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

The pharmacological mechanisms involved in the substance P (SP)-induced pulmonary oedema were studied in isolated perfused rabbit lungs. Substance P induced a dose-dependent increase in the capillary filtration coefficient (Kf,c), responsible for oedema. Atropine, hemicholinium-3 and ruthenium red pretreatment partly protected the lungs against SP effects, while tetrodotoxin and hexamethonium did not significantly modify them. (+/-)CP96,345, a NK1 receptor antagonist, completely inhibited the SP-induced increase in the Kf,c. Like SP, acetylcholine (ACh) and capsaicin also increased the Kf,c. Atropine and (+/-)CP96,345 completely blocked the oedema induced by both drugs. Tetrodotoxin and ruthenium red strongly inhibited the response to capsaicin and acetylcholine. It was concluded that SP-induced pulmonary oedema is in part mediated by a stimulating action on cholinergic efferent nerves, with subsequent release of endogenous acetylcholine. Acetylcholine can, in turn, stimulate the release of SP from excitatory non adrenergic, non cholinergic nerves. The effects induced by capsaicin and exogenous acetylcholine, thus endogenous SP, involve tetrodotoxin-sensitive mechanisms, while those produced by exogenous SP are tetrodotoxin-resistant.
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PMID:Mechanisms of substance P-induced pulmonary oedema in the rabbit: interactions between parasympathetic and excitatory NANC nerves. 861 9

Pituitary adenylate cyclase-activating peptide (PACAP)-like immunoreactivity was demonstrated by immunocytochemistry together with calcitonin gene-related peptide (CGRP)-like immunoreactivity in small to medium-sized neurons in the trigeminal ganglion and in nerve fibers in the iris, ciliary body, cornea, choroid and sclera of the rabbit eye. The regional distribution of PACAP-27- and PACAP-38-like immunoreactivity in the eye was studied by radioimmunoassay: the highest concentrations were found in the iris sphincter and ciliary body. The distribution pattern resembled that of CGRP-like immunoreactivity, which is a well-known constituent of sensory C-fibre neurons. Intravitreal injection of PACAP-27 or PACAP-38 induced conjunctival hyperemia, swelling of the anterior segment of the eye, miosis and breakdown of the blood-aqueous barrier, manifested as a marked aqueous flare response. Tetrodotoxin pretreatment inhibited the conjunctival hyperemia, the swelling of the anterior segment of the eye, and the miosis but not the aqueous flare response. The concentration of PACAP-like immunoreactivity in the aqueous humor was increased greatly following infrared irradiation of the iris, topical application of formaldehyde to the cornea, or intravitreal injection of endotoxin or bovine serum albumin. Also the concentration of CGRP-like immunoreactivity in the aqueous humor was increased greatly. Both in vivo and in vitro studies showed that capsaicin caused a parallel release of PACAP-like immunoreactivity and CGRP-like immunoreactivity from the uvea. Injection of PACAP-27 and PACAP-38 resulted in the release of CGRP-like immunoreactivity (and PACAP-like immunoreactivity) into the aqueous humor and PACAP-27 and PACAP-38 were also found to evoke tachykinin-mediated contractions of the isolated iris sphincter muscle, indicating that PACAP induces positive feedback on C-fibres. Thus, PACAP is a sensory neuropeptide in the eye. Since the PACAP-induced ocular responses mimicked the symptoms of inflammation, and since the PACAP-like immunoreactivity concentration in the aqueous humor was greatly increased following noxious stimulation, we suggest that it takes part in the inflammatory responses of the rabbit eye.
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PMID:Distribution and effects of pituitary adenylate cyclase-activating peptide in the rabbit eye. 863 27

