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)

1. In guinea-pig isolated bronchus treated with indomethacin (2.8 microM), electrical field stimulation (EFS; 10 Hz, 0.5 ms, 60-70 V, for 10 s) evoked a tetrodotoxin (3 microM)-sensitive, biphasic contraction comprising a rapid, atropine (1 microM)-sensitive cholinergic response succeeded by a slowly developing, capsaicin (10 microM)-sensitive, non-adrenergic, non-cholinergic excitatory (NANCe) response. 2. BRL 38227 (0.3-3 microM), salmeterol (0.003-3 microM) and ketotifen (1.0-300 microM) each produced concentration-dependent inhibition of both NANCe and cholinergic responses to EFS in guinea-pig isolated bronchus. 3. Substance P (SP; 1 microM) and neurokinin A (NKA; 0.07 microM) produced contractions equivalent in magnitude to the NANCe response to EFS, which were inhibited by salmeterol (1 microM), but not by BRL 38227 (3 microM) or ketotifen (100 microM). 4. Acetylcholine (ACh; 6 microM) was equi-effective with the electrical activation of cholinergic neurones. BRL 38227 (3 microM) slightly inhibited responses to ACh (6 microM). Salmeterol (1 microM) and ketotifen (100 microM) markedly inhibited responses to ACh (6 microM). 5. In bronchial rings pre-contracted with ACh (100 microM), BRL 38227 (0.1-30 microM), salmeterol (0.001-3 microM) and ketotifen (0.1-100 microM) each produced concentration-dependent relaxation. Unlike ketotifen, BRL 38227 and salmeterol only partially (18.8 +/- 2.1% and 51.8 +/- 3.9% respectively) reversed the ACh-induced contraction. 6. The (+)-analogue of BRL 38227, BRL 38226 (0.3-100 microM), was without effect on responses to EFS and had no effect on the inhibition caused by BRL 38227. The K+-channel activators pinacidil (3.0-30 microM) and RP 52891 (3.0-30 microM) exerted similar inhibitory actions on responses to EFS as BRL 38227, but were less potent. Glibenclamide (0.1-1.O microM) and phentolamine (3 microM) antagonized the inhibitory effects of BRL 38227 on responses to EFS.7. It is concluded that BRL 38227 and ketotifen can inhibit NANCe neuroeffector transmission at concentrations exerting little or no inhibitory effects on responses to exogenously applied tachykinins.By contrast, in addition to suppressing NANCe responses to EFS, salmeterol also markedly inhibits responses to SP and NKA. At concentrations markedly suppressing cholinergic neuroeffector transmission, BRL 38227 has only minor effects on responses to exogenously-applied ACh. Salmeterol and ketotifen both depress responses to ACh within the concentration-range over which they inhibit cholinergic responses to EFS. The inhibitory effects of BRL 38227 on responses to EFS exhibit stereo-specificity and may involve the opening of a neuronal K+-channel. This K+-channel is glibenclamide-and phentolamine-sensitive and appears similar to the smooth muscle K+-channel which is modulated by BRL 38227.
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PMID:Effects of BRL 38227 on neurally-mediated responses in the guinea-pig isolated bronchus. 150 20

1. The effects of rat- and human-CGRP and capsaicin were studied in isolated rings of rat proximal epicardial (PC) and distal intramyocardial (DC) coronary arteries. 2. The relaxing effect of rat-CGRP was dependent on the level of vessel tone induced by prostaglandin F2 alpha (PGF2 alpha) in PC but not in DC arteries. Submaximally contracted DC and PC arteries were more sensitive to rat- than human-CGRP. There was no difference in sensitivity to rat- and human-CGRP between PC and DC arteries. 3. Substance P elicited a small relaxation only in 4 of the 6 PC arteries tested. PC and DC arteries were concentration-dependently relaxed by capsaicin. The relaxation was partly inhibited by ruthenium red, thus suggesting that capsaicin causes specific release of CGRP from sensory nerve endings in rat coronary arteries. 4. The relaxant effect of rat-CGRP was antagonized by endothelium removal and indomethacin but not methylene blue in endothelium-intact PC arteries. The relaxation in DC arteries was not affected by any of these treatments, indicating a heterogeneous involvement of the endothelium in CGRP-mediated coronary vasodilatation and the release of a cyclo-oxygenase product in PC arteries in rats. 5. Glibenclamide had no inhibitory effect on the CGRP-induced relaxation of PC and DC arteries, thus excluding the involvement of glibenclamide-sensitive K(+)-channels in the mechanism of action of CGRP in rat coronary arteries.
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PMID:Heterogeneous involvement of endothelium in calcitonin gene-related peptide-induced relaxation in coronary arteries from rat. 171 22

