Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: K01C8 .1
 572,118 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of substance P, substance P-(1-7) and substance P-(5-11) on endogenous dopamine outflow in rat striatal slices were investigated. The dose-response curves (0.01 nM to 10 microM) were bell-shaped, with significant increases at 0.1 and 1 nM but with no effect at higher concentrations. The tachykinin NK1 receptor agonist, [Sar9,Met(O2)11]substance P, significantly increased dopamine outflow at 10 and 100 nM. The effects of substance P or substance P-(5-11) and 25 mM KCl were additive. A negative interaction was observed with substance P-(1-7) and K+. The increase in dopamine outflow elicited by 1 nM substance P and substance P-(5-11) was reversed by the tachykinin NK1 receptor antagonist WIN 51,708 (17 beta-hydroxy-17 alpha-ethynyl-5 alpha-androstano[3,2-b]pyrimido[1,2- alpha]benzimidazole) (25 and 250 nM), whereas only partial reversal was observed for the effect of substance P-(1-7). These results show that substance P fragments locally modulate striatal dopamine outflow and the mechanisms underlying this modulation may differ between N- and C-terminal fragments.
 ...
PMID:Substance P-(1-7) and substance P-(5-11) locally modulate dopamine release in rat striatum. 749 81

We have characterized the receptor(s) mediating contraction and relaxation produced by tachykinins in the rabbit isolated jugular vein. The tachykinin NK1 receptor-selective agonists septide and [Pro9]substance P produced concentration-dependent contractions which were potentiated by either the removal of the vascular endothelium (Emax = +106% and +72%, respectively) or by pretreatment with L-nitroarginine (100 microM; 60 min before) (Emax = +123% and +71%, respectively). The tachykinin NK1 receptor-selective antagonist, (+/-)-CP-96,345 ([2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo[2,2,2]octan-3-amine]) (10-300 nM) competitively antagonized septide (pKB = 9.0) with 10-fold greater potency than [Pro9]substance P (pKB = 8.0). In preparations with intact endothelium both septide and [Pro9]substance P (from 0.1 to 100 nM) relaxed the noradrenaline-(10 microM) induced tone, and their effects were markedly reduced by (+/-)-CP-96,345 (100 nM). In noradrenaline-precontracted veins L-nitroarginine (100 microM) reversed the tachykinin-induced vasodilation into a contraction, providing evidence for the involvement of nitric oxide in this response. The tachykinin NK3 and NK2 receptor-selective agonists senktide and [beta Ala8]neurokinin A-(4-10) were either ineffective, or produced small effects antagonized by (+/-)-CP-96,345 (100 nM), respectively. In conclusion, tachykinin NK1 receptors mediate both tachykinin-induced contraction and relaxation in the rabbit jugular vein. This preparation, deprived of the endothelium or pretreated with L-nitroarginine, is suitable for evaluating tachykinin agonists or antagonists.
 ...
PMID:Tachykinin NK1 receptors mediate both vasoconstrictor and vasodilator responses in the rabbit isolated jugular vein. 749 15

