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 GRP receptor mediated growth response in Swiss 3T3 cells has been used to identify BN/GRP antagonists. Analysis of bombesin antagonism by substance P analogues and by truncated GRP analogues revealed that deletion of the C-terminal methionine residue was important for antagonism. Des-Met analogues showing potent antagonist activity in the in vitro 3T3 system (IC50 approximately 2nM) were synthesized. Further structural modification of these peptides led to the identification of (CH3)2CHCO-His-Trp-Ala-Val-D-Ala-His-Leu-NHCH3 (ICI 216140) which reduced bombesin-stimulated rat pancreatic amylase secretion to basal levels when administered subcutaneously at 2.0 mg per kg.
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PMID:N-isobutyryl-His-Trp-Ala-Val-D-Ala-His-Leu-NHMe (ICI 216140) a potent in vivo antaconist analogue of bombesin/gastrin releasing peptide (BN/GRP) derived from the C-terminal sequence lacking the final methionine residue. 255 38

1. The effect of 5-hydroxytryptamine (5-HT) was studied on excitatory neurally mediated non-adrenergic non-cholinergic (NANC) contractions evoked by electrical field stimulation (EFS) in guinea-pig isolated bronchi. 2. 5-HT (0.1-100 microM) produced a concentration-dependent inhibition of the excitatory NANC response with 50.9 +/- 5.0% (n = 5, P < 0.01) inhibition at 100 microM. This inhibition was not significantly affected by the 5-HT2 antagonist, ketanserin (1 microM) when inhibitions (+/- ketanserin) at each concentration of 5-HT were compared by unpaired t tests; however, this concentration appeared to produce a leftward shift (approximately 10 fold) of the 5-HT concentration-inhibition curve. Ketanserin (1 microM) was effective in blocking bronchoconstriction evoked by activation of 5-HT2A receptors on airway smooth muscle. In the presence of ketanserin (1 microM) 5-HT (100 microM) evoked an inhibition of 57.4 +/- 5.9% (n = 5, P < 0.01) with an EC50 of 0.57 microM. 3. Inhibition evoked by 5-HT (0.1-100 microM) was unaffected by the alpha-adrenoceptor antagonist phentolamine (1 microM), the beta 2-adrenoceptor antagonist, ICI 118551 (0.1 microM), the 5-HT1A/B antagonist, cyanopindolol (1 microM) or the 5-HT3/4 antagonist, ICS 205-930 (1 microM). 4. Methiothepin (0.1 microM) produced an insurmountable inhibition of the effect of 5-HT (0.1-100 microM), reducing the maximum inhibition produced by 5-HT (100 microM) to 30.2 +/- 5.0% (n = 5, P < 0.001) and suggesting a non-competitive antagonism. Methiothepin inhibited the effect of 5-HT (10 microM) in a concentration-dependent manner with an IC50 of 81 nM. 5. Selective 5-HT receptor agonists were also tested on excitatory NANC responses. 5-Carboxamidotryptamine (5-CT, 0.1-100 MicroM) was the most potent, producing a concentration-dependent inhibition with an EC50 of 0.13 MicroM. Calculation of approximate IC25 values (concentration of the agonist required to give a 25% inhibition of the excitatory NANC response) gave a rank order of potency 5-CT > 5-HT> > 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) >alpha-methyl-5-hydroxytryptamine (alpha-Me-5HT). Sumatriptan, 5-methoxytryptamine (5-MeOT) and 2-methyl-5-hydroxytryptamine (2-Me-5HT) were essentially inactive with IC25> 100 MicroM.6. 5-HT (10 microM) did not significantly affect contractile responses to exogenously applied substance P(1 nM-10 Microm).7. The effect of 5-HT was unchanged after incubation with the nitric oxide (NO) synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 100 Microm). However, pretreatment with charybdotoxin (ChTX,0.1-30 nM), a blocker of the large conductance Ca2+-activated K+channel (K+ca), produced a concentration-dependent inhibition of the effect of 5-HT (10 MicroM).8. 5-HT evokes a concentration-dependent inhibition of e-NANC bronchoconstriction in guinea-pig isolated bronchi but does not affect cumulative concentration-dependent contractile responses to substance P, suggesting that inhibition is via a prejunctional receptor. Effects of selective antagonists and agonists suggest that an atypical 5-HT receptor mediates this inhibition. The inhibitory effect of 5-HT does not involve the production of NO, but may involve the opening a ChTX-sensitive K+ca channel.These data suggest that an atypical 5-HT receptor inhibits the release of neuropeptides from sensory C fibres and may act as other inhibitory neuromodulators via the opening of a common K'channel.
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PMID:Inhibition of excitatory non-adrenergic non-cholinergic bronchoconstriction in guinea-pig airways in vitro by activation of an atypical 5-HT receptor. 751 94

