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Pharmacological examination of the neurokinin-1 receptor mediating relaxation of human intralobar pulmonary artery

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第1期292卷 319-325页

作者： Pedersen, KE Buckner, CK Meeker, SN Undem, BJ Johns Hopkins Univ Sch Med Johns Hopkins Asthma & Allergy Ctr Baltimore MD 21224 USA Univ Oklahoma Coll Pharm Oklahoma City OK USA

The effect of selective tachykinin receptor agonists and antagonists on human isolated intralobar pulmonary arterial rings was investigated. Neither Substance P (SP) nor neurokinin A (NKA) contracted the arteries. Both of these agonists, however, were potent and efficacious at relaxing the arteries that were precontracted with phenylephrine. The negative log (M) EC50 values for SP and NKA were 9.0 and 8.3, respectively. The neurokinin (NK)-3 selective agonist, senktide-analog, and the NK-2 receptor selective agonist, [beta-Ala(8)]NKA(4-10), caused neither contractions nor relaxations of the arteries, whereas the NK-1 receptor agonist Ac-[Arg6, Sar9, Met(O2)11] SP( 6-11) (ASM-SP) relaxed the tissue with a potency similar to SP. The relaxations to SP, NKA, and ASM-SP were competitively antagonized by the selective NK-1 receptor antagonist CP 99994, with a pK(b) in the nanomolar range. Antagonism of the ASM-SP-induced relaxations was also noted with FK 888, RP 67580, and L 732,138, although these antagonists were much less potent than CP 99994 in this regard. Another NK-1 receptor selective antagonist, SR 140333, caused an insurmountable antagonism of the SP-induced relaxations. The NK-1 receptor-mediated relaxations could be blocked by removing the endothelium, or by a combination of N- nitro-L-arginine and indomethacin. Measurement of prostanoid generation revealed that in endothelial-intact but not endothelial-denuded tissue, ASM-SP caused a selective increase in the production of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin. The results indicate that stimulation of NK-1 receptors leads to relaxation of human intralobar pulmonary arteries, which is mediated largely by nitric oxide and prostacyclin released from the endothelium of these vessels.

关键词：剂量效应关系药物药物相互作用内皮血管/生理学依前列醇/生理学依前列醇/分泌肺/生理学神经激肽a/药理学一氧化氮/生理学肽碎片/药理学苯福林/药理学肺动脉/生理学受体神经激肽1/生理学受体速激肽/激动剂受体速激肽/拮抗剂和抑制剂 P物质/类似物和衍生物 P物质/药理学血管收缩/药物作用血管舒张/生理学青少年成年人女(雌)性人类男(雄)性中年人

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Hormonal variation of rat uterine contractile responsiveness to selective neurokinin receptor agonists

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BIOLOGY OF REPRODUCTION 2000年第6期62卷 1661-1666页

作者： Hamlin, GP Williams, MJ Nimmo, AJ Crane, LH James Cook Univ N Queensland Dept Physiol & Pharmacol Townsville Qld 4811 Australia

Regulated uterine contractions are important in many reproductive functions such as sperm transport and embryo positioning during implantation The role of classical neurotransmitters including acetylcholine and norepinephrine in regulating myometrial contractility has been well studied;however, the peripheral role of sensory neurotransmitters such as the neurokinins is less clear The major neurokinins are substance P, neurokinin A, and neurokinin B, which predominantly activate neurokinin receptors (NK-Rs) 1, 2, and 3, respectively. This study utilized selective receptor agonists to examine the role of NK-Rs in uterine contractility. Uterine tissues, obtained from the major stages of the rat estrous cycle, were stimulated with selective NK-R agonists. Addition of each agonist resulted in a significant contractile response. However, the magnitude and nature of the response were dependent upon the stage of the estrous cycle, with responses to all agonists being significantly decreased in tissue from proestrus and estrus. Furthermore, the nature of NK3-R-mediated contraction was different in tissue from proestrus and estrus compared to metestrus and diestrus. The hormonal dependence of NK-R-mediated contractility was then examined in the ovariectomized estrogen-supplemented rat model. These studies confirmed that the magnitude and nature of uterine contractility in response to NK-R activation depend upon the hormonal environment.