1. The present study was undertaken to determine the mechanism of action of endothelin-1 (ET-1)-induced contraction of the guinea-pig isolated trachea. 2. ET-1 (1 nM-0.3 microM) produces a concentration-dependent contraction of guinea-pig trachea with an EC50 of approximately 25 nM. The combination of the peptidoleukotriene receptor antagonist, SK&F 104353 (10 microM) and the H1-histamine receptor antagonist, mepyramine (10 microM), which abolishes antigen-induced contraction in guinea-pig trachea, was without effect on ET-1 concentration-response curves. Furthermore, the platelet-activating factor (PAF) receptor antagonist, WEB 2086, (1 or 10 microM) did not inhibit ET-induced contraction. 3. ET-1 (0.3 microM) did not stimulate histamine or immunoreactive peptidoleukotriene release from guinea-pig isolated trachea. 4. The release of various prostanoids from guinea-pig trachea was increased significantly by ET-1 (0.3 microM); the profile of release was prostaglandin D2 (PGD2) = PGE2 = 6-keto PGF1 alpha (PGI2 metabolite) > thromboxane B2 = PGF2 alpha >> 9 alpha, 11 beta PGF2 (PGD2 metabolite). ET-1-induced release of prostaglandins, which was about 30% of that elicited by antigen in sensitized tissues, was not affected by epithelium removal and was observed in tissues from which the smooth muscle had been removed. Previous studies in our laboratory indicated that indomethacin potentiated contraction produced by high concentrations of ET-1, whereas a thromboxane receptor antagonist was without appreciable effect on ET-1 concentration-response curves. 5. Pretreatment of tissues for 1 h with capsaicin (10 microM), which depletes different sensory neurones, produced a small, but significant, inhibitory effect on ET-1 concentration-response curves in the presence but not the absence of the epithelium. The combination of the NK1 tachykinin receptor antagonist,CP-96,345 (0.1 microM), and the NK2 tachykinin receptor antagonist, SR 48968 (0.1 microM), was without effect on ET-l concentration-response curves but substantially antagonized capsaicin-induced contraction.6. The present data suggest that in guinea-pig isolated trachea, ET- 1 produces contraction predominantly via a direct mechanism: there is no significant contribution of the release of histamine,leukotrienes, PAF, or tachykinins (acting on NK1 or NK2 receptors). Although ET-1 evokes the release of an array of prostanoids from the trachea they do not appear to have a major influence on the contractile response.
 ...
PMID:Relative contributions of direct and indirect mechanisms mediating endothelin-induced contraction of guinea-pig trachea. 750 80

We have identified three novel mouse homeobox genes that are related to the Drosophila NK gene family. Two genes without direct homologues in Drosophila were designated Nkx-5.1 and Nkx-5.2; the third gene Nkx-1.1 constitutes the mouse homologue to NK1.Nkx-5.1 and Nkx-5.2 are closely linked on mouse chromosome 7, whereas Nkx-1.1 is located on a different chromosome. Here, we report the spatiotemporal expression pattern of Nkx-5.1 during prenatal mouse development. Nkx-5.1 gene activity begins at Embryonic Day 10.5 in the developing ear, the neural tube, and dorsal root ganglia. It continues to be active throughout prenatal life in discrete regions of the brain with an anterior border in the ventral diencephalon at the optic chiasma and expression domains in mesencephalon, metencephalon, and myelencephalon. At midgestation, Nkx-5.1 is also expressed in mesenchyme of the head and branchial arches, and in some cranial ganglia, as well as in derivatives of neural crest, such as the truncus sympathicus and myenteric ganglia. The time pattern of Nkx-5.1 expression and its confinement to primarily postmitotic cells of the central and peripheral nervous system suggest that Nkx-5.1 may play a role in the specification of neuronal cell types.
 ...
PMID:A novel NK-related mouse homeobox gene: expression in central and peripheral nervous structures during embryonic development. 751 Feb 54

CZ-1 is a novel sialic acid-dependent epitope of the murine CD45RB molecule which is expressed on cells that proliferate when cultured in IL-2. Because IL-2 appears to be important in the differentiation of NK cells, the authors examined the expression of CZ-1 on immature NK-lineage cells within the bone marrow. All mature NK1.1+ cells as well as their NK1.1- IL-2 responsive precursors were CZ-1+. Furthermore, IL-2 unresponsive transplantable NK progenitor cells expressed CZ-1 also. To examine expression of CZ-1 on other immature lymphoid progenitor cells, CZ-1+ and CZ-1- marrow cells were transplanted into lightly irradiated scid mice. Transfer of CZ-1+ cells resulted in rapid and sustained generation of thymocytes and splenic B cells, whereas CZ-1- cells caused delayed repopulation. This suggested that the slowly repopulating pluripotent stem cells lacked CZ-1. Therefore, expression of CZ-1 on Ly6+ Lin- c-kit+ cells, highly enriched for pluripotent stem cells, was examined. This population appeared to be homogeneously CZ-1dull. Thus, it appears that expression of CZ-1 is developmentally regulated, with differentiation associated with increased expression. Since CZ-1 is expressed on a protein tyrosine phosphatase, it is likely that this molecule regulates differentiation of NK and other lymphoid cells.
 ...
PMID:Expression of CZ-1: a CD45RB epitope on progenitors of natural killer and other haematopoietic cells. 751 Apr 13