Contractions induced by electrical field stimulation of sensory non-cholinergic excitatory nerves in guinea-pig isolated bronchi are due to the release of substance P (SP) and related tachykinins. Release of such neuropeptides are thought to play a pathophysiological role in asthma. Two K+ channel openers cromakalim (pD2 = 6.45; Emax = 95%) and pinacidil (pD2 = 6.06; Emax = 87%) were shown to concentration-dependently inhibit non-cholinergic nerve-mediated contractions in guinea-pig bronchi in vitro. Cromakalim (pD2 = 6.27; Emax = 25%) and pinacidil (pD2 = 6.03; Emax = 25%) each had a much lower inhibitory efficacy against contractions induced by exogenously applied SP but the same potency as found against contractile responses to non-cholinergic neurostimulation. Also the beta 2-adrenoceptor agonist terbutaline (pD2 = 8.29; Emax = 83%), the xanthine derivative theophylline (pD2 = 4.19; Emax = 100%) and the Ca2+ blocker verapamil (pD2 = 5.55; Emax = 100%) suppressed responses to non-cholinergic neurostimulation. Terbutaline (pD2 = 6.32; Emax = 74%), theophylline (pD2 = 3.25; Emax = 71%) and verapamil (pD2 = 4.01; Emax = 100%) had a 10-100-fold lower inhibitory potency against SP-induced contractions but each drug showed about the same efficacy as found against nerve-mediated contractions. Glibenclamide (1 microM) reversed the inhibitory effects of cromakalim and pinacidil on neurally-mediated contractions but did not influence the effects of terbutaline, theophylline and verapamil. The results demonstrate that cromakalim, pinacidil, terbutaline, theophylline and verapamil inhibit non-cholinergic excitatory neurotransmission in guinea-pig bronchi and suggest that they act preferentially at a pre-junctional site.
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PMID:Inhibition by cromakalim, pinacidil, terbutaline, theophylline and verapamil of non-cholinergic nerve-mediated contractions of guinea-pig isolated bronchi. 754 49

Perfusion of histamine (10(-3) M) elicited a significant increase of immunoreactive substance P release in the subcutaneous perfusate in the rat hindpaw. The active L-enantiomer of cromakalim, lemakalim (50 micrograms/kg, i.v.), a selective K+ channel activator, significantly inhibited the immunoreactive substance P release. Glibenclamide (10 mg/kg, i.v.), an ATP-sensitive K+ channel blocker, abolished the response to lemakalim on the release of immunoreactive substance P. R(-)-alpha-methylhistamine (1 mg/kg, i.v.), a specific histamine H3 receptor agonist, significantly inhibited the release of immunoreactive substance P. Glibenclamide (10 mg/kg, i.v.) antagonized the inhibitory effect of R(-)-alpha-methylhistamine. Tetraethylammonium (10 mg/kg, i.p.), a K+ channel blocker, also reduced the inhibitory effect significantly. These results suggest that the inhibition of substance P release from sensory nerve endings via prejunctional histamine H3 receptors may be achieved by activating the ATP-sensitive K+ channel coupled to the histamine H3 receptor in the rat skin.
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PMID:ATP-sensitive K+ channels mediate regulation of substance P release via the prejunctional histamine H3 receptor. 754 12

The effects of the potassium channel activators (KCA) levcromakalim and RP52891 on NANCe nerve-mediated changes in pulmonary dynamics were investigated in the anaesthetized guinea-pig, using a newly-developed respiratory dynamics computer. Levcromakalim (0.025-0.2 mg/kg i.v.) and RP52891 (0.05-0.5 mg/kg i.v.) caused dose-dependent inhibition of NANCe nerve-mediated increases in airways resistance (RAW) and decreases in dynamic compliance (Cdyn). These effects of the KCAs persisted for at least 1 h. Unlike NANCe nerve-mediated responses, equivalent challenges with exogenously-administered substance P (SP; 10-25 micrograms/kg i.v.) and neurokinin A (NKA; 0.5-2.0 micrograms/kg i.v.) tended to produce progressively increasing responses but this effect was not statistically significant. Levcromakalim (0.2 mg/kg i.v.) and RP52891 (0.5 mg/kg i.v.) did not significantly decrease responