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)

Cold air was delivered to anesthetized, artificially ventilated, pathogen-free F344 rats via a tracheal cannula. Inhalation of cold air increased Evans blue dye extravasation in the trachea in a time-dependent (1 to 10 min) manner. Plasma extravasation increased after 3 min exposure to cold air and reached a maximum after 10 min exposure. The neutral endopeptidase inhibitor, phosphoramidon (2.5 mg/kg, intravenously), increased by 84% the plasma extravasation induced by inhalation of cold air for 1 min. The plasma extravasation evoked by 5 min exposure to cold air was abolished by the NK1 tachykinin receptor antagonist, CP-99,994 (4 mg/kg, intravenously); was reduced 30% by the B2 bradykinin receptor antagonist, HOE140 (0.1 mumol/kg, intravenously); and was not affected by H1 (pyrilamine, 10 mg/kg, intraperitoneally) or H2 (cimetidine, 10 mg/kg, intraperitoneally) histamine receptor antagonists or the cyclooxygenase inhibitor indomethacin (5 mg/kg, intravenously). In rats infected with Sendai virus, plasma extravasation evoked by inhalation of cold air was greater than in pathogen-free rats. Pretreatment with CP-99,994 (4 mg/kg, intravenously) inhibited completely the plasma extravasation induced by cold air in virus-infected rats. These findings indicate that cold air increases plasma extravasation in the rat trachea by a neurogenic mechanism that involves the release of tachykinins from sensory nerves. Kinin release may also play a role in this neurogenic inflammatory response.
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PMID:Plasma extravasation in the rat trachea induced by cold air is mediated by tachykinin release from sensory nerves. 769 24

1. In the present study, we have investigated the role of kinins in allergen-induced bronchoconstriction. 2. Anaesthetized guinea-pigs were sensitized to ovalbumin, ventilated artificially, pretreated with atropine (1.4 mumol kg-1, i.v.) and total pulmonary resistance (RL) measured. In preliminary studies in the presence of the neutral endopeptidase inhibitor, phosphoramidon (4.5 mumol kg-1, i.v.), the bradykinin B2 receptor antagonist Hoe 140 (0.1 mumol kg-1, i.v.) completely abolished the increase in RL following aerosolized bradykinin (1 mM, 40 breaths), but had no effect on the increase in RL following aerosolized neurokinin A (NKA, 10 microM, 40 breaths). On the other hand, a combination of the NK1 (CP-96,345, 2 mumol kg-1, i.v.) and NK2 (SR 48968, 0.3 mumol kg-1, i.v.) tachykinin receptor antagonists abolished completely the increase in RL produced by NKA and partially inhibited the increase in RL produced by bradykinin. These results confirm previous studies that suggest that bradykinin induces the release of tachykinins from sensory nerves in guinea-pig airways. 3. Aerosolized ovalbumin (0.5%, 5 breaths) increased RL in sensitized guinea-pigs pretreated with atropine (1.4 mmol kg-1, i.v.), an effect that began within 2 min and reached a maximum within 5 min; RL remained above baseline at 20 min. Pretreatment with the bradykinin B2 receptor antagonist, Hoe 140, decreased the bronchoconstrictor effect of ovalbumin markedly at 10 to 20 min. In the presence of phosphoramidon (4.5 mumol kg-1, i.v.) the inhibition induced by Hoe 140 was apparent earlier and remained over the 20 min period of study. 4. Pretreatment with a combination of NK1 (CP-96,345) and NK2 (SR 48968) tachykinin receptor antagonists also markedly inhibited ovalbumin-induced bronchoconstriction; addition of the bradykinin B2 receptor antagonist to the NK1 and NK2 tachykinin receptor antagonists had no additional inhibitory effect on antigen-induced bronchoconstriction.5. These findings confirm that activation of sensory nerves to release tachykinins in guinea-pig airways contribute to antigen-induced bronchoconstriction, and provide evidence that tachykinin release is due to kinins generated during the allergic response.
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PMID:Role of kinins in anaphylactic-induced bronchoconstriction mediated by tachykinins in guinea-pigs. 783 2

