted to the right in parallel with no depression of the maximal contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:FK 224, a novel cyclopeptide substance P antagonist with NK1 and NK2 receptor selectivity. 137 96

FK224 (N-[N2-[N-[N-[N-[2,3-didehydro-N-methyl-N-[N-[3-(2- penthylphenyl)-propionyl]-L-threonyl]tyrosyl]-L-leucynyl]-D- phenylalanyl]-L-allo-threonyl]-L-asparaginyl]-L-serine-nu-lactone) is a novel neurokinin (NK) antagonist that exhibits selectivity for NK1 and NK2 receptors. The effects of FK224 on airway constriction and airway edema induced by NKs and nerve stimulation have been investigated in guinea pigs. FK224 inhibited the contraction of isolated guinea pig trachea induced by substance P (SP, 10(-8) M), NKA (10(-9) M) and NKB (10(-8) M) in a concentration-dependent manner, and the IC50 values were 2.6 x 10(-6), 1.3 x 10(-6) and 2.3 x 10(-7) M, respectively. Tracheal contraction induced by histamine and acetylcholine was not affected by FK224, suggesting a specific effect on NK-mediated responses. FK224 also inhibited the atropine-resistant contraction of isolated guinea pig bronchi induced by electrical field stimulation with an IC50 value of 3.5 x 10(-6) M. In in vivo experiments, FK224 given i.v. inhibited SP (13.5 micrograms kg-1)-, NKA (1.1 micrograms kg-1)- and capsaicin (3.1 micrograms kg-1)-induced airway constriction in guinea pigs with ED50 values of 0.39 mg kg-1, 0.36 mg kg-1 and 1.1 mg kg-1, respectively. FK224 also inhibited SP (1.3 micrograms kg-1)-, NKA (11 micrograms kg-1)- and capsaicin (100 micrograms kg-1)-induced airway edema with ED50 values of 0.14 mg kg-1, 0.29 mg kg-1 and 0.30 mg kg-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Effects of FK224, a novel compound NK1 and NK2 receptor antagonist, on airway constriction and airway edema induced by neurokinins and sensory nerve stimulation in guinea pigs. 137 97


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