关键词：动情间期/生理学雌激素类/药理学雌激素类/生理学动情期/生理学动情后期/生理学神经激肽A/类似物和衍生物神经激肽a/药理学卵巢切除术肽碎片/药理学哌啶类/药理学动情前期/生理学大鼠 Sprague-Dawley 受体神经激肽1/激动剂受体神经激肽1/生理学受体神经激肽2/激动剂受体神经激肽2/生理学受体神经激肽3/激动剂受体神经激肽3/拮抗剂和抑制剂受体神经激肽3/生理学 P物质/类似物和衍生物 P物质/药理学子宫收缩/药物作用动物女(雌)性大鼠

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Relevance of aromatic residues in transmembrane segments V to VII for binding of peptide and nonpeptide antagonists to the human tachykinin NK₂ receptor

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第2期290卷 487-495页

作者： Renzetti, AR Catalioto, RM Criscuoli, M Cucchi, P Ferrer, C Giolitti, A Guelfi, M Rotondaro, L Warner, FJ Maggi, CA Menarini Ric SpA Dept Pharmacol I-50131 Florence Italy Menarini Ric SpA Dept Drug Design I-50131 Florence Italy Menarini Ric SpA Dept Biotechnol I-50131 Florence Italy Univ New S Wales Sch Physiol & Pharmacol Sydney NSW Australia

We used membranes from Chinese hamster ovary cells stably transfected with the human tachykinin NK2 receptor, either wild-type or mutated, at four aromatic residues (His(198), Tyr(266), Phe(270), Tyr(289)) located in transmembrane segments V to VII, to assess the role of these residues in the binding of natural tachykinins and peptide and nonpeptide antagonists. Three radioligands, the agonist [I-125]neurokinin A (NKA), the peptide antagonist [H-3]MEN 11420, and the nonpeptide antagonist [H-3]SR 48968 bound to the wild-type receptor with high affinity (K-d = 2.4 nM, 0.3 nM, and 4.0 nM, respectively). Four of the six mutant receptors tested retained high affinity for at least one of the radioligands. H(198)A mutation abrogated the binding of NKA but not that of MEN 11420 or SR 48968 (K-d = 4.8 and 11.5 nM, respectively);(YF)-F-266 mutation abrogated the binding of MEN 11420 but not that of NKA or SR 48968 (K-d = 2.8 nM and 1.2 nM, respectively);F(270)A mutation abrogated the binding of both NKA and MEN 11420 but not that of SR 48968 (K-d = 1.6 nM);(YF)-F-289 mutation abrogated the binding of SR 48968 but not that of NKA and MEN 11420 (K-d = 2.0 and 2.9 nM, respectively). Y(266)A and Y(289)A mutations abrogated the binding of all radioligands. Among the unlabeled antagonists, the affinity of the nonpeptide GR 159897, at variance with SR 48968, resulted heavily compromised by H(198)A and (YF)-F-266 mutations;the peptide antagonists R396 and MEN 10376 essentially followed the binding profile of NKA, but R396 showed markedly increased affinity for the (YF)-F-289 mutant receptor. Taken together, these results indicate that different, partially overlapping sets of sites may be involved in the binding of agonists and diverse antagonists to the human tachykinin NK2 receptor.

关键词：苯甲酰胺类/化学苯甲酰胺类/代谢苯甲酰胺类/药理学结合竞争性 CHO细胞仓鼠亚科 DNA 互补/药物作用 DNA 互补/遗传学吲哚类/化学吲哚类/代谢吲哚类/药理学诱变定点突变神经激肽A/化学神经激肽A/代谢神经激肽a/药理学肽类/化学肽类/代谢肽类环/化学肽类环/代谢肽类环/药理学哌啶类/化学哌啶类/代谢哌啶类/药理学蛋白质构象动物人类

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Tachykinin receptor subtypes in the isolated guinea pig heart and their role in mediating responses to neurokinin a

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第1期294卷 147-154页

作者： Chang, YZ Hoover, DB Hancock, JC Smith, FM E Tennessee State Univ Coll Med Dept Pharmacol Johnson City TN 37614 USA Dalhousie Univ Fac Med Dept Anat & Neurobiol Halifax NS Canada

Selective tachykinin agonists were used to identify cardiac and coronary responses mediated by specific tachykinin receptor subtypes in isolated, perfused guinea pig hearts. Receptor desensitization with selective agonists and blockade with selective antagonists were used to determine the role of specific subtypes in generating responses to neurokinin A (NKA). Dose-dependent cardiac and coronary effects were evoked by bolus injections of [Sar(9),Met(O-2)(11)]substance P ([Sar(9),Met(O-2)(11)]SP), GR64349, and [MePhe(7)]neurokinin B ([MePhe(7)]NKB) (selective agonists for NK1, NK2, and NK3 receptors, respectively). Each agonist caused bradycardia, but GR64349 was most effective (34 +/- 4% decrease in heart rate with 32 nmol, n = 8). Prominent increases in ventricular contractility and perfusion pressure also occurred with 32 nmol of GR64349 (25 +/- 6 and 33 +/- 4%, respectively). [Sar(9),Met(O-2)(11)]SP was unique in having a high potency for decreasing ventricular contractility and perfusion pressure. Bolus injections of 25 nmol of NKA decreased rate (48 +/- 2%, n = 51), increased contractility (26 +/- 2%), and had biphasic effects on perfusion pressure (24 +/- 1% decrease followed by 9.2 +/- 1.4% increase). Desensitization with GR64349 or treatment with the NK2 antagonist SR48968 reduced the bradycardic response to NKA by greater than 75% and eliminated the positive inotropic response. The remaining bradycardia occurred through NK3 receptors. Desensitization with [Sar(9),Met(O-2)(11)]SP or NK1 blockade with FK888 eliminated the coronary relaxant action of NKA and enhanced the pressor response. It is concluded that three tachykinin receptor subtypes are present in the guinea pig heart and that each contributes to the overall response evoked by NKA.