Peptide mediators may play a role in the control of myocardial perfusion. We found immunohistochemical evidence of the peptide-degrading enzyme neutral endopeptidase (NEP) in cultured rat myocytes. Therefore, we examined the effect of an NEP inhibitor, phosphoramidon, on myocardial perfusion in rats after (1) stimulating sensory nerves with capsaicin and (2) inducing myocardial hypoperfusion with isoproterenol, with or without pretreatment with selective antagonists of the substance P (NK1) and bradykinin (B2) receptors. Three to five sequential determinations of myocardial blood flow were made in anesthetized rats by injecting 100,000 radionuclide-labeled microspheres suspended in 70% dextrose into the left ventricle. Phosphoramidon doubled coronary blood flow in response to a dose of capsaicin that was ineffective in the absence of the inhibitor. Isoproterenol (50 mg/kg IP) caused an immediate fall in blood pressure and coronary blood flow; after 20 minutes, flow had returned to normal but pressure was still subnormal. Administration of phosphoramidon reduced the recovery of blood pressure but greatly increased coronary blood flow. These changes were not altered by a substance P NK1 receptor blocker but were completely abolished by a selective bradykinin B2 receptor blocker. Our data indicate that (1) NEP is present in the rat myocardium, (2) sensory nerve-induced coronary vasodilation is markedly potentiated by NEP inhibition, (3) isoproterenol-induced myocardial hypoperfusion is prevented by NEP inhibition, and (4) this effect of NEP inhibition is due to reduced degradation of bradykinin.
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PMID:Neutral endopeptidase in the heart. Neutral endopeptidase inhibition prevents isoproterenol-induced myocardial hypoperfusion in rats by reducing bradykinin degradation. 792 22

1. Cyclophosphamide (CYP) (150 mg kg-1, i.p. 0.5-48 h before) caused a time-dependent plasma protein extravasation in the rat urinary bladder with the maximal extravasation occurring at between 2 and 4 h after administration of the drug. 2. Prior capsaicin desensitization of capsaicin-sensitive primary afferent neurones (CSPANs) (50 mg kg-1, s.c., 4 days before) resulted in approximately 50% inhibition of the magnitude of the extravasation response at the 2 h time-point. 3. Intraperitoneal (i.p.) pretreatment with the tachykinin NK1 receptor antagonist, RP 67,580 (0.44 mg kg-1) or the bradykinin B2 receptor antagonist, Hoe 140 (0.13 mg kg-1) had significant inhibitory effects, giving responses of 56 +/- 6% and 39 +/- 4% of the control extravasation response to CYP treatment after 2 h. Pretreatment with the tachykinin NK2 receptor antagonist, SR 48,968 (0.3 mg kg-1, i.p.), the histamine H1 receptor blocker, chlorpheniramine (10 mg kg-1, i.p.), the 5-HT receptor blocker, methysergide (6 mg kg-1, i.p.) or the cyclo-oxygenase inhibitor indomethacin (5 mg kg-1, i.p.) had no significant effect upon the development of the extravasation response at this same time-point. 4. In rat isolated urinary bladder strips, the active metabolite of CYP, acrolein (1-300 microM) produced a concentration-dependent contraction that was significantly reduced by in vitro capsaicin desensitization (10 microM for 15 min) indicating direct stimulation of CSPANs. CYP was without appreciable effect. 5. The effect of acrolein in vitro was significantly reduced by pretreatment of the bladder with a combination of tachykinin NK1 and NK2 receptor antagonists, RP 67,580 (3 microM) and SR 48,968 (1 microM). The dose-response curve to acrolein was also significantly inhibited by treatment with indomethacin (10 microM) and slightly affected by Hoe 140 (1 microM). 6. These findings demonstrate the contribution of CSPANs to the development of CYP-induced cystitis.Plasma protein extravasation involves activation of tachykinin NKI and bradykinin B2 receptors.Activation of CSPANs in the urinary bladder is likely to be due to the conversion of CYP into its active metabolite, acrolein, and not to a direct effect of CYP upon these nerve-endings.
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PMID:Characterization of the capsaicin-sensitive component of cyclophosphamide-induced inflammation in the rat urinary bladder. 803 84