1. In the progress of experiments aimed at evaluating the role of tachykinins as enteric nonadrenergic noncholinergic (NANC) transmitters, we noted that certain tachykinin receptor antagonists produce a relaxation of circular muscle strips in the rat small intestine. This study aimed to assess the nature of this response and to determine the receptor type involved. The majority of the experiments were performed in capsaicin- (10 microM for 15 min) pretreated mucosa-free circular muscle strips from the rat small intestine, in the presence of atropine (1 microM), guanethidine (3 microM) and indomethacin (10 microM). 2. Under isometric recording of mechanical activity, the tachykinin NK1 receptor antagonist SR 140,333 (0.1 microM) had no effect on resting tone or spontaneous activity in duodenal or ileal circular muscle strips. The NK2 receptor antagonists, MEN 10,627 (0.1 microM) and GR 94,800 (0.1 microM) produced, after a delay of 10-15 min, a relaxation which averaged 61 +/- 3 and 57 +/- 6% (n = 6 and 4, respectively) of the maximal response (Emax) to isoprenaline (1 microM). The effect of maximal concentrations of MEN 10,627 and GR 94,800 when applied together was non-additive. The relaxant effect of MEN 10,627 (0.1 microM) was similar in the absence and presence of apamin (0.3 microM) and L-nitroarginine (100 microM). 3. Under isotonic recording of mechanical activity, MEN 10,627 (10 nM-1 microM) produced a concentration- and time-related relaxation of duodenal strips. The maximal relaxation averaged 72 +/- 4 and 69 +/- 4% (n = 5 each) of Emax to isoprenaline (1 microM) and was achieved 15-20 or 20-30 min after application of 1.0 or 0.1 microM MEN 10,627, respectively. 4. Duodenal strips were relaxed by other NK2 receptor selective antagonists (values in parentheses are % of Emax to isoprenaline at the given concentration of antagonist) GR 94,800 (69 +/- 3% at 1 microM, n = 4), SR 48,968 (60 +/- 3% at 1 microM, n = 4) and MDL 29,913 (66 +/- 4% at 1 microM, n = 4). SR 48,965 (1 microM), the inactive enantiomer of SR 48,968, was without effect. The NK1 receptor selective antagonists, SR 140,333 (0.1 microM), FK 888 (10 microM) RP 67,580 (1 microM) and GR 82,334 (10 microM) were also without effect (n = 4-5). 5. A cocktail of peptidase inhibitors, thiorphan, bestatin and captopril (1 microM each) had no significant effect on tone or spontaneous activity of duodenal strips. In the presence of peptidase inhibitors, MEN 10,627 (1 microM) produced a relaxation of duodenal strips (72 +/- 6% of Emax to isoprenaline, n = 5), whilst GR 82,334 (10 microM, n = 6) had no significant effect. 6. The relaxant response to MEN 10,627 was preserved in mucosa-free strips not pre-exposed to capsaicin. Tetrodotoxin (1 microM), saxitoxin (1 microM), hexamethonium (100 microM) and omega-conotoxin (0.1 microM) had no significant effect on the resting tone of duodenal strips nor did they affect the relaxation to MEN 10,627. L-Nitroarginine (100 microM) increased the tone of the strips but did not affect the response to MEN 10,627. Nifedipine (1 microM) relaxed the strips by 62 +/- 4% (n = 4), but in its presence a small relaxant effect to MEN 10,627 (26 +/- 5%, n = 4) was still evident. 7. Under isotonic recording of mechanical activity along the longitudinal axis, MEN 10,627 (1 microM) produced a slowly developing relaxation (39 +/- 3% of Emax to isoprenaline; n = 6) of whole segments of rat duodenum. When similar experiments were performed on whole segments of rat proximal colon MEN 10,627 had no effect. 8. The present findings document the observation that tachykinin NK2 receptors contribute to the maintenance of resting tone of the rat isolated small intestine. We found no evidence to suggest that this effect follows the blockade of the contractile effect of spontaneously released endogenous tachykinins. The present findings raise the possibility that constitutively active NK2 receptors account for the relaxant effect produced by NK2 receptor ant
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PMID:Evidence that tachykinin NK2 receptors modulate resting tone in the rat isolated small intestine. 881 52

The role of trout substance P (tSP) and neurokinin A (tNKA) in cardiovascular regulation was investigated in the rainbow trout, Oncorhynchus mykiss, in vivo and in vitro. In vivo, the coeliac arterial and ventral aortic relative blood flows were measured with Doppler flow probes, and blood pressure was measured via a cannula inserted into the dorsal aorta. tSP (0.1 and 1 nmol kg-1) and tNKA (1 nmol kg-1) increased both systemic and coeliac vascular resistances, leading to hypertension and bradycardia. In addition, cardiac output was decreased. The mammalian NK1 tachykinin receptor antagonist CP-96,345 did not affect the responses to tSP or tNKA. In vitro perfusions of the dorsal aortic and coeliacomesenteric vascular beds were performed using peristaltic pumps. The dorsal aortic vascular resistance was dose-dependently increased following infusion of the two peptides (pD2 values 7.6 +/- 0.1 and 7.3 +/- 0.1 for tSP and tNKA, respectively). Tetrodotoxin did not affect the tSP-induced hypertension. Increases in coeliac vascular resistance caused by tSP was correlated with stomach contractions when measurement of intragastric pressure was made using an inserted balloon. In conclusion, native SP and NKA are potent vasoconstrictors of rainbow trout vasculature, a property quite unusual to tachykinins compared with the vasodilation normally seen in mammals.
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PMID:Vasoconstrictive effects of native tachykinins in the rainbow trout, Oncorhynchus mykiss. 882 8

