UNIPROT:P20366 - FACTA Search

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)

The possibility that pituitary adenylyl cyclase-activating peptide (PACAP) is an inhibitory neurotransmitter has been investigated in the taenia of the guinea-pig caecum. The action of PACAP on muscle contractility and its ability to alter levels of adenosine-3':5'-cyclic monophosphate (cyclic AMP) and guanosine-3':5'-cyclic monophosphate (cyclic GMP) were investigated. PACAP-1-27 was an effective agonist, giving relaxations comparable in magnitude to isoproterenol; its EC50 was 3.4 x 10(-7) M. PACAP (10(-6) M) caused an almost two-fold increase in cyclic AMP levels; but the level of cyclic GMP was not affected. The relaxation caused by PACAP was slow in onset, with a latency of 5.8 +/- 0.8 s and reached a maximum at 9.1 +/- 1.1 s after onset. The relaxation was significantly reduced by apamin (10(-6) M) and suramin (10(-4) M) but was not reduced by tetrodotoxin (10(-7) M). Relaxation of the taenia coli caused by electrical stimulation of the inhibitory nerves was greatly reduced by apamin but only slightly reduced by suramin. PACAP-like immunoreactivity (-IR) was localised immunohistochemically in varicose nerve fibres within the taenia coli and in the underlying myenteric plexus and circular muscle. Approx. 50% of vasoactive intestinal peptide (VIP)-IR nerve fibres in the taenia also had immunoreactivity for PACAP; conversely, almost all PACAP-IR fibres were immunoreactive for VIP. PACAP-IR and substance P (SP)-IR were generally in separate fibres; only about 5% of SP-IR fibres were PACAP-IR. Radioimmunoassay revealed tissue concentrations of PACAP-1-27 and PACAP-1-38 of 1.0 +/- 0.1 and 2.1 +/- 0.3 (SEM) pmol/g wet weight of tissue, respectively. Material with PACAP-1-27 immunoreactivity co-eluted with authentic PACAP-1-27 on gel filtration chromatography, and PACAP-1-38 immunoreactivity also co-eluted with the authentic peptide. This study provides structural, chemical and pharmacological evidence that PACAP could be involved in inhibitory neurotransmission to the taenia coli of the guinea-pig caecum.
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PMID:Histochemical, pharmacological, biochemical and chromatographic evidence that pituitary adenylyl cyclase activating peptide is involved in inhibitory neurotransmission in the taenia of the guinea-pig caecum. 771 25

Changes in substance P (SP) receptor concentration have been implicated in neuropsychiatric disorders, Parkinson's disease, arthritis, inflammatory bowel disease and asthma. Since, SP and peptide analogs are rapidly metabolized and do not penetrate into the CNS, they are not useful for PET. Recently, a non-peptide SP antagonist, (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994) was developed. As a prelude to PET studies, this compound was radiolabeled with 11C and biodistribution was determined in hamsters. CP-99,994 was radiolabeled by methylation of tert-Boc, desmethyl CP-99,994 with 11CH3I followed by deprotection and HPLC purification. The time required for the synthesis was 40 min from the end of bombardment. Radiochemical purity of the final product was > 95% and specific activity was routinely > 1000 mCi/mumol [EOS]. The biodistribution of 11C-CP-99,994 was determined in groups of six Syrian hamsters at 5 and 30 min after injection. The results of these studies demonstrated that significant concentrations (%ID/g +/- SEM) of CP-99,994 accumulate in most tissues of the hamster. The highest levels of drug were detected in the lung: 21.04 +/- 1.26 (5 min) and 13.49 +/- 1.71 (30 min). Brain accumulation was: 1.44 +/- 0.06 (5 min), 1.32 +/- 0.05 (30 min). These results indicate that 11C-CP-99,994 can be prepared in high purity and specific activity. This new radiopharmaceutical may be useful for studying both central and peripheral SP receptors by PET.
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PMID:Synthesis of a 11C-labeled NK1 receptor ligand for PET studies. 773 67