The effect of Hoe 140, a potent bradykinin B2 receptor antagonist, on the micturition reflex and detrusor hyperreflexia induced by chemical cystitis has been investigated in anaesthetized rats. Hoe 140 (1-100 nmol/kg i.v.) produced a dose-dependent blockade of the contraction of the rat urinary bladder induced by i.v. administration of bradykinin (100 nmol/kg) without affecting the response produced by the selective tachykinin NK-1 receptor agonist, [Sar9] substance P (SP) sulfone (1 nmol/kg i.v.). At doses which produce selective and long-lasting blockade of bradykinin receptors in the urinary bladder, Hoe 140 did not modify urodynamic parameters in normal rats. Intravesical instillation of xylene in female rats decreased bladder capacity and increased micturition frequency. These effects also occurred in rats pretreated with capsaicin as adults. Hoe 140 did not modify xylene-induced cystitis. Intraperitoneal administration of cyclophosphamide (150 mg/kg, 48 h before) decreased bladder capacity and increased micturition frequency. These effects of cyclophosphamide were abolished in rats pretreated with capsaicin as adults. Hoe 140 increased bladder capacity and decreased micturition frequency in rats pretreated with cyclophosphamide. Addition of bradykinin (10 mumol/l) to the medium in the superfused rat urinary bladder preparation evoked a prompt increase in the outflow of calcitonin gene-related peptide like immunoreactivity (CGRP-LI). Hoe 140 (3 mumol/l) inhibited (by about 50%) the CGRP-LI out-flow stimulated by bradykinin. These findings demonstrate the participation of bradykinin, through B2 receptors, in the genesis of detrusor hyperreflexia during cyclophosphamide-induced cystitis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence for the involvement of bradykinin in chemically-evoked cystitis in anaesthetized rats. 838 87

1. This study investigated the effect of the recently described non-peptide bradykinin B2 receptor antagonist, WIN 64338 ([[4-[[2- [[bis(cyclohexylamino)methylene]amino]-3-(2-naphthalenyl)-1-oxopropyl] amino]phenyl]methyl]tributylphosphoniumchloride monohydrochloride), in experimental models of bradykinin-evoked sensory nerve stimulation. 2. In the rabbit isolated iris sphincter in vitro, bradykinin-evoked contractile responses are mediated via tachykinins released from peripheral endings of the trigeminal sensory nerve. WIN 64338 (1-10 microM) competitively antagonised contractile responses to bradykinin with a pKB estimate of 6.6 +/- 0.1 (n = 11). The antagonism was selective since WIN 64338 (10 microM) did not significantly inhibit submaximal contractile responses to the direct-acting spasmogens substance P (10 nM), neurokinin A (3 nM), substance P methyl ester (10 nM) or senktide (100 nM); nor by sensory non-adrenergic non-cholinergic nerve stimulation evoked by capsaicin (10 microM), or electrical field-stimulation (3, 10, 30 Hz) (P > 0.05; n = 3-11). 3. Topical application of bradykinin to the conjunctiva and to the nasal mucosa of the guinea-pig in vivo causes plasma extravasation predominantly via the release of tachykinins from peripheral endings of the trigeminal nerve. The increases in plasma extravasation (measured by extravasation of Evans blue dye) induced by bradykinin in the guinea-pig conjunctiva (20 nmol) and nasal mucosa (50 nmol) were markedly reduced (by 81 +/- 3% and 69 +/- 5%, respectively) following pretreatment with WIN 64338 (30 nmol kg-1, i.v.) (n = 5-6; P < 0.05), with almost complete inhibition at a higher dose of WIN 64338 (300 nmol kg-1, i.v.; n = 5-6). This inhibition was selective since at 300 nmol kg-1, WIN 64338 did not inhibit plasma extravasation evoked by substance P in the conjunctiva (5 nmol; P > 0.05; n = 6) or in the nasal mucosa (50 nmol; P > 0.05; n = 5). 4. This study demonstrates that WIN 64338 is a selective and competitive bradykinin B2 receptor antagonist and can be useful for analysing bradykinin-evoked trigeminal nerve stimulation both in vitro and in vivo.
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PMID:Inhibition of bradykinin-evoked trigeminal nerve stimulation by the non-peptide bradykinin B2 receptor antagonist WIN 64338 in vivo and in vitro. 871 91