Many inflammatory mediators trigger the adhesion of leukocytes to the vascular endothelium. We sought to determine whether the beta 2-adrenergic receptor agonist formoterol can inhibit the adhesion of neutrophils and eosinophils to the endothelium of venules in the rat airway mucosa. We also tested whether this action is mediated by beta 2-adrenergic receptors. Inflammation was induced in the airways of anesthetized pathogen-free F344 rats by injecting substance P (5 micrograms/kg) or bradykinin (10 mg/kg) intravenously. The rats were perfused with fixative 5 min later, and the tracheas were removed. Adherent intravascular neutrophils and eosinophils, stained by a histochemical reaction for myeloperoxidase, were counted in tracheal whole mounts. We found that, after the injection of substance P, formoterol (0.1, 1.0, or 10.0 micrograms/kg i.v.) reduced the number of adherent neutrophils by 8, 59, or 56% and reduced the number of eosinophils by 59, 90, or 86%, respectively. The three doses of formoterol reduced the amount of substance P-induced extravasation of Monastral blue by 21, 66, or 80%, respectively. Both effects of formoterol were blocked by the beta 2-adrenergic receptor antagonist ICI-118,551, which by itself produced neither leukocyte adhesion nor plasma extravasation. After the injection of bradykinin, the three doses of formoterol reduced the number of adherent neutrophils by 28, 67, or 62% and reduced the number of eosinophils by 17, 38, or 57%, respectively. We conclude that formoterol, acting via beta 2-adrenergic receptors, not only can reduce the amount of plasma leakage but also can reduce the number of neutrophils and eosinophils that adhere to the vascular endothelium at sites of inflammation.
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PMID:Inhibition of neutrophil and eosinophil adhesion to venules of rat trachea by beta 2-adrenergic agonist formoterol. 752 29

Our previous studies have shown that the inhibition of neutral endopeptidase, an enzyme which degrades tachykinins, increases anaphylactic construction of guinea-pig tracheal smooth muscle. To investigate this observation further, we examined the effects of phosphoramidon, an inhibitor of a neutral endopeptidase, on constriction induced by the non-immunological mast cell degranulator-compound 48/80. Phosphoramidon produced significant leftward shift of the compound 48/80 concentration-response curve with corresponding decrease in the EC50 value from 51 (28-80) micrograms/ml to 42 (20-72) micrograms/ml. When added during the compound 48/80-induced constriction, phosphoramidon significantly increased the magnitude of this constriction by 69.7% after 30 min, and 78.9% after 45 min. Phosphoramidon was ineffective in tracheal rings from tachykinin-depleted guinea pigs. The incubation of tracheal rings with H1-histamine receptor antagonist (diphenhydramine HCl, 10 microM) and leukotriene receptor antagonist (ICI 198.615, 5 microM) significantly diminished the contractile response to compound 48/80 and prevented a phosphoramidon-dependent increase of this constriction. These results suggest that compound 48/80 induces the release of tachykinins by the stimulatory activity of histamine and leukotrienes. Anaphylactic release of tachykinins would therefore not depend directly on the antigen-antibody reaction.
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PMID:Inhibition of neutral endopeptidase potentiates compound 48/80-induced constriction of guinea-pig tracheal smooth muscle. 754 50

Nonadrenergic noncholinergic (NANC) contractile responses in guinea pig bronchi are due to the release of tachykinins from airway sensory nerves. The purpose of this study was to determine whether beta 2-receptor agonists modulate NANC contractions in guinea pig bronchi in vitro. Bronchial rings were suspended in organ baths for isometric measurement of tension, and comparable contractions were induced by electrical field stimulation (EFS; 40 V, 0.5 ms, 8 Hz for 20 s) or by exogenous substance P (3 microM). Aformoterol and salbutamol produced concentration-dependent inhibition of the NANC contraction, with aformoterol being ninefold more potent than salbutamol; approximate 50% inhibitory concentrations for aformoterol and salbutamol were 1.03 nM (n = 6) and 9.3 nM (n = 6), respectively. Aformoterol also inhibited the contraction induced by exogenous substance P but to a far lesser extent than its inhibition of EFS-induced responses. The inhibitory effects of formoterol (10 nM) on responses to EFS at 8 Hz were significantly prevented by propranolol (1 microM) and ICI 118551 (a beta 2-antagonist, 0.1 microM) but not by atenolol (a beta 1-antagonist, 1 microM) or phentolamine (10 microM). These experiments demonstrate that beta 2-agonists may modulate the release of tachykinins from airway sensory nerves by prejunctional receptors.
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PMID:Beta 2-adrenoceptor agonists inhibit NANC neural bronchoconstrictor responses in vitro. 768 10