The effects of a novel nonpeptide NK1 tachykinin receptor antagonist, SR 140333, on the functional consequences of NK1 receptor activation in a human astrocytoma cell line, U373MG, were investigated. Radioligand binding conducted with 125I-Bolton-Hunter substance P revealed a competitive inhibition by SR 140333 and its R enantiomer SR 140603 with Ki values of 0.74 and 7.40 nM, respectively. The NK1-selective agonist, [Sar9,Met(O2)11]-substance P, stimulated the formation of inositol phosphates with an EC50 of 3.8 x 10(-9) M. SR 140333 blocked the stimulatory effect of this agonist (10(-7) M) with an IC50 of 1.6 x 10(-9) M, whereas the effect of another NK1 agonist, septide (EC50 = 1.5 x 10(-8) M) was antagonized with an IC50 of 2.1 x 10(-10) M. Enhancement of [3H]taurine release by [Sar9,Met(O2)11]-substance P (EC50 = 7.4 x 10(-9) M) was also inhibited by SR 140333 with an IC50 of 1.8 x 10(-9) M. SR 140603 was 10-fold less potent than SR 140333 in inhibiting inositol monophosphate formation and [3H]taurine release. The calcium mobilization induced by [Sar9,Met(O2)11]-substance P (10(-8) M) was totally prevented by 10(-8) M SR 140333. Patch-clamp experiments showed that SR 140333 depressed the outward current evoked by 5 x 10(-8) M [Sar9, Met(O2)11]-substance P with an IC50 of 1.3 x 10(-9) M. The expression of c-fos was stimulated by [Sar9,Met(O2)11]substance P with an EC50 of 2.5 x 10(-10) M, an effect that was also inhibited by SR 140333 with an IC50 of 1.1 x 10(-9) M.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:SR 140333, a novel, selective, and potent nonpeptide antagonist of the NK1 tachykinin receptor: characterization on the U373MG cell line. 751 Jul 80

Acetaldehyde administered intravenously at various doses (20, 40 and 80 mg/kg) elicits a dose-dependent increase in intratracheal pressure (ITP) and a proportional rise in histamine blood concentration in anaesthetized guinea-pigs. Similar effects were observed in ovalbumin-sensitized guinea-pigs upon aerosol of acetaldehyde (20 mg/ml) which has been administered at the flow rate of 0.1 ml/min for 2 min. Theophylline (CAS 58-55-9) antagonized both the increase of ITP values and the rise of histamine in the blood caused by acetaldehyde given intravenously (ED50 = 5.8 mg/kg i.v.) or by aerosol (ED50 = 4.9 mg/kg i.v.). Furthermore, in animals where combined treatment with pyrilamine (2 mg/kg i.v.) and captopril (2 mg/kg i.v.) resulted in a remarkable potentiation of the bronchoconstrictor response to acetaldehyde (20 mg/kg i.v.), the administration of theophylline (5 mg/kg i.v.) or of the substance P (SP) receptor antagonist, [D-Pro4, D-Trp7.9] SP 4-11 (10 mg/kg i.v.) reduced the augmented action of acetaldehyde on respiratory airways induced by captopril by more than 50%. Moreover, the bronchoconstriction induced by acetaldehyde (40 mg/kg i.v.) was also associated with a significant increase of extravasation of Evans blue in tracheal tissue. Both these effects of acetaldehyde were inhibited by theophylline (10 mg/kg i.v.), whereas a NK1-TK (neurokinin 1-tachykinin) receptor antagonist (412 micrograms/kg i.v.) reduced (81%; p < 0.001) only the vascular permeability changes caused by acetaldehyde.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Influence of theophylline on both bronchoconstriction and plasma extravasation induced by acetaldehyde in guinea-pigs. 751 75

