UNIPROT:P20366 - FACTA Search

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Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of substance P on blood flow, plasma extravasation, and knee joint sizes in the rabbit were investigated. Topical bolus application of substance P (1 nmol) onto the exposed rabbit knee joint capsule increased its blood flow from 15 min onwards and reached a peak of 46% at 90 min compared to saline administration. However, administration by the same route and the same dose of the NK(1) receptor agonist [Sar(9), Met (O(2))(11)]substance P produced no change on the knee joint blood flow compared to the saline control. The NK(1) receptor antagonist N(2)-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N-m ethyl-N-phenylmethyl-3-(2-naphthyl)-L-alaninamide (FK888) and the NK(2) receptor antagonist (S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino)-2-(3, 4-dichlorophenyl)-butyl] benzamide (SR48968), at 2x1 nmol and 2x10 nmol, had no effect on the substance P-induced response, which however was reduced by pyrilamine, cimetidine, and flurbiprofen (all at 2x10 nmol). N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-nitro-D-arginine methyl ester (D-NAME), both at 2x100 nmol, did not significantly affect the substance P-induced response. Unilateral intra-articular administration of substance P (1 nmol) into synovial cavities of the rabbit knee joint increased basal blood flow of the ipsilateral joint at 4 h post-injection, and bilateral increase of basal blood flow was observed at 24 h. Plasma extravasation was significantly higher in the substance P-injected knee compared to the contralateral saline-injected knee at 4 h after intra-articular administrations, but not at 24 h. Knee joint sizes were not affected at both time points. The present study is the first to demonstrate that substance P possesses a gradual and persistent vasorelaxant action in the rabbit knee joint. This novel action of substance P is not mediated by NK(1) or NK(2) receptors, but involves histamine and prostaglandins. The degree of plasma extravasation elicited by substance P in the rabbit knee joint is small and short-lived, and with no concurrent oedema of the joint. These results suggest that substance P can evoke acute inflammatory responses in the rabbit knee joint, but on its own, it is unlikely to cause chronic joint inflammation in this species.
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PMID:Unique gradual and sustained vasodilator response to substance P in the rabbit knee joint. 1098 51

The role of endogenous tachykinins and the mechanisms whereby they act on NK2 receptors, modulating spontaneous motility, were investigated in rat isolated proximal colon. The mechanical activity was detected as changes in intraluminal pressure. The NK2 receptor antagonist, MEN 10627, produced a concentration-dependent reduction of the contraction amplitude. [beta-Ala8]-neurokinin A(4-10), an NK2 receptor agonist, and [Sar9, Met(O2)11]-Substance P ([Sar9, Met(O2)11]-SP), an NK1 receptor agonist, induced a concentration-dependent contractile response, characterized by an increase in basal tone with superimposed phasic contractions. MEN 10627 antagonized the response to [beta-Ala8]-neurokinin A(4-10), without affecting that to [Sar9, Met(O2)11]-SP. Tetrodotoxin (TTX), hexamethonium and Nomega-nitro-L-arginine methyl ester (L-NAME) significantly reduced the response to MEN 10627. The NK3 receptor agonist, senktide, was able to activate the nitrergic inhibitory pathway, as it induced a TTX-and L-NAME-sensitive inhibitory effect. [beta-Ala8]-neurokinin A(4-10) was able to antagonize the inhibitory response to senktide. These findings suggest that tachykinins acting on NK2 receptors play a role in the modulation of the spontaneous mechanical activity. The mechanism of this action would be, in part, acting directly on the smooth muscle cells, and, in part neurogenic, sustained by nicotinic inputs, and possibly due to inhibition of NO tonic release.
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PMID:Involvement of tachykinin NK2 receptors in the modulation of spontaneous motility in rat proximal colon. 1101 46