We studied the effects of selective beta-adrenoceptor agonists on the cholinergic and non-adrenergic non-cholinergic (excitatory NANC) contractions elicited by electrical field stimulation of guinea pig main bronchi in vitro. Addition of the selective beta 2-adrenoceptor agonists, fenoterol and salbutamol, and the selective beta 3-adrenoceptor agonist, BRL 37344 (4-[2-[(2-hydroxy-2-(3-chlor-phenyl)ethyl)amino]-propyl]-phenoxyac etic acid), induced a dose-dependent inhibition of the cholinergic contraction (pD2 7.89, 6.71 and 4.56, respectively) and the excitatory NANC response (pD2 9.11, 8.16 and 7.42, respectively). Fenoterol- and BRL 37344-induced inhibition of the excitatory NANC response was blocked with high potency (pKB 8.77 and 9.07, respectively) by the selective beta 2-adrenoceptor antagonist, ICI 118,511 (erythro-1-(7-methylindan-4-yloxy)-3-(isopropylamino)-but an-2-ol). A comparable contraction induced by neurokinin A (2 or 5 nM) was also inhibited by fenoterol, salbutamol and BRL 37344, but at significantly higher concentrations than for the inhibition of the excitatory NANC response (pD2 8.72, 7.56 and 6.66, respectively). Such a preferential inhibition of electrical field stimulation- versus agonist-induced effects was not observed for cholinergic contractions (pD2 versus methacholine-induced tone 7.86, 6.93 and 5.10, respectively). The results clearly exclude the involvement of beta 3-adrenoceptors in these responses. Furthermore they show that beta 2-adrenoceptors are involved in the prejunctional inhibition of excitatory NANC contractions, presumably via modulation of tachykinin release from sensory nerves, and solely in the postjunctional inhibition of cholinergic contractions.
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PMID:Beta 2- but not beta 3-adrenoceptors mediate prejunctional inhibition of non-adrenergic non-cholinergic contraction of guinea pig main bronchi. 779 55