1. Exogenous tachykinins modulate cholinergic neurotransmission in rabbit and guinea-pig airways. We have investigated the effect of selective tachykinin receptor agonists and antagonists on cholinergic neurotransmission evoked by electrical field stimulation (EFS) of bronchial rings in rabbit, guinea-pig and human airways in vitro to assess which type of tachykinin receptor is mediating this facilitatory effect. 2. Bronchial rings were set up for isometric tension recording. Contractile responses to EFS (60 V, 0.4 ms, 2 Hz for 10 s every min) and exogenous acetylcholine (ACh) were obtained and the effects of selective tachykinin agonists and antagonists were investigated. 3. In rabbit bronchi the endogenous tachykinins, substance P (SP) and neurokinin A (NKA) (10 nM) potentiated cholinergic responses to EFS (by 287.6 +/- 121%, P < 0.01 and 181.4 +/- 56.5%, P < 0.001 respectively). 4. The NK1 receptor selective agonist, [Sar9]SP sulphone (10 nM) evoked a maximal facilitatory action on cholinergic responses of 334.9 +/- 63% (P < 0.01) (pD2 = 8.5 +/- 0.06) an effect which was blocked by the selective NK1-receptor antagonist, CP 96,345 (100 nM) (P < 0.05) but not by the NK2 receptor antagonist, MEN 10,376 (100 nM). The NK2 receptor selective agonist, [beta Ala8]NKA(4-10) (10 nM), produced a maximum enhancement of 278 +/- 83.5% (P < 0.01) (pD2 = 8.7 +/- 0.1) an effect which was blocked by MEN 10,376 (100 nM) (P < 0.05) and not by CP 96,345. [MePhe7]NKB, an NK3 receptor selective agonist was without effect. 5. The rank order of potency of NK2 receptor antagonists against enhancement of cholinergic responses by [Beta Ala8]NKA(4-10) was MEN 10,376> L 659,877> R 396. This pattern together with the observation of the full agonist activity of MDL 28,564 indicates that the NK2 receptors in the rabbit bronchus are similar to those which are present in the rabbit pulmonary artery.6. Neither [Sar9]SP sulphone (5 nM) nor [Beta Ala8]NKA(4- 10) (1 nM) had any effect on contractile responses to ACh (10 MicroM) suggesting a pre-junctional mechanism of action.7. By contrast, in guinea-pig bronchi only the NK1-receptor agonist [Sar9]SP sulphone (3 nM) was effective in enhancing cholinergic neurotransmission but the effect was relatively small (maximal enhancement 25.7 +/- 5.5%, P<0.01). In human bronchial rings all the selective neurokinin agonists were without effect on cholinergic neurotransmission.8. These results suggest that tachykinins may play an important role in modulating cholinergic neurotransmission in rabbit (via NK1 and NK2 receptors) and guinea-pig airways (via NK1 receptor) but have no demonstrable effect on human airways
 ...
PMID:Facilitatory effects of selective agonists for tachykinin receptors on cholinergic neurotransmission: evidence for species differences. 751 99

We have used one peptide (FK888) and two non-peptide ((+/-)-CP-96,345 and RP 67580) antagonists, along with the preferred endogenous agonist, substance P, to compare the pharmacological (binding) profile of NK1 receptors expressed by human B lymphoblastoma (IM9) and astrocytoma (U373 MG) cells. Of the ligands tested, substance P was the most potent in both cell lines: binding affinities were 0.1 nM for IM9 cells, and 0.3 nM for U373 MG cells, respectively. The high-affinity dipeptide antagonist, FK888, bound to NK1 receptors in both cell lines with similar potencies: Ki values were 1.2 nM and 3.6 nM for IM9 cells and U373 MG cells, respectively. Of the non-peptide antagonists, as expected, (+/-)-CP-96,345 displayed higher affinity (0.4 nM in IM9 cells, and 1.2 nM in U373 MG cells) than did RP 67580 (33 nM and 223 nM in IM9 cells and U373 MG cells, respectively) in both cell lines. We conclude that the pharmacological profile of NK1 receptors is similar in the human lymphoblastoma and astrocytoma cells, i.e. if NK1 receptor subtypes exist in humans, these cell lines are likely to express a similar subtype. Because IM9 cells grow faster and are easier to maintain, this cell line may be preferable to the astrocytoma cells as a primary screen to identify NK1 receptor antagonists.
 ...
PMID:Comparison of tachykinin NK1 receptors in human IM9 and U373 MG cells, using antagonist (FK888, (+/-)-CP-96,345, and RP 67580) binding. 751 85

