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)

Neuropeptides acting on tachykinin NK receptors play an important role in the amplification of inflammatory responses. We have assessed the effects of tachykinin NK receptor blockade on the injuries following intestinal ischaemia and reperfusion (I/R) in rats. The tachykinin NK(1) receptor antagonist SR140333 dose-dependently (0.05 to 0.5 mg kg(-1)) suppressed the local (intestine) and remote (lung) increases in vascular permeability and neutrophil recruitment following mild I/R injury. A structurally-distinct NK(1) receptor antagonist, CP99,994, but not tachykinin NK(2) or NK(3) receptor antagonists also suppressed mild I/R injury. Neonatal pretreatment with capsaicin effectively depleted sensory neurons and abrogated the injuries following mild I/R. Treatment with SR140333 (0.5 mg kg(-1)) significantly reversed severe reperfusion-induced local and remote increases in vascular permeability, neutrophil recruitment, intestinal haemorrhage and blood neutropaenia, but did not prevent the lethality associated with severe I/R. Post-ischaemic treatment with SR140333 significantly inhibited the elevations of TNF-alpha in the intestine and lung, but not serum, following severe I/R. The increase in the concentrations of IL-10 in the lung and serum were also suppressed. Post-ischaemic blockade of tachykinin NK(1) receptors markedly inhibited the local and remote injuries, but not lethality, following reperfusion of the SMA in rats. Neuropeptides, possibly substance P, released from sensory nerves appear to account for the activation of these tachykinin NK(1) receptors. Antagonists of the tachykinin NK(1) receptor may be useful adjuncts in the treatment of the injuries which occur following reperfusion of an ischaemic vascular territory.
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PMID:Role of tachykinin NK receptors on the local and remote injuries following ischaemia and reperfusion of the superior mesenteric artery in the rat. 1181 65

This study was designed to test the hypotheses that (1) neurokinin (NK) receptor activity modulates hyperventilation-induced bronchoconstriction (HIB) in canine peripheral airways and (2) NK receptor activity is stimulated via hyperventilation-induced eicosanoid production and release. A bronchoscope was used in anesthetized dogs to record peripheral airway resistance (Rp); to test airway reactivity to NK A (NKA), substance P, and hypertonic saline; and to examine HIB before and after combined treatment with NK-1 (CP 99,994) and NK-2 (SR 48,968) receptor antagonists. Bronchoalveolar lavage fluid cells, prostaglandin D2, and cysteinyl leukotrienes from hyperventilated airways pretreated with either vehicle or NK antagonists were also measured. Pretreatment with NK-1 and NK-2 antagonists significantly attenuated HIB and the response to substance P, virtually abolished the response to NKA, and had little effect on the response to HS. Blockade of NK-1 and NK-2 receptors did not affect either the cell profiles or the mediator concentrations recovered in bronchoalveolar lavage fluid after hyperventilation. We conclude that NKs modulate the development of HIB and appear to do so via hyperventilation-induced eicosanoid production and release.
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PMID:Neurokinins modulate hyperventilation-induced bronchoconstriction in canine peripheral airways. 1257 71

The effects of neurokinins and neurokinin receptor selective agonists have been investigated on human intralobar pulmonary vessels. Substance P (SP) and [Sar(9) Met(O(2)) ]SP(11), a selective NK(1) receptor agonist, induced concentration-dependent relaxation of pulmonary vessels precontracted with phenylephrine. The mean negative log (M) EC (50) values for SP and [Sar (9) Met(O2))]SP(11) were 8.6 and 8.9, respectively, on arterial preparations and 8.9 and 8.6, respectively, on venous preparations. Relaxations to [Sar(9) Met(O(2) ) ]SP were abolished by the NK receptor antagonist SR140333. The relaxations to a second application of [Sar(9) Met(O (2)) ]SP were markedly reduced, suggesting a rapid desensitization of the NK(1) receptor. Such desensitization was not observed with acetylcholine. The selective NK receptor agonist, [Nle(10)]NKA, and the selective NK (3) receptor agonist, [MePhe(7)]NKB, caused neither contractions nor relaxations of pulmonary vessels. The NK(1) receptor-mediated relaxations were abolished by removing the endothelium or by a combination of -nitro-L-arginine and indomethacin, whereas each compound exerted a partial inhibitory effect. Similar results were observed with acetylcholine. Positive immunostaining for NK(1) receptors was only found in the endothelium. Reverse transcription-polymerase chain reaction detected messenger RNA for NK(1) receptors without any detection of messenger RNA for NK(2) or NK(3) receptors. In conclusion, human pulmonary arteries and veins express endothelial NK(1) receptors that mediate relaxation through a combination of cyclooxygenase and nitric oxide activities and are subjected to rapid tachyphylaxis.
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PMID:Neurokinins induce relaxation of human pulmonary vessels through stimulation of endothelial NK1 receptors. 1260 12

We explored the dysfunction of tachykinins on monocrotaline (MCT)-induced pulmonary hypertension by using double-stranded preprotachykinin (ds PPT) RNA and neurokinin receptor (NK) antagonists. Here, we showed the possibility to attenuate the PPT gene expression by ds RNA, RNA interference (RNAi), in fully developed tissue of rats. We designed four groups (control, MCT, RNAi + MCT, and solvent + MCT) of experiments in series 1 and seven groups (control, MCT, MCT + CP-96345-3.4, MCT + CP-96345-10, MCT + CP-96344-10, MCT + SR-48968, and MCT + SR-48965) of experiments in series 2. Rats in the control groups received saline injection. MCT-treated rats received a single MCT injection (60 mg/kg sc). One day prior to MCT, bilateral nodose ganglia were microinjected with ds PPT RNA in rats of the RNAi + MCT group or with solvent in the solvent + MCT group. Beginning from 1 day post-MCT, MCT-treated rats received a daily injection of the NK(1) receptor antagonist, CP-96345 (3.4 or 10 mg/kg ip) or its inactive enantiomer CP-96344 (10 mg/kg ip). The NK(2) receptor antagonist SR-48968 (3 mg/kg ip) or its inactive enantiomer SR-48965 (3 mg/kg ip) was injected to MCT-treated rats every other day starting 1 day post-MCT. Functional study was carried out 2 weeks (series 1) or 3 weeks (series 2) after MCT. MCT induced right ventricular hypertrophy, as well as increases in pulmonary arterial pressure, PPT mRNA (nodose ganglia and lung tissue), and lung tissue substance P level. All of the above MCT-induced alterations were attenuated by either RNAi or NK receptor antagonists. We conclude that tachykinins play an important role in MCT-induced pulmonary hypertension.
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PMID:Tachykinin dysfunction attenuates monocrotaline-induced pulmonary hypertension. 1266 1

Neurokinin (NK)-1 and NK-2 receptors regulate hematopoiesis by interacting with neurotransmitters that belong to the tachykinin. This report studies the relationship between NK-1 and NK-2 in primary human bone marrow (BM) stroma, which supports hematopoiesis. Use of NK receptor antagonists and deficient stromal cells indicate that the neurotransmitter, substance P (SP), could exert dual hematopoietic effects (inhibitory or stimulatory), depending on the interacting receptor and crosstalk between NK-1 and NK-2. Cloning and identification of the minimal promoter for NK-2 and comparison with NK-1 promoter showed that the hematopoietic functions of NK receptors involve receptor crosstalk and the particular cytokine (IL-3, GM-CSF, TGF-beta or IL-1alpha). Crosstalk between NK-1 and NK-2 adds to communication within neural-hematopoietic axis.
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PMID:Crosstalk between neurokinin receptors is relevant to hematopoietic regulation: cloning and characterization of neurokinin-2 promoter. 1274 55

The mammalian tachykinin (TK) peptides and their three neurokinin (NK) receptors represent an effector system with wide-ranging actions on neuronal, airway smooth muscle, mucosal, endothelial, immune, inflammatory and remodeling cell function. Recent clinical and preclinical data suggests pathophysiological relevance for TKs in various diseases including asthma, emesis and depression. The promiscuous TK-NK receptor interactions and incompletely overlapping functions mediated by each NK receptor may indicate added therapeutic benefit of using multiple NK receptor blockade. Consequently, there has been substantial pharmaceutical effort in projects to develop nonpeptide dual and triple NK receptor antagonists. This review identifies the chemical and biological approach used to develop a TK antagonist active at the three NK receptors. Clinical activity has been observed using single and/or dual NK receptor antagonists in asthma, depression/anxiety and, most notably, emesis trials but no compound with mono or multiple NK receptor antagonist activities has cleared all the development and regulatory hurdles to commercialization. Current experience indicates that potent dual and triple NK receptor-selective antagonists possessing appropriate affinity and pharmacokinetic properties can be developed. As an example, the biological and pharmacokinetic profiles of a new representative of this class of agent, SCH 206272, is detailed in the present review. Whether such agents will fulfill researchers' expectations must await further clinical trials.
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PMID:Development and potential utility of dual and triple NK receptor antagonists. 1287 Nov 72

1. Adhesion of neutrophils (PMNs) to vascular endothelial cells (EC) is a critical step in recruitment and infiltration of leukocytes into tissues during inflammation. Substance P (SP), a neuropeptide released from sensory nerves, evoked PMN adhesion to EC. The NK receptor subtype(s) and the cell type(s) involved were investigated. 2. SP was coincubated with human PMNs and EC from the human umbilical vein (HUVEC); adhesion was quantitated by computerised microimaging fluorescence analysis. 3. The proadhesive effects of SP (range 10(-18)-10(-6) M) were illustrated in a biphasic dose-response curve, with a maximum at 10(-15) M (276+/-16% adhesion vs control; P<0.01) and another one at 10(-10) M (200+/-18% adhesion vs control; P<0.01). Neurokinin A was less active and neurokinin B was inactive. The adhesion molecules LFA-1 and OKM-1, but not selectins, were involved according to results with selective mAbs. 4. The NK(1) agonist [Sar(9),Met(O(2))(11)]SP reproduced the effects of SP, whereas the NK(2) agonist [betaAla(8)]-neurokininA (4-10) acted at 10(-13)-10(-8) M only. The NK(3) agonist, senktide, was ineffective. 5. The NK(1) antagonists, CP 96,345 and L 703,606 (both 10(-6) M), abolished the effect of 10(-15) M SP and inhibited that of 10(-10) M SP by 56+/-5% (P<0.01). By comparison, the NK(2) antagonist, SR 48,968 (10(-7) M), partially antagonised the adhesion evoked by 10(-10) M SP (% inhibition: 61+/-6; P<0.05). 6. Since preincubation of PMNs and HUVEC with SP gave the same results it is clear that both cell types contributed to its proadhesive effects. 7. These results indicate that SP induced a proadhesive effect during inflammatory processes, which was mediated by NK(1) and NK(2) receptors.
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PMID:Substance P increases neutrophil adhesion to human umbilical vein endothelial cells. 1287 28