Repeated oesophageal acidification is a definitive feature of gastro-oesophageal reflux disease, which in turn is caused by relaxation of the lower oesophageal sphincter (LOS). This study in anaesthetised ferrets investigates the reflex pathways involved in effects of oesophageal acidification on motor function of the LOS, with particular focus on the role of tachykinins. LOS pressure was monitored with a perfused micromanometric sleeve assembly. Oesophageal acidification reduced LOS pressure by 48 +/- 5% until washout with saline. This reduction became larger with repeated tests, and was unaffected in amplitude by acute bilateral vagotomy, although the response became slower in onset. Intra-oesophageal capsaicin (0.5% solution) caused a 68 +/- 17% decrease in LOS pressure which remained unchanged with repeated tests. The NK-1 receptor antagonist CP96,345 (1-5 mg/kg intravenous (i.v.) blocked the post-vagotomy LOS responses to both intra-luminal acid and capsaicin. Close intra-arterial (i.a.) injections of capsaicin (1-100 micrograms) gut induced LOS relaxation which was neither vagally nor NK-1 receptor-mediated. Substance P or the selective NK-1 receptor agonist [Sar9, Met(O2)11] substance P (25-500 ng close i.a.) caused a biphasic LOS response, consisting of initial brief contraction followed by prolonged, dose-dependent relaxation. Tetrodotoxin (10 micrograms/kg close i.a.) changed the biphasic response to substance P to excitation only. The neurokinin-1 (NK-1) receptor antagonist CP96,345 (0.3-10 mg/kg i.v.) dose-dependently reduced the inhibitory response to substance P. The excitatory phase of the response to substance P was larger and prolonged after guanethidine (5 mg/kg, i.v.), or propranolol (1 mg/kg, i.v.). L-NAME (100 mg/kg i.v.) reduced the inhibitory phase. The selective NK-2 receptor agonist [beta-Ala8] neurokinin A(4-10) caused LOS excitation only. These data indicate that intra-oesophageal acid causes substance P release from extrinsic afferent nerve endings which activates local inhibitory pathways to the LOS via NK-1 receptors.
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PMID:Lower oesophageal sphincter responses to noxious oesophageal chemical stimuli in the ferret: involvement of tachykinin receptors. 940 24

1. We studied the effect of the natural tachykinins and of synthetic agonists selective for the tachykinin NK1, NK2 and NK3 receptors, on the motility of guinea-pig isolated common bile duct longitudinally-oriented smooth muscle. 2. All the tachykinins tested (both natural and synthetic) produced a concentration-dependent contractile response of the guinea-pig isolated common bile duct: these effects underwent a marked tachyphylaxis, especially the responses elicited by NK1 and NK3 receptor-selective agonists. 3. Among the natural tachykinins neurokinin B (EC50 = 3.2 nM; 95% c.l. = 2.0-5.1; n = 4) was the most potent, being about 40 and 25 fold more potent than substance P (EC50 = 121.6 nM; 95% c.l. = 94-157; P < 0.01; n = 4) and neurokinin A (EC50 = 83.4 nM; 95% c.l. = 62-112; P < 0.01; n = 4), respectively. Among the synthetic analogues the NK3 receptor-selective agonist senktide (EC50 = 1.1 nM; 95% c.l. = 0.7-1.8; n = 8) was the most potent, being about 120, 110 and 20 fold more potent than [Sar9]substance P sulfone (NK1 receptor-selective) (EC50 = 130.4 nM; 95% c.l. = 99-172; P < 0.01; n = 8), [beta Ala8]NKA (4-10) (NK2 receptor-selective) (EC50 = 120.1 nM; 95% c.l. = 95-151; P < 0.01; n = 8) and septide (NK1 receptor-selective) (EC50 = 22.6 nM; 95% c.l. = 18-28; P < 0.01; n = 8), respectively. All tachykinins (natural or synthetic receptor agonists) produced a similar Emax, averaging about 50% of that produced by KCl (80 mM). 4. Atropine (1 microM) did not affect the responses to either NK1 or NK2 receptor-selective agonists, whereas it reduced the Emax of senktide by about 50%, without affecting its potency (EC50). Tetrodotoxin (1 microM) totally blocked senktide-induced contractions, as did the combined pretreatment with atropine plus the tachykinin NK1 and NK2 receptor-selective antagonists GR 82334 and MEN 11420 (1 microM each), respectively. 5. GR 82334 (1 microM) blocked with apparent competitive kinetics septide- (apparent pKB = 7.46 +/- 0.10; n = 5) and [Sar9]substance P sulfone- (apparent pKB = 6.80 +/- 0.04; n = 4) induced contractions. MEN 11420 (30-300 nM), a novel potent NK2 receptor antagonist, potently antagonized [beta Ala8]NKA (4-10), with competitive kinetics (pKB = 8.25 +/- 0.08; n = 12: Schild plot slope = -0.90; 95% c.l. = -1.4; -0.35). The NK3 receptor-selective antagonist SR 142801 (30 nM) produced insurmountable antagonism of the senktide-induced contractions (Emax inhibited by 64%). None of the above antagonists, tested at the highest concentrations employed against tachykinins, affected the concentration-response curve to methacholine (0.1-300 microM). 6. We conclude that tachykinins produce contraction of the guinea-pig isolated common bile duct by stimulating NK1, NK2 and NK3 receptors. The responses obtained by activating NK1 and NK2 receptors are atropine-resistant. The contraction obtained by stimulating NK3 receptors is totally neurogenic, being mediated by the release of endogenous acetylcholine and tachykinins; the latter act, in turn, on postjunctional tachykinin NK1/NK2 receptors. The role of the NK3 receptor as prejunctional mediator of the excitatory transmission operated by tachykinins is discussed.
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PMID:Characterization of receptors mediating contraction induced by tachykinins in the guinea-pig isolated common bile duct. 942 8