We have investigated the ability of protease-activated receptor-1 (PAR-1), PAR-2, PAR-3 and PAR-4 agonists to induce contractile responses in isolated guinea-pig gallbladder. Thrombin, trypsin, mouse PAR-1 activating (SFLLRN-NH(2)) peptide, and mouse PAR-2 activating (SLIGRL-NH(2)) and human PAR-2 activating (SLIGKV-NH(2)) peptides produced a concentration-dependent contractile response. Mouse PAR-4 activating (GYPGKF-NH(2)) peptide, the mouse PAR-1 reverse (NRLLFS-NH(2)) peptide, the mouse PAR-2 reverse (LRGILS-NH(2)) and human PAR-2 reverse (VKGILS-NH(2)) peptides caused negligible contractile responses at the highest concentrations tested. An additive effect was observed following the contractile response induced by either trypsin or thrombin, with the addition of a different PAR agonist (SFLLRN-NH(2) and SLIGRL-NH(2), respectively). Desensitization to PAR-2 activating peptide attenuated the response to trypsin but failed to attenuate the response to PAR-1 agonists, and conversely desensitization to PAR-1 attenuated the response to thrombin but failed to alter contractile responses to PAR-2 agonists. The contractile responses produced by thrombin, trypsin, SFLLRN-NH(2) and SLIGRL-NH(2) were markedly reduced in the presence of the cyclo-oxygenase inhibitor, indomethacin, whilst the small contractile response produced by NRLLFS-NH(2) and LRGILS-NH(2) were insensitive to indomethacin. The contractile responses to thrombin, trypsin, SFLLRN-NH(2) and SLIGRL-NH(2) were unaffected by the presence of: the non-selective muscarinic antagonist, atropine; the nitric oxide synthase inhibitor, L-NAME; the sodium channel blocker, tetrodotoxin; the combination of selective tachykinin NK(1) and NK(2) receptor antagonists, (S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl) piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2] octane chloride (SR140333) and (S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino-2-(3, 4-dichlorophenyl)-butyl] benzamide (SR48968), respectively. The results indicate that PAR-1 and PAR-2 activation causes contractile responses in the guinea-pig gallbladder, an effect that is mediated principally by prostanoid release, and is independent of neural mechanisms.
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PMID:Evidence that PAR-1 and PAR-2 mediate prostanoid-dependent contraction in isolated guinea-pig gallbladder. 1103 Jul 17

Correolide (1 - 10 microM), a nortriterpene purified from Spachea correae and a selective blocker of Kv1 potassium channels, elicits repetitive twitching in guinea-pig ileum. This effect is not seen in guinea-pig duodenum, portal vein, urinary bladder or uterine strips, nor in rat or mouse ileum. The time course and amplitude of the correolide-induced twitches in guinea-pig ileum are similar to those elicited by electrical stimulation of the enteric nervous system. The correolide-induced twitching is not affected by pre-treatment with capsaicin (1 microM), but is facilitated by the NO synthase inhibitor, N(G)-nitro-L-arginine methyl esther (L-NAME, 200 microM). The correolide-induced twitching is abolished by tetrodotoxin (1 microM) or hexamethonium (100 microM), and is markedly inhibited by nifedipine (0.3 microM) or atropine (0.2 microM). The atropine-resistant component is inhibited by selective antagonists of NK1 and NK2 tachykinin receptors, namely GR 82334 and GR 94800 (1 microM each). The former compound is more effective in inhibiting the correolide-induced, atropine-resistant activity. Correolide intensified the twitching of ileum segments exposed to saturating concentrations of margatoxin (MgTX), which suggests that Kv1 sub-types other than Kv1.1 (Kv1.4 or Kv1.5) are involved in the relatively greater degree of stimulation of the enteric nervous system by correolide, as compared to MgTX. We propose that blockade of Kv1 channels by correolide increases the excitability of intramural nerve plexuses promoting release of acetylcholine and tachykinins from excitatory motor neurons. This, in turn, leads to Ca(2+)-dependent action potentials and twitching of the muscle fibres.
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PMID:Correolide, a nor-triterpenoid blocker of Shaker-type Kv1 channels elicits twitches in guinea-pig ileum by stimulating the enteric nervous system and enhancing neurotransmitter release. 1103 Jul 27

Neurokinin A (NKA) is a tachykinin that participates in the control of neuroendocrine functions. The posterior pituitary lobe (PP) contains abundant nitric oxide synthase (NOS), suggesting that nitric oxide (NO) may play a role in controlling the release of neuropeptides and neurotransmitters. In the present project, we investigated the in vitro effect of NKA on oxytocin release from hypothalamic explants and PP of male rats and the possible involvement of NO in the action of NKA. Since NKA inhibits gamma-aminobutyric acid (GABA) release from PP, we also examined the role of NO in the effect of NKA on basal and K(+)-evoked GABA release. NKA (10(-7)-10(-5) M) significantly decreased oxytocin release from PP, whereas it did not affect its release from hypothalamic explants. The inhibitory effect of NKA on oxytocin release from PP was completely blocked by the NOS inhibitors N(G)-monomethyl-L-arginine (L-NMMA, 0.5 mM) or N(G)-nitro-L-arginine-methyl-ester (L-NAME, 1 mM). Sodium nitroprusside (0.5 mM), an NO releaser, had no effect on basal GABA release but significantly decreased K(+)-evoked GABA release. L-NMMA (0.3 mM) and L-NAME (0.5 mM) increased K(+)-evoked GABA release, indicating that NO plays an inhibitory role in GABA release from PP. The inhibition in both basal and K(+)-evoked GABA release induced by NKA (10(-7) M) was reduced by L-NAME (1 mM). Also, NKA (10(-7) M) increased NO synthesis as measured by [(14)C] citrulline production. Considered all together, our data indicate that NO may mediate the inhibitory effect of NKA on the release of both oxytocin and GABA from PP.
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PMID:Neurokinin A inhibits oxytocin and GABA release from the posterior pituitary by stimulating nitric oxide synthase. 1111 87