Reperfusion of ischaemic intestine is characterised by an initial hyperaemia with ensuing mucosal repair. This study investigated possible roles for gut vasoactive neuropeptides and trophic peptides in these phenomena. Groups of rats were monitored during superior mesenteric artery occlusion for five or 20 minutes, with or without subsequent reperfusion for five minutes. Peptide concentrations (fmol/ml) in arterial blood, were measured using specific radioimmunoassays. Intestinal ischaemia alone did not cause haemodynamic disturbance or peptide release. Reperfusion, after five minutes of ischaemia, resulted in arterial hypotension and a rise in plasma vasoactive intestinal polypeptide (mean (SEM)) (37 (3), control 11 (4), p < 0.001). After 20 minutes of ischaemia, reperfusion resulted in greater hypotension (p < 0.05) and release of both vasoactive intestinal polypeptide (31 (3), p < 0.05 v control) and the more potent vasodilator beta-calcitonin gene related peptide (49 (3), control 23 (1), p < 0.001). By contrast, the vasodilators alpha-calcitonin gene related peptide and substance P and the vasoconstrictors neuropeptide Y, peptide YY, and somatostatin were not released. Bombesin, a stimulatory neuropeptide, was released after 20 minutes of ischaemia/reperfusion (13 (2), control 7 (3), p < 0.05). Plasma enteroglucagon rose from control (51 (4)) to 110 (16) (p < 0.001) and to 158 (27) (p < 0.005) after five and 20 minutes of ischaemia/reperfusion. The potent enteric vasodilators vasoactive intestinal polypeptide and beta-calcitonin gene related peptide, unopposed by vasoconstrictors, may promote post-ischaemic intestinal hyperaemia. The rise in plasma enteroglucagon may point to diffuse mucosal injury and is consistent with the putative trophic role of this peptide.
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PMID:Release of vasodilator, but not vasoconstrictor, neuropeptides and of enteroglucagon by intestinal ischaemia/reperfusion in the rat. 782 5

A decrease in the airways' nonadrenergic noncholinergic inhibitory (NANC-i) system is one of the mechanisms that may contribute to allergen-induced changes in neural control within airways. We measured the airways' neurally mediated contractile and relaxant (NANC-i) responses in tracheal segments and left mainstem bronchus (LMB) from normal (control), immune (ragweed sensitized), and immune challenged rabbits. Immune rabbits were sensitized to mixed ragweed extract through parenteral injections from birth, while the immune challenged group had an additional airway exposure to aerosolized ragweed 48 hours prior to the in vitro studies. Neurally mediated contractile responses to electrical field stimulation (EFS) were increased in the immune challenged group, with the increase most significant in tracheal smooth muscle at a stimulation frequency of 20 Hz. To assess NANC-i responses, airway smooth muscle (ASM) segments from these groups were placed in tissue baths containing atropine (10(-6) M) and propranolol (5 x 10(-6) M). After contraction of the tissue with neurokinin A (NKA, 10(-5) M), the NANC-i response to EFS at 20 Hz was measured and reported as the mean (+/- SEM) percent relaxation. No significant differences were seen in the contractile responses of ASM segments to NKA among the three groups. The tracheal segments showed a significantly different NANC-i relaxation response among all groups: in the control group, 29.1 +/- 3.7; in the immune group 15.8 +/- 2.3%; and in the immune challenged group, 2.1 +/- 4.2%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Decrease in the airways' nonadrenergic noncholinergic inhibitory system in allergen sensitized rabbits. 805 23

In a previous study we have shown that inhibition of the endogenous neuropeptide-degrading enzyme, neutral endopeptidase (NEP), potentiates airway narrowing to neurokinin A (NKA) in normal humans in vivo. In the present study, we tested the hypothesis that hyperresponsiveness to NKA in asthma is caused by a reduction in endogenous NEP activity. To that end, we used the NEP inhibitor, thiorphan, or placebo as inhaled pretreatment to NKA challenge in eight atopic asthmatic men, who were controlled by on-demand usage of beta 2-agonists alone. The dose of thiorphan pretreatment was obtained from pilot experiments in which 0.5 ml of a 2.5-mg/ml concentration appeared to be the maximally effective nebulized dose. Dose-response curves to inhaled NKA (1 to 125 micrograms/ml, 0.5 ml/dose) were recorded on 2 randomized days 1 wk apart, in a cross-over study. To detect any effects of thiorphan on bronchoconstriction per se, we also investigated the effect of thiorphan or placebo on the dose-response curve to inhaled methacholine in a separate set of experiments. The response was measured by FEV1 and by partial expiratory flow-volume curves (V40p). The position of the dose-response curves was expressed as the concentration causing a 20% fall in FEV1 (PC20FEV1) or a 40% fall in V40p (PC40V40p). Baseline FEV1 and V40p were not affected by either pretreatment (p > 0.06). PC20FEV1 and PC40V40p to NKA were significantly lower after thiorphan pretreatment as compared with placebo (mean difference +/- SEM: 2.3 +/- 0.6 and 1.6 +/- 0.5 doubling dose, respectively; p < 0.015).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neutral endopeptidase activity and airway hyperresponsiveness to neurokinin A in asthmatic subjects in vivo. 825 86