1. The pharmacological properties of the novel diarylacetamide kappa-opioid receptor agonist, EMD 61753, have been compared with those of ICI 197067 (a centrally-acting kappa agonist) and ICI 204448 (a peripherally-selective kappa agonist). 2. EMD 61753 binds with high affinity (IC50 5.6 nM) and selectivity (kappa:mu:delta:sigma binding ratio 1:536:125: > 1,786) to kappa-opioid receptors and is a full and potent (IC50 54.5 nM) agonist in an in vitro assay for kappa-opioid receptors (rabbit vas deferens preparation). 3. Systemically-applied [14C]-EMD 61753 is found in high concentrations in the lungs, liver, adrenal glands and kidneys. Considerably less radioactivity is detected in the whole brain, and this radioactivity is concentrated in the region of the cerebral ventricles in the choroid plexuses. EMD 61753 penetrates only poorly into the CNS. 4. EMD 61753 was weakly effective in pharmacological tests of central activity. This compound reversed haloperidolol-induced DOPA accumulation in the nucleus accumbens of the rat only at a dose of 30 mg kg-1, s.c., (doses of 0.1, 1.0 and 10 mg kg-1, s.c., and 1.0, 10 and 100 mg kg-1, p.o., were inactive). Hexobarbitone-induced sleeping in mice was prolonged by EMD 61753 at threshold doses of 10 mg kg-1, s.c., and 100 mg kg-1, p.o., whereas the motor performance of rats in the rotarod test was impaired by EMD 61753 with an ID50 value of 453 mg kg-1, s.c. 5. EMD 61753 produced dose-dependent, naloxone-reversible antinociception in the mouse formalin test (1st phase ID50 1.9 mg kg-1, s.c., and 10.4 mg kg-1, p.o.; 2nd phase ID50 0.26 mg kg-1, s.c., and 3.5 mg kg-1, p.o.) and rodent abdominal constriction test (ID50 mouse 1.75 mg kg-1, s.c., and 8.4 mg kg-1, p.o.; ID50 rat 3.2 mg kg-1, s.c., and 250 mg kg-1, p.o.). EMD 61753 was inactive, or only weakly effective, in the rat pressure test under normalgesic conditions. After the induction of hyperalgesia with carrageenin, however, this compound elicited potent, dose-dependent (ID50 0.08 mg kg-1, s.c., and 6.9 mg kg-1, p.o., after remedial application, and 0.2 mg kg-1, s.c., and 3.1 mg kg-1, p.o., after prophylactic application) and naloxone-reversible antinociception. The antinociceptive action of systemically-applied (50 mg kg-1, p.o.) EMD 61753 in the hyperalgesic pressure test was completely inhibited by injection of the K-opioid antagonist norbinaltorphimine (100 Lg) into the inflamed tissue, a result which indicates that this opioid effect is mediated peripherally.6. Cutaneous plasma protein extravasation produced by antidromic electrical stimulation of the rat saphenous nerve was dose-dependently inhibited by systemically-applied EMD 61753 (ID13 values 3.7 mg kg-1, s.c., and 35.8 mg kg-1, p.o.), and this effect was completely antagonized by intraplantar application of norbinaltorphimine (50 microg). Extravasation elicited by the intraplantar application of substance P (10 microg) was not influenced by the administration of EMD 61753.7. EMD 61753 produced dose-dependent diuresis in non-hydrated rats at doses of and above 1.0 mg kg-1, s.c., and 10 mg kg-1, p.o., and in saline-loaded rats at doses of and above 10 mg kg-1, s.c.,and 30mgkg-1, p.o.8. The prostaglandin-mediated fall in mean arterial blood pressure elicited in anaesthetized rats by i.v.application of arachidonic acid was not inhibited by prior treatment with EMD 61753 (10mg kg-1,p.o.). Thus, a blockade of prostaglandin synthesis via inhibition of cyclo-oxygenase activity does not contribute to the in vivo effects of EMD 61753 and its metabolites.9 The present experiments therefore indicate that EMD 61753 is a potent, selective and orally-effective full ic-opioid receptor agonist which has a limited ability to penetrate the blood-brain barrier and elicit centrally-mediated sedation, putative aversion, diuresis, and antinociception. The inhibitory actions of systemically-applied EMD 61753 against hyperalgesic pressure nociception and neurogenic inflammation are mediated peripherally, probably by opioid receptors on the endings of sensory nerve fibres.
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PMID:A pharmacological profile of the novel, peripherally-selective kappa-opioid receptor agonist, EMD 61753. 788 87

1. The aim of the present study was to investigate the type of adrenoceptor which modulates constriction of the guinea-pig isolated main bronchus in response to electrical field stimulation (EFS). Drugs used were salbutamol and two agonists reportedly selective for the putative beta 3-adrenoceptor: BRL 37344 and SR 58611A. 2. At basal tone, all three drugs induced relaxation, however, SR 58611A and BRL 37344 (10(-9) to 10(-6) M) relaxed guinea-pig isolated main bronchus more weakly than salbutamol (10(-9) to 10(-6) M). The effects observed at 10(-6) M were 43% +/- 9%, 63% +/- 4% and 98% +/- 1% of the maximal effect induced by theophylline (3 x 10(-3) M) for SR 58611A, BRL 37344 and salbutamol, respectively. 3. SR 58611A and BRL 37344 (10(-8) to 10(-6) M) did not significantly modify the cholinergic component of the response to EFS, but caused a concentration-dependent reduction of the nonadrenergic non-cholinergic (NANC) excitatory component (41.8% +/- 10.1% and 56.8% +/- 7.4% respectively at 10(-6) M, n = 6-7). Salbutamol (10(-9) to 10(-7) M) strongly inhibited both components, with 91.1% +/- 4.2% of inhibition for the NANC contraction and 62.0% +/- 5.2% of inhibition for the cholinergic contraction (10(-7) M, n = 7). 4. Whereas the inhibitory effects of salbutamol were strongly inhibited by both propranolol (10(-6) M) and ICI 118,551 (10(-6) M), those of BRL 37344 were only slightly, albeit significantly reduced by both propranolol and ICI 118,551, and those of SR 58611A were unaffected by treatment with either beta-adrenoceptor antagonist. An alpha2-adrenoceptor antagonist, yohimbine, did not influence the inhibitory effects of any of the beta-adrenoceptor agonists tested.5. Concentration-response curves to acetylcholine (10-8 to 10-3 M), [Nle10]NKA(4-10) (10-10 to10-6 M) and substance P (10- to 3 x 10-6 M) were also significantly shifted to the right by salbutamol(10-6 M), whereas SR58611A and BRL37344 (10-6 M) had no effect.6. These results suggest that the stimulation of putative beta 3-adrenoceptors exerts a specific prejunctional inhibitory action on NANC excitatory response induced by EFS of the isolated main bronchus of the guinea-pig. They also suggest that a beta2-adrenoceptor agonistic component may be involved in the effects of BRL 37344.
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PMID:Effects of two beta 3-adrenoceptor agonists, SR 58611A and BRL 37344, and of salbutamol on cholinergic and NANC neural contraction in guinea-pig main bronchi in vitro. 790 68