Antioxidants and antioxidant enzymes are known to protect against cell death induced by reactive oxygen species. However, apart from directly quenching free radicals, little is known about the effect of antioxidants on hormone-activated second messenger systems. We previously found that antioxidants such as 17-beta estradiol and resveratrol activate membrane-bound guanylate cyclase GC-A, the receptor for atrial natriuretic factor (ANF), in PC12 cells. It is possible that other antioxidants may also activate membrane-bound guanylate cyclase GC-A. The aim of this study was to determine if dithiothreitol (DTT), vitamin C, and vitamin E activate membrane-bound guanylate cyclase GC-A in PC12 cells. The results showed that both DTT and vitamin C increased cGMP levels in PC12 cells, whereas vitamin E had no effect. DTT and vitamin C inhibited membrane-bound guanylate cyclase activity stimulated by ANF in PC12 cells. In contrast, DTT and vitamin C had no effect on soluble guanylate cyclase activity stimulated by substance P. Furthermore, NO synthase inhibitors L-NAME and aminoguanidine did not affect DTT- and vitamin C-stimulated guanylate cyclase activity. The results indicate that DTT and vitamin C, but not vitamin E, activate membrane-bound guanylate cyclase GC-A in PC12 cells.
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PMID:Antioxidants, vitamin C and dithiothreitol, activate membrane-bound guanylate cyclase in PC12 cells. 1127 22

This study investigates whether nitric oxide (NO) is involved in the anxiogenic profile of action of substance P (SP) in mice in the elevated plus-maze (EPM). Adult Swiss mice were injected with NOS inhibitors such as L-NOARG (20 nmol/kg) i.p., L-NAME (3 nmol per site), 7-NI (0.25 nmol per site) i.c.v. or vehicle (NaCl 0.9% i.p. or PBS i.c.v.). About 30 min (i.p. pretreatment) or 5 min later (i.c.v. pretreatment), the animals received i.c.v. injections of SP (10 pmol) or phosphate buffered saline (PBS) (2 microl). Afterwards, they were observed in the EPM. SP per se reduced the time spent on open arms, an anxiogenic-like effect. This effect was reverted by different NOS inhibitors and the NO donor. NOS inhibitors had no influence on the EPM parameters but the NO-releasing compound SNAP, as well as its parent thiol NAP, increased the animals' locomotor activity. 8-Br-cGMP (20 nmol), a permeable cGMP analog, promoted an anxiogenic-like effect per se and enhanced the SP effect on the EPM. Altogether, these results suggest a putative NO role in the mediation of the anxiogenic-like effect of SP.
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PMID:Nitric oxide involvement in the anxiogenic-like effect of substance P. 1127 97

Chronic administration of erythropoietin (EPO) is often associated with hypertension in animals and humans. The aim of this study was to estimate whether 1-week treatment with EPO can affect the vascular endothelial function. Rabbits were given with EPO (400 iu kg(-1) s.c.) or saline each other day for 1 week. Hypotensive responses to intravenously given acetylcholine (ACh), endothelium-independent nitric oxide donors (NOC7, nitroprusside and nitroglycerin) and prostaglandin I2 were tested before and after administration of N(G)-nitro-L-arginine methyl ester (L-NAME), a specific nitric oxide synthase inhibitor, under pentobarbitone anaesthesia. Blood haemoglobin concentration in EPO group was significantly higher than that in control group, whereas baseline values of aortic pressure, heart rate and femoral vascular resistance were similar. The dose of ACh (172 ng kg(-1)) requiring for a 15 mmHg hypotension from the baseline in EPO group was apparently higher than that (55 ng kg(-1)) in control group. On the contrary, hypotensive responses to NOC7, nitroprusside, nitroglycerin and prostaglandin I2 were comparable between two groups. The extent of ACh-induced hypotension did not correlate with haemoglobin concentration. L-NAME significantly inhibited the ACh-induced vasodilating response in control group but did not in EPO group. In another set of rabbits, the same treatment with EPO also decreased vasodilating responses to carbachol, bradykinin and substance P besides ACh as compared with control group. These results indicate that 1-week treatment with EPO selectively attenuates depressor responses to endothelium-dependent vasodilators in anaesthetized rabbits, most likely due to inhibition of endothelial nitric oxide synthase.
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PMID:Effect of 1-week treatment with erythropoietin on the vascular endothelial function in anaesthetized rabbits. 1137 56