1. The possibility that tachykinin NK1 receptors are involved in the plasma extravasation evoked by intradermal (i.d.) injection of Phoneutria nigriventer venom (PNV) in rat dorsal skin in vivo has been investigated. 2. Local oedema formation induced by the i.d. injection of test agents was measured by the extravascular accumulation of intravenously (i.v.) injected 125I-labelled human serum albumin over a 30 min period. 3. The tachykinin NK1 agonist, GR73632 (30 pmol per site), induced local oedema formation which was potentiated by co-injection with the neuropeptide vasodilator, calcitonin gene-related peptide (CGRP, 10 pmol per site). The non-peptide tachykinin NK1 receptor antagonist, SR140333 (0.03-1 nmol per site co-injected, i.d.) significantly inhibited (0.3 nmol per site, P < 0.05; 1 nmol per site, P < 0.001) local oedema formation induced by GR73632 with CGRP but not that induced by histamine (10 nmol per site) with CGRP. 4. PNV (0.03-0.3 microgram per site) injected i.d. induced dose-dependent local oedema formation. SR140333 (1 nmol per site, co-injected i.d.) inhibited oedema formation; with complete inhibition observed at doses of 0.03 microgram (P < 0.05) and 0.1 microgram (P < 0.001); and partial inhibition (50%) observed with the highest dose of PNV, 0.3 microgram (P < 0.05). 5. Local oedema formation induced by PNV was not affected by systemic pretreatment with the bradykinin B2 receptor antagonist, Hoe 140 (80 nmol kg-1, i.v.), which was used at a dose which significantly inhibited oedema formation by bradykinin (1 nmol per site). 6. Local oedema formation induced by PNV was significantly inhibited (P < 0.01) by co-injection of the histamine H1 receptor antagonist, mepyramine (2.5 nmol per site), together with the 5-hydroxytryptamine (5-HT) antagonist, methysergide (2.8 nmol per site). 7. In the presence of all three antagonists (mepyramine 2.5 nmol per site; methysergide, 2.8 nmol per site and SR140333 1 nmol per site), the plasma extravasation induced by PNV was further significantly inhibited (P < 0.001, when compared with PNV injected i.d. alone; P < 0.05 when compared with PNV co-injected with mepyramine and methysergide and P < 0.01, when compared with PNV co-injected with SR140333). 8. These results suggest that oedema formation evoked by i.d. PNV in rat skin may be partially mediated via a mechanism involving tachykinin NK1 receptors and that this effect is independent of histamine and 5-HT.
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PMID:The effect of a tachykinin NK1 receptor antagonist, SR140333, on oedema formation induced in rat skin by venom from the Phoneutria nigriventer spider. 873 30

We have investigated the effects of CP-99,994 [(+)-(2s,3s)-3-(2-methoxybenzylamino)-2-phenylpiperidine], a tachykinin NK1 receptor antagonist, HOE 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]bradykinin), a bradykinin B2 receptor antagonist, and ketotifen (4-(1-methyl-4-piperidylidene)4 H-benzo[4,5]cycloheptal[1,2-b]thiophen-10(9H)-one hydrogen fumarate), a histamine H1 receptor antagonist with mast cell-stabilizing properties, on microvascular leakage induced by gaseous formaldehyde. Extravasation of Evans blue dye into airway tissues was used as an index of airway microvascular leakage. Leakage of dye in the trachea and main bronchi increased significantly in a concentration-dependent fashion after 10 min inhalation of formaldehyde (5-45 parts per million (ppm)). The airway response induced by 10 min inhalation of 15 ppm formaldehyde (trachea: 119.5 +/- 13.9 ng/mg, n = 7; main bronchi: 139.6 +/- 7.9 ng/mg, n = 7) was abolished by the administration of CP-99,994 (3 and 6 mg/kg i.v.), but not by the administration of HOE 140 (0.65 mg/kg i.v.) nor ketotifen (1 mg/kg i.v.). The increase in vascular permeability induced by formaldehyde in the rat airway was mediated predominantly by NK1 receptor stimulation. Activation of bradykinin receptors and mast cells did not appear to play an important role in this airway response.
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PMID:Role of tachykinin and bradykinin receptors and mast cells in gaseous formaldehyde-induced airway microvascular leakage in rats. 883 17

1. Substance P (SP) and capsaicin induced a mechanical hyperalgesia when injected into rat knee joints. 2. The NK1 receptor antagonists CP 99994 (10-100 nmol) and RP 67580 (0.1-1 nmol) blocked the development of, and also reversed, SP-induced hyperalgesia. Capsaicin (10 nmol)-induced hyperalgesia was blocked by capsazepine (0.5-5 nmol). 3. Capsaicin-induced hyperalgesia was prevented and reversed by the NK1 receptor antagonists CP 99994 (100 nmol) and RP 67580 (1 nmol). 4. The bradykinin B2 receptor antagonist icatibant (5 pmol) blocked the development of both SP and capsaicin-induced hyperalgesia. Icatibant (100 pmol kg-1, i.v.) also reversed an established SP and capsaicin-induced hyperalgesia. 5. Both low dose SP (1 nmol) and capsaicin (1 nmol)-induced hyperalgesia were potentiated by the kininase II inhibitor captopril (100 micrograms). 6. The B1 receptor antagonists desArg9Leu8-bradykinin (BK) (0.5-5 nmol) and desArg10[Hoe 140] (5-50 pmol) only blocked the development of SP-induced hyperalgesia for 30 min after administration. desArg9Leu8-BK (10 nmol kg-1 i.v.) did not reverse an established SP-induced hyperalgesia. 7. Capsaicin-induced hyperalgesia was blocked by desArg9Leu8-BK (0.5 nmol) and this antagonist also reversed an established capsaicin-induced hyperalgesia. 8. Interleukin-1 receptor antagonist (IL-1ra 0.1 microgram) reduced the development of SP-induced hyperalgesia up to 4 h after administration, but did not reverse an established hyperalgesia. IL-1ra (0.1 microgram) also blocked the development of and reversed an established capsaicin-induced hyperalgesia. 9. Indomethacin pretreatment (1 mg kg-1, s.c.) did not reduce the development of either SP- or capsaicin-induced hyperalgesia but following indomethacin-pretreatment desArg9Leu8-BK (10 nmol kg-1, i.v.) failed to reverse a capsaicin-induced hyperalgesia. 10. In conclusion, both SP and capsaicin can induce behavioural hyperalgesia when injected into the knee joint of rats. In addition, blockade of NK1, bradykinin B1, B2 and IL-1 beta receptors can substantially modulate this hyperalgesia.
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PMID:Substance P and capsaicin-induced mechanical hyperalgesia in the rat knee joint; the involvement of bradykinin B1 and B2 receptors. 886 63