Treating rats with the glucocorticoid dexamethasone has been shown to reduce the amount of plasma extravasation produced in the trachea by tachykinins released from sensory nerves. We sought to determine whether dexamethasone works by increasing the activity of neutral endopeptidase (NEP), the principal enzyme thought to be responsible for degrading tachykinins in the airways. Rats were treated for 2 days with either saline or 4 mg/kg/day of dexamethasone, a dose we found to be maximally effective in reducing tachykinin-induced plasma extravasation. The tracheas were then removed and processed to reveal NEP-specific histofluorescence. Tissue sections were photographed through a fluorescence microscope, and the relative intensity of fluorescent staining was quantified in five regions of the tracheal wall using computerized image analysis. In the saline-treated rats, the rank order of fluorescent staining was perichondrium > chondrocytes = submucosal >> epithelium > lamina propria. Neither the amount nor distribution of NEP fluorescence was altered in the dexamethasone-treated rats. Biochemical measurements of NEP activity in tracheal homogenates (nmol product/h/mg protein) likewise revealed no significant difference between the two groups (34.1 +/- 3.5 vs 29.0 +/- 3.2; mean +/- SEM, n = 8). These findings suggest that dexamethasone may be working through a mechanism unrelated to NEP activation.
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PMID:Effect of dexamethasone treatment on the regional distribution of neutral endopeptidase activity in the rat trachea. 858 63

The tachykinins substance P and neurokinin A (NKA) are present in sensory airway nerves and have been implicated in the pathogenesis of asthma. FK224 is a cyclopeptide tachykinin antagonist previously shown to inhibit both tachykinin NK-1 and NK-2 receptor mediated airway responses in guinea pigs. Inhaled FK224 protected against bradykinin-induced bronchoconstriction and cough in asthmatics. In this study we examined the reproducibility of the NKA challenge and the effect of inhaled FK224 on NKA-induced bronchoconstriction in 10 patients with stable asthma. On Day 1 baseline lung function and PC20 methacholine were determined. On Days 2 and 3 increasing doubling concentrations of NKA (3.3 x 10(-9) to 1.0 x 10(-6) mol/ml) were administered via inhalation, with intervals of 10 min. On both days NKA caused a concentration-dependent decrease in specific airways conductance (sGaw) and FEV1. Mean +/- SEM, log PC35, sGaw NKA (mol/ml) was -6.61 +/- 0.10 on Day 2 and -6.57 +/- 0.14 on Day 3 (not significant [NS]). On Days 4 and 5 FK224 (4 mg) or placebo (P) was administered via metered-dose inhaler 30 min before NKA challenge in a double-blind, crossover manner. The study medication was well tolerated. FK224 had no significant effect on baseline lung function. After P and FK224, NKA caused a comparable concentration-dependent bronchoconstriction. The mean +/- SEM log PC35 sGaw NKA (mol/ml) was -6.04 +/- 0.18 after P and -6.19 +/- 0.23 after FK224 (NS). In conclusion, inhaled FK224 had no effect on baseline lung function and offered no protection against NKA-induced bronchoconstriction in a group of mild asthmatic patients.
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PMID:The effect of inhaled FK224, a tachykinin NK-1 and NK-2 receptor antagonist, on neurokinin A-induced bronchoconstriction in asthmatics. 866 34