关键词：冠状血管/药物作用冠状血管/生理学剂量效应关系药物心脏/药物作用心率/药物作用心肌收缩/药物作用神经激肽a/药理学受体神经激肽1/生理学受体神经激肽2/生理学受体神经激肽3/生理学动物豚鼠男(雄)性

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Tachykinin activation of human monocytes from patients with interstitial lung disease, healthy smokers or healthy volunteers

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NEUROPEPTIDES 2000年第1期34卷 45-50页

作者： Brunelleschi, S Nicali, R Lavagno, L Viano, I Pozzi, E Gagliardi, L Ghio, P Albera, C Univ Piemonte Orientale Fac Med Dept Med Sci I-28100 Novara Italy Univ Turin Dept Clin & Biol Sci Pulm Branch Turin Italy

'Three types of tachykinin receptors, NK1, NK2 and NK3, have been described to preferentially interact with substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) respectively. Experimental evidence indicates that SP and NKA modulate the activity of inflammatory and immune cells, including mononuclear ones, and points to their involvement in lung pathophysiology. We previously reported that NK1 and NK2 receptors are present on monocytes (MO) isolated from healthy donors or rheumatoid patients - a greater sensitivity to NK2 receptor stimulation was observed in the latter condition. This study evaluated the effects of SP and NKA, as well as NK1 and NK2 selective agonists and antagonists, on MO obtained from healthy volunteers, healthy smokers or patients with interstitial lung diseases (e.g. sarcoidosis and idiopathic pulmonary fibrosis). Superoxide anion (O-2(-)) production was chosen as a parameter of cell activation. SP and NKA dose-dependently evoked O-2(-) production from MO in all the conditions evaluated, their effects being competitively antagonized by selective antagonists (CP 96 345 and MEN 10 627, respectively). When selective NK1 and NK2 agonists were used, [Sar (9)Met(O-2)(11)]SP, a selective NK1 agonist, induced a more than doubled O-2 production in MO obtained from patients with interstitial lung diseases as compared to healthy volunteers, whereas MO isolated from healthy volunteers were more sensitive to NK2 receptor stimulation. (C) 2000 Harcourt Publishers Ltd.

关键词：细胞培养的肺疾病间质性/血液单核细胞/生理学神经激肽A/类似物和衍生物神经激肽a/药理学肽碎片/药理学肺纤维化/血液受体神经激肽1/血液受体神经激肽2/血液受体神经激肽3/血液参考值结节病/血液吸烟/血液 P物质/类似物和衍生物 P物质/药理学超氧化物类/血液速激肽类/药理学成年人老年人女(雌)性人类男(雄)性中年人

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N-[(R,R)-(E)-1-(4-chloro-benzyl)-3-(2-oxo-azepan-3-ylcarbamoyl)-allyl]-N-methyl-3,5-bis-trifluoromethyl-benzamide:: An orally active neurokinin NK₁/NK₂ antagonist

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 2000年第13期10卷 1467-1470页

作者： Gerspacher, M von Sprecher, A Mah, R Anderson, GP Bertrand, C Subramanian, N Hauser, K Ball, HA Novartis Pharma AG Pharma Res CH-4002 Basel Switzerland Actel Ltd CH-4123 Basel Switzerland Univ Melbourne Dept Pharmacol Parkville Vic 3052 Australia Roche Biosci Inflammatory Dis Unit Palo Alto CA USA

The stereoselective synthesis of N-[(R,R)-(E)-1-(4-chloro-benzyl)-3-(2-oxo-azepan-3-ylcarbamoyl)-allyl]-N-methyl-3,5-bis-trifluoromethyl-benzamide (4) and its NK1 and NK2 receptor binding properties are reported. In addition the potent inhibitory effects in vivo on sar(9)-SP- and -beta-Ala-NKA-induced airway bronchoconstriction in guinea pigs are demonstrated. (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：投药口服抗哮喘药/化学抗哮喘药/代谢抗哮喘药/药理学氮杂化合物/药理学苯甲酰胺类/药理学支气管收缩/药物作用药物设计分子结构神经激肽A/类似物和衍生物神经激肽a/药理学肽碎片/药理学受体神经激肽2/拮抗剂和抑制剂立体异构现象 P物质/药理学动物豚鼠

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