Our previous studies have shown that the inhibition of neutral endopeptidase, an enzyme which degrades tachykinins, increases anaphylactic contraction of guinea pig tracheal smooth muscle. Anaphylactic release of tachykinin-like substances was indicated. To investigate this observation further, we examined the effects of phosphoramidon, an inhibitor of a neutral endopeptidase, on contraction induced by mediators of anaphylaxis. Phosphoramidon significantly increased histamine- and leukotriene D4-induced contractions of tracheal rings from unsensitized animals (by 14 and 48%, respectively), but failed to alter the contractile responses to prostaglandins D2 and F2 alpha. In tracheal rings preincubated with tachykinin antagonist-[D-Pro4, D-Trp7,9]-substance P(4-11), or in capsaicin-desensitized tracheal rings, phosphoramidon did not change histamine- and leukotriene D4-induced contractions. In the second part of the study, performed on tracheal rings obtained from ovalbumin-sensitized guinea pigs, we examined the effects of phosphoramidon on contractile responses to histamine and leukotrienes which are released after antigen challenge. The incubation of tracheal rings with H1-histamine receptor antagonist (diphenhydramine HCl) or leukotriene receptor antagonist (ICI 198.615) prevented a phosphoramidon-dependent increase of antigen-induced contraction. These results indicate that histamine and leukotrienes may be involved in the anaphylactic release of tachykinin-like substances or other neutral endopeptidase substratum.
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PMID:Phosphoramidon augments contraction of guinea pig tracheal smooth muscle induced by histamine and leukotriene-D4. 811 Dec 47

Guinea pigs mechanically hyperventilated with dry gas exhibit hyperpnea-induced bronchoconstriction (HIB) and hyperpnea-induced bronchovascular hyperpermeability (HIBVH). Tachykinins released from airway C-fiber neurons are the central mediators of guinea pig HIB but play only a contributory role in HIBVH. Recent studies suggest that eicosanoid mediators can provoke bronchoconstriction and bronchovascular hyperpermeability, are released by dry gas hyperpnea, and can themselves elicit or modulate tachykinin release. We therefore hypothesized that eicosanoids may participate in HIB and/or HIBVH. To test these hypotheses, we analyzed respiratory system resistance changes and Evans blue-labeled albumin extravasation into the airways of 60 tracheostomized and mechanically ventilated guinea pigs. Animals were subjected to 10 min of isocapnic dry gas hyperpnea or to quiet breathing of humidified gas and received as pretreatment either piroxicam, a cyclooxygenase (CO) inhibitor; A-63162, a 5-lipoxygenase (5-LO) inhibitor; BW-755c, a combined CO and 5-LO inhibitor; ICI-198,615, a leukotriene D4 receptor antagonist; or no drug. HIB was substantially (50-80%) reduced by each of the four eicosanoid-modulating drugs. In contrast, HIBVH was reduced only by BW-755c, and this effect occurred only within the extrapulmonary airways (42% reduction). These data indicate that both CO and 5-LO products, including leukotriene D4, participate in the pathogenesis of HIB but that, like tachykinins, they play only a small contributory role in HIBVH. Together with our previous demonstration that sensory neuropeptide release is critical for the occurrence of HIB, we conclude that the roles of eicosanoids and tachykinins in guinea pig HIB are interdependent.
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PMID:Role of eicosanoids in hyperpnea-induced airway responses in guinea pigs. 812 4


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