The effects of substance P (SP) and the selective NK1 receptor agonist [Sar9Met(O2)11] substance P on neonate rat spinal motoneurones were examined using intracellular recordings. Bath-administration of SP (0.1-3 microM) or [Sar9Met(O2)11] substance P (0.01-3 microM) induced a tetrodotoxin (TTX)-insensitive (10 microM) depolarization and a tetraethylammoniumchloride (TEA)-sensitive (3 mM) decrease in membrane conductance. The duration of the slow afterhyperpolarizations (AHPs) following the action potentials were significantly reduced (p = 0.003) by both NK1 receptor agonists. The mean duration of the sAHPs (+/- SEM) in control was 67.8 +/- 6.3 ms whereas in the presence of SP and [Sar9Met(O2)11] substance P their duration was reduced to 41.7 +/- 4.6 ms. Low Ca2+ (0.2 mM)-containing artificial cerebrospinal fluid (ACSF) or addition of BaCl2 or CdCl2 (2 mM) reduced the durations of the slow AHPs by 55%. In the presence of these agents SP and [Sar9Met(O2)11] substance P practically abolished the remaining slow AHPs, suggesting that the agonists also reduce a calcium-independent current. None of the effects induced by the NK1 receptor agonists were antagonized by the NK1 receptor antagonists (+/-)-CP-96,345 (10 microM), RP 67580 (1 microM) or GR 82334 (3-5 microM). In conclusion this study demonstrates that SP and [Sar9Met(O2)11] substance P elicit their effects on NK1 receptors by modulating at least two potassium currents, namely IK and ICa(K).
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PMID:The effects of neurokinin-1 receptor agonists on spinal motoneurones of the neonatal rat. 879 15

Impairment of myocardial contraction ("myocardial stunning") occurs during reperfusion after short ischemic periods. Substance P (SP) is widely distributed in heart and can be released by various stimuli including myocardial hypoxia. Our previous study shows SP has a negative inotropic effect in guinea pig heart. The objective of this study was to investigate whether SP contributes to the myocardial stunning after brief global ischemia. Guinea pig hearts in a Langendorff preparation were subjected to 15 min of global ischemia followed by 60 min reperfusion. Experiments were performed without and with pretreatment with neurokinin-1 (NK1) receptor antagonists, spantide (10(-6)M) or CP-99,994-01 (10(-6)M) in order to study the role of SP. Experiments were also performed in hearts which were perfused with atropine, phentolamine, and nadolol (10(-6)M each) to examine the role of neurotransmitters and autonomic receptors. A group of hearts obtained from capsaicin-pretreated guinea pigs was also investigated. Left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), heart rate, and perfusion pressure were monitored. At the end of reperfusion, the LVDP of control hearts recovered to only 55 +/- 6% (+/- SEM) of preischemic baseline and the LVEDP increased significantly (P > 0.05). With pretreatment with spantide or CP-99,994-01, LVDP recovered to 88 +/- 2% or 78 +/- 2% of the preischemic baseline, respectively. The LVEDP of these hearts was not different from preischemic baseline and much smaller than in control hearts. There were no differences in heart rate and perfusion pressure compared to baseline among all groups. Similar results were obtained in hearts perfused with autonomic blockers. However, recoveries of LVDP and LVEDP were faster in hearts perfused with autonomic blockers during the first 10 min of reperfusion. Pretreatment with capsaicin also significantly improved recovery of LVDP and LVEDP. In conclusion, substance P is involved in postischemic myocardial dysfunction and neurokinin-1 receptors mediate this action. The NK1 receptor antagonists may be useful in prevention of "myocardial stunning".
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PMID:The role of substance P in myocardial dysfunction during ischemia and reperfusion. 893 6

The tachykinins, substance P (SP) and neurokinin A (NKA), are agonists for the NK(1) and NK(2) receptors, respectively. Tachykinins have various respiratory effects, including bronchoconstriction. This study characterizes tachykinin binding sites in the rabbit lung. We hypothesize that (2-[(125)I]iodohistidyl(1))Neurokinin A ([(125)I]NKA) interacts with NK1 and NK2 binding sites in the rabbit lung. The K d determined from saturation isotherms was 0.69 times/divided by 1.14 nM (geometric mean times/divided by SEM) and the B max was 4.15 + or - 0.22 femtomole/mg protein (arithmetic mean + or - SEM). Competitive inhibition studies with NKA, SP and various selective tachykinin agonists showed the rank order of potency; [beta-Ala(8)]-Neurokinin A 4-10 = SP >> NKA >> [Sar(9),Met(02)11]-Substance P. [beta-Ala(8)]-Neurokinin A 4-10, a selective NK(2) agonist, and SP inhibition of [(125)I]NKA binding were best described using a two-site model. Competitive inhibition studies using the selective nonpeptide NK(2) antagonist (SR 48968) and the selective nonpeptide NK(1) antagonist (CP 96,345) revealed Ki's of 5.5 nM and 8.1 nM, respectively. Our data therefore suggest that [(125)I]NKA binds to both the NK(1) and NK(2) receptors in the lung.
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PMID:Heterogeneity of tachykinin receptors in the rabbit lung. 918 53

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