Extensive efforts since 1931, on the structural determination of the mammalian tachykinin SP by NMR, CD and IR have turned out to be inconclusive. Studies are now being concentrated on the structural properties and characteristics of various NK receptors (NK(1), NK(2) and NK(3)) with the help of genetics, cloning, receptor engineering, mutagenesis and modeling. This knowledge is now being fruitfully used in the development of non-peptide NK(1) receptor antagonists that essentially block the pharmacological effects of SP. It is now being realized that the simultaneous blockade of two or more receptors gives promising results in emesis, depression and pulmonary obstructive diseases. In addition to the synthetic compounds, the discovery of antagonists from natural origin has added a great value to this field. In this review we have made an attempt to present the structural characteristics of SP, its analogs and antagonists, the structural characteristics of the NK receptor, and structure activity relationships that have helped to improve the therapeutic utilities of SP antagonists.
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PMID:Substance P: structure, function, and therapeutics. 1475 78

Parkinson's disease (PD) is a serious motor disorder and it is the second most common brain degenerative disease in human. PD is known to be caused by degeneration of dopamine neurons in the substantia nigra but the cause of cell death is largely unknown. Mammalian neurokinins [NKs] are a group of neuropeptides that include substance P (SP; neurokinin-1, NK-1), substance K (SK; NK-2; neurokinin A), and neuromedin K (NK; NK-3; neurokinin B). Their biological effects as neurotransmitters, neuromodulators, or neurotrophic-like factors are mediated by three distinct neurokinin receptors, namely SP receptor (SPR: NK-1 receptor, NK-1R), SKR (NK-2R), and NKR (NK-3R). Several lines of evidence have indicated that neurokinins are implicated in the pathogenesis of PD. First, decreases of SP level and SP-immunoreactivity have been found in nigral and striatal tissues of animals with PD and postmortem PD patients. Second, NKs exert neuroprotective effects on neurons. In addition, NK receptors, namely NK-1 and NK-3 receptors, are abundantly localized in dopaminergic and cholinergic neurons of the basal ganglia, indicating that these neurons are under the physiological regulation of NKs. Moreover, modulation in motor activity occurred in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, PD animal model, after systemic administration of NK receptor agonists. NKs and NK receptors, therefore, might be important molecules that are associated with functions and survival of neurons in the basal ganglia, in particular the dopamine neurons. Further studies should be devoted to elucidate the functional roles of NK systems in (a) the neuropathogenesis and neuroprotection during the course of PD, (b) the efficacy of NK receptor drugs towards PD, and (c) potential therapeutic intervention that targets at the prevention or treatment of PD.
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PMID:Neurokinin peptides and neurokinin receptors as potential therapeutic intervention targets of basal ganglia in the prevention and treatment of Parkinson's disease. 1501 53

Despite intensive therapy, approximately 60-80% of children who are diagnosed with metastatic neuroblastoma (NB) succumb to the disease. NB preferentially metastasizes to the bone marrow (BM). In the present study we used SY5Y and CHP212 (NB cell lines) to study the roles of the preprotachykinin-I (PPT-I) gene and the natural receptors for PPT-I peptides, neurokinin-1 (NK-1) and NK-2, in the biology of NB. PPT-I, NK-1 and NK-2 were constitutively expressed in the NB cells. Functional studies, with specific NK receptor antagonists, showed that PPT-I peptides mediate autocrine proliferation of the NB cells through both NK-1 and NK-2 receptors. Full-length and truncated NK-1 receptors were detected in NB cells. Since there is one copy of the NK-1 gene, we used NK-1-specific siRNA to suppress the expression of NK-1. The NK-1-deficient NB cells showed phenotypes consistent with cell differentiation. Suppression of NK-1 did not appear to cause cell death, as demonstrated by trypan blue exclusion and by undetectable active caspase. NK-1 suppression reduced the proliferation of the NB cells beginning by 10-fold at day 1 and reached a 10(5)-fold reduction by day 10. The NK-1 deficient cells did not proliferate when they were placed as cocultures with BM stroma, which suggests that NK-1 signaling is important for the survival of NB cells in the BM. The results show potential roles for NK receptors in the proliferation of NB.
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PMID:Autocrine proliferation of neuroblastoma cells is partly mediated through neurokinin receptors: relevance to bone marrow metastasis. 1569 Jan 22


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