1. Purinergic and cholinergic components of parasympathetic neurotransmission and contractile responses to exogenous alpha,beta-methylene ATP, acetylcholine, substance K, substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide and capsaicin have been investigated in the urinary bladder of hibernating hamsters (4 weeks), cold exposed (4 weeks) and age-matched controls. 2. Electrical field stimulation (EFS) evoked increased frequency-dependent contractions in the detrusor strips from hibernating hamsters compared with those obtained from cold-exposed and age-matched animals. Tetrodotoxin (10(-6) M) completely blocked the frequency-dependent contractions in all groups. 3. The purinergic component of the parasympathetic neurotransmission was not affected in hibernating and cold-exposed animals while the cholinergic component was increased with respect to age-matched animals. The neurogenic response to EFS, still present after incubation with atropine (10(-6) M) and suramin (10(-4) M), was attenuated by indomethacin (10(-6) M) and blocked by tetrodotoxin (10(-6) M). 4. Exogenous administration of alpha,beta-methylene ATP elicited a significantly reduced contraction in strips from hibernating and cold-exposed hamsters relative to age-matched animals. The contractile response to exogenous acetylcholine was greater in the detrusors from hibernating hamsters than in cold-exposed and age-matched animals. Substance K elicited reduced contractions in preparations from hibernating animals compared with cold-exposed and control animals. Calcitonin gene-related peptide, vasoactive intestinal polypeptide, substance P and capsaicin did not elicit any relaxant or contractile response either at resting tone or in carbachol (5 x 10(-7) M)-precontracted tissues. 5. In summary, our findings indicate that 4 weeks of hibernation can significantly increase neurogenic responses in the hamster urinary bladder. This appears to be due to an increase in postjunctional responses to acetylcholine. In contrast, there was a decrease of the postjunctional responses to the parasympathetic cotransmitter ATP and also to the sensory-motor neurotransmitter substance K.
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PMID:Neurogenic and non-neurogenic responses in the urinary bladder of hibernating hamster. 955 16

Substance P containing nerves are widely distributed throughout the gastrointestinal tract. The aims of this study were to determine the distribution of substance P containing nerves in the extrahepatic biliary tree of the Australian brush-tailed possum and to characterize the effect of exogenous substance P on the sphincter of Oddi (SO) motility and transphincteric flow in vivo. Immunohistochemical staining of fixed specimens (n = 8) found moderate numbers of substance P containing nerve cell bodies and fibres throughout the neural plexuses of the SO, in particular in the serosal and intraluminal nerve trunks of the SO and gallbladder. Synthetic porcine substance P (1-2000 ng kg-1), administered by close intra-arterial injection (i.a.; n = 7), produced a dose-dependent elevation in basal pressure [P < 0.01] and an associated dose-dependent reduction in trans-sphincteric flow [P < 0.0001]. Substance P had no significant dose-dependent effect on SO phasic contraction amplitude or frequency. Tetrodotoxin (9 micrograms kg-1, i.a.) did not inhibit the effect of substance P on SO motility and trans-sphincteric flow (n = 5). In conclusion, substance P containing nerves are found throughout the possum extrahepatic biliary tree. Exogenous substance P stimulates SO motility and reduces trans-sphincteric flow in vivo by acting directly on the sphincter smooth muscle.
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PMID:Substance P stimulates sphincter of Oddi motility and inhibits trans-sphincteric flow in the Australian brush-tailed possum. 961 75