The changes induced in the mean arterial blood pressure of anaesthetised rats following the administration of armed spider (Phoneutria nigriventer) venom have been investigated. The intravenous injection of Phoneutria nigriventer venom (0.1 mg/kg) evoked a brief and reversible decrease in the mean arterial blood pressure whereas a higher dose of venom (0.3 mg/kg) caused a biphasic response characterized by a short-lasting hypotension followed by a sustained and prolonged hypertension (40-50 min). These changes were accompanied by tachycardia, salivation, fasciculations, defecation and respiratory disturbances. Pretreatment of the animals with atropine (10 mg/kg), propranolol (100 mg/kg), phenoxybenzamine (100 mg/kg) and indomethacin (4 mg/kg) did not significantly affect the mean arterial blood pressure changes induced by Phoneutria nigriventer venom. Similarly, the bradykinin B2 receptor antagonist Hoe 140 (D-Arg-[Hyp3,Thi5,DTic7,Oic8]-bradykinin) (0.6 mg/kg), the PAF receptor antagonist WEB 2086 (3-(4-(2-chlorophenyl)-9-methyl-6H-thieno-(3,2f) (1,2,4)-triazolo-(4,3-a) (1,4)-diazepine-2-yl)-(4-morpholinyl)-1-propanone) (20 mg/kg), the tachykinin NK1 receptor antagonist SR 140333 ((S)1-(2-[3-(3,4-dichlorophenyl)-1-(3-iso-propoxyphenyl acetyl) piperidin-3-yl] ethyl)-4-phenyl-1-azoniabicyclo[2.2.2] octane, chloride) (0.5 mg/kg), the tachykinin NK2 receptor antagonist SR 48968 ((S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophen yl) butyl]benzamide) (0.5 mg/kg) and the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (10 mg/kg) had no significant effect on the mean arterial blood pressure changes induced by Phoneutria nigriventer venom. The increase in the blood pressure induced by Phoneutria nigriventer venom was also not significantly affected by either the angiotensin II receptor antagonist losartan (10 mg/kg) or the endothelin ETA receptor antagonist FR 139317 ((R)2-[(R)-2-[[1-(hexahydro-1H-azepinyl]carbonyl]amino-4-methyl- pentanoyl]amino-3-[3-(1-methyl-1H-indoyl)]propionyl] amino-3-(2-pyridyl) propionic acid) (30 mg/kg). The ATP-dependent K+ channel antagonist glibenclamide (50 mg/kg) reduced by 40% the hypotension induced by Phoneutria nigriventer venom without affecting the hypertensive response. Pretreatment of the animals with L-type Ca2+ channel antagonists such as verapamil (10-100 micrograms/kg/min), diltiazem (40-120 micrograms/kg/min) and nifedipine (0.3-10 mg/kg) markedly attenuated the hypertension induced by Phoneutria nigriventer venom. Verapamil (30 micrograms/kg/min) and diltiazem (120 micrograms/kg/min) also promptly reversed the established hypertension induced by Phoneutria nigriventer venom when infused 8 min after venom injection. Our results indicate that the brief decrease of blood pressure induced by Phoneutria nigriventer venom is partially due to ATP-dependent K+ channel activation. The prolonged hypertension seems to result from direct Ca2+ entry into vascular and/or cardiac muscles.
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PMID:The effect of Phoneutria nigriventer (armed spider) venom on arterial blood pressure of anaesthetised rats. 886 97


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