1. NK1 and NK2 tachykinin receptors were characterized in guinea-pig and rat bronchopulmonary systems and in the vasculature of the rat by use of radioligand binding and/or functional studies. 2. The radioligands for NK1 and NK2 receptors ([3H]-SP and [3H]-pNKA, respectively) did not label tachykinin receptors in homogenates of rat lungs or bronchi. In contrast, in the guinea-pig, [3H]-SP bound with high affinity to these tissues (KD = 0.23 +/- 0.08 nM and 0.34 +/- 0.05 nM, for lungs and bronchi, respectively). The total number of binding sites was 4.6 fold greater in bronchus (Bmax = 135 +/- 27 fmol mg-1 protein) than in lung homogenates (Bmax = 29.3 +/- 0.1 fmol mg-1 protein). Furthermore, this binding was markedly displaced by CP-96,345 (pKi = 9.5 +/- 0.1) and RP 67580 (pKi = 7.6 +/- 0.1), antagonists of NK1 receptors, slightly displaced by SR 48968 (pKi = 6.6 +/- 0.1), but not affected by actinomycin D or L-659,877, antagonists of NK2 receptors. Specific binding of [3H]-pNKA, detected in guinea-pig bronchi (KD = 5.2 +/- 0.1 nM, and Bmax = 203 +/- 19 fmol mg-1 protein) but not in lungs, was similarly (40 to 53%) displaced by RP 67580 (1 microM), CP-96,345 (10 and 100 nM) or SR 48968 (10 and 100 nM). The displacement approximately doubled (87 to 91%) when SR 48968 (10 nM) was combined with either RP 67580 (1 microM) or CP-96,345 (10 nM), but not when RP 67580 was combined with CP-96,345. 3. In urethane-anaesthetized guinea-pigs, i.v. injections of the NK1 receptor agonists SP, [Pro9]-SP, [Sar9,Met(O2)11]-SP and septide, as well as the NK2 receptor agonists NKA and [Lys5,MeLeu9,NLeu10]-NKA(4-10) (0.1-10 micrograms kg-1, i.v.), dose-dependently increased lung inflation pressure. The most potent of these peptides were septide and [Lys5, MeLeu9,NLeu10]-NKA(4-10) (EC50 = 0.38 +/- 0.07 and 0.07 +/- 0.02 microgram kg-1, respectively). Interestingly, septide was 130 fold less potent than SP in displacing [3H]-SP from its binding sites in the guinea-pig lung, whereas it was 14 fold more potent than SP as a bronchoconstrictor. RP 67580 (0.3-5 mg kg-1, i.v.) and CP-96,345 (0.01-3 mg kg-1, i.v.) dose-dependently reduced the bronchoconstriction produced by the NK1 receptor agonists. Conversely, the NK2 receptor antagonists actinomycin D (1-10 mg kg-1, i.v.) and SR 48968 (0.03-0.3 mg kg-1, i.v.) inhibited specifically the responses induced by NK2 receptor agonists.4. In pentobarbitone-anaesthetized rats, the NK1 and NK2 receptor agonists (0.01-4 microg kg-1, i.v.)produced dose-dependent hypotensive responses. The order of potency was SP = [Sar9, Met(0211]-SP = [Pro9]-SP > septide = NKA >[Lys5, MeLeu9, NLeu 10-NKA.(4-10). RP 67580 (0.13-0.5 mg kg-1,i.v.) and CP-96,345 (0.5-2 mg kg-1, i.v.) antagonized in a dose-related manner (20 to 64%) the vascular effects of both NK, and NK2 receptor agonists, whereas actinomycin D (3 mg kg-1, i.v.) and SR 48968(2 mg kg-1, i.v.) did not. RP 67580 was approximately 4 times more potent than CP-96,345.5. These studies indicate that NK1 and NK2 receptors are both present in the guinea-pig bronchopulmonary system whereas only NK1 receptors are detectable in the rat vasculature under our experimental conditions. Furthermore, NK1 receptors in the guinea-pig bronchopulmonary system are pharmacologically distinct from those present in the rat vascular system, since both agonist potencies and antagonist affinities differ between the two species.
 ...
PMID:Characterization of NK1 and NK2 tachykinin receptors in guinea-pig and rat bronchopulmonary and vascular systems. 751 28


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