We examined the effects of the muscarinic agonist carbachol on ion secretion induced by substance P (SP) in piglet jejunal tissues mounted in Ussing chambers. Tetrodotoxin was present in all solutions to inhibit neural activity. Carbachol added 10 min prior to 0.75 microM SP dose dependently inhibited subsequent SP responses, with 90% inhibition at 10 microM carbachol. Addition of an equipotent dose of SP (7.5 microM) had no effect on subsequent carbachol-induced secretion. Carbachol's inhibition of SP-induced secretion was evident for at least 45 min and was abolished by prior addition of the M3 receptor antagonist 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP), but remained intact in the presence of the M2 antagonist gallamine or the nicotinic antagonist mecamylamine. Atropine added 10 min after carbachol restored subsequent SP responses toward control levels. Carbachol also reduced secretory responses to histamine and, to a lesser extent, prostaglandin E2 (PGE2). SP-induced secretion was not affected by prior addition of histamine and was reduced by PGE2 only at the highest PGE2 concentration. The results suggest that activation of the epithelial M3 receptor by carbachol inhibits subsequent secretory responses to the calcium-mediated agonists SP and histamine in piglet jejunum. This may reflect muscarinic activation of a negative messenger in epithelial cells that limits Cl- secretion.
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PMID:Muscarinic inhibition of substance P induced ion secretion in piglet jejunum. 963 56

1. The effects of the tachykinin NK2 receptor antagonist MEN 11420 (100 nmol kg(-1), i.v.) and isoprenaline (400 nmol kg(-1), i.v.) were compared in a model of distension-induced bladder activity in isovolumetric conditions. MEN 11420 induced a relaxation of the basal tone of the urinary bladder that was dependent on the volume of the viscus: the effect was absent at low volumes (0.2 and 0.5 ml) and it was maximal at high volumes of distension (1 and 2 ml), approaching about 60% of the isoprenaline-induced relaxation. The relaxant effect of isoprenaline was always evident at all volumes of distension. 2. Tetrodotoxin (1-100 microM, intravesically applied) abolished distension-evoked micturition contractions, but did not prevent the relaxant effect of MEN 11420- or isoprenaline on the bladder tone. 3. The cyclo-oxygenase inhibitor S-ketoprofen (0.5 micromol kg(-1), i.v.) produced a marked decrease of the bladder tone and a concomitant reduction of bladder motility at 1 ml volume of distension. At 2 ml of distension, S-ketoprofen still decreased the minimal pressure but had no significant effect on other parameters of vesical motility. In S-ketoprofen-pretreated rats, the relaxant effect of MEN 11420 was significant at 2 but not at 1 ml of distension, and that of isoprenaline was reduced by 50% at both 1 and 2 ml. 4. Ruthenium red (10 micromol kg(-1), i.v.) had no effect at a low volume of distension (0.2 ml) or at highest volume (2 ml) but decreased the basal tone and the frequency of bladder contractions at 1 ml of distension. In ruthenium red-pretreated rats, MEN 11420 failed to decrease bladder tone at 1 ml, whereas at 2 ml the effect of MEN 11420 was not different from that observed in controls (43 vs 60% of isoprenaline-induced relaxation, respectively). 5. At both 1 and 2 ml of distension, capsaicin pretreatment (164 micromol kg(-1), s.c. 5 days before) reduced the frequency of micturition contractions but had no effect on the bladder tone. Capsaicin pretreatment prevented the relaxant effect of MEN 11420 on the bladder tone both at 1 and at 2 ml of distension. 6. It is concluded that the release of tachykinins from capsaicin-sensitive afferent nerves induced by bladder distension is resistant to tetrodotoxin and to prostaglandin synthesis inhibition. Tachykinins modulate the vesical tone by acting through NK2 receptors.
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PMID:Bladder distension and activation of the efferent function of sensory fibres: similarities with the effect of capsaicin. 964 41


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