In the gastrointestinal tract, tachykinin NK(2) receptors are localized both on smooth muscle and nerve fibres. NK(2) receptor antagonists reduce exaggerated intestinal motility in various diarrhoea models but the site of action contributing to this effect is unknown. In this study we investigated the effects of atropine (1.4 micromol kg(-1), i.v.), hexamethonium (13.5 micromol kg(-1), i.v.), and nepadutant (0.1 micromol kg(-1), i.v.), a selective tachykinin NK(2) receptor antagonist, on distension (0.5 and 1 ml)-, or irritation (acetic acid, 0.5 ml of 7.5% v v(-1))-induced motility in the rat distal colon in vivo. The effects of atropine, hexamethonium or N(omega)-nitro-L-argininemethylester (L-NAME, 1.85 micromol kg(-1), i.v.) on [betaAla(8)]NKA(4-10) (10 nmol kg(-1), i.v.)-induced colonic contractions were also investigated. When the colonic balloon was filled with a subthreshold volume (0.5 ml), the intraluminal instillation of acetic acid triggered a high-amplitude phasic colonic motility which was partially reduced by nepadutant and suppressed by either hexamethonium or atropine. Filling of the balloon with 1 ml evoked reflex (hexamethonium-sensitive), atropine-sensitive phasic colonic motility: nepadutant had no significant effect on the distension-evoked motility. Neither hexamethonium nor atropine significantly reduced [betaAla(8)]NKA(4-10)-induced colonic contractions, whereas nepadutant suppressed them. Following L-NAME pretreatment, [betaAla(8)]NKA(4-10)-induced colonic contractions were inhibited by both atropine and hexamethonium. In hexamethonium-pretreated animals, an atropine-sensitive component of [betaAla(8)]NKA(4-10)-induced colonic contractions was also evident. These results indicate that the application of irritants onto the colonic mucosa induces the release of endogenous tachykinins which enhance excitatory cholinergic mechanisms through the stimulation of NK(2) receptors.
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PMID:Tachykinin NK(2) receptors and enhancement of cholinergic transmission in the inflamed rat colon: an in vivo motility study. 1148 22

It has been reported that several bronchoconstrictors generate nitric oxide (NO), counteracting bronchoconstriction, and removal of bronchial epithelia reduces NO production. However, it has not been elucidated whether neurokinin A (NKA), a potent bronchoconstrictor liberated from nerve terminals, generates NO. Specific questions in this study were (1) does NKA also generate NO, (2) does NO counteract NKA-induced bronchoconstriction, and (3) does the NO generation require bronchial epithelial cells? In an in vivo study exogenous as well as endogenous (capsaicin-induced) NKA increased airway opening pressure (P(ao)) and the exhaled NO level, and both were inhibited by an antagonist selective for NK(2) receptor (a receptor for NKA), SR48968. The exhaled NO level became negligible with an inhibitor of NO synthase (NOS) type 1-3 (N(G)-nitro-L-arginine methyl ester, L-NAME) with increased P(ao), but not with a NOS type 2 inhibitor. In an in vitro study, NKA increased the nitrite/nitrate level in superfused fluid of tracheal segments. Removing smooth muscle reduced nitrite/nitrate in the fluid to negligible levels, while the level was unchanged with removal of the epithelia. Pretreatment with l-NAME enhanced the tension of epithelia-removed tracheal segments. These findings indicate that (1) NKA generates NO, (2) NO counteracts NKA-induced bronchoconstriction, and (3) NKA activates NOS in the muscle layer, independently of bronchial epithelia.
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PMID:Nitric oxide is generated in smooth muscle layer by neurokinin A and counteracts constriction in guinea pig airway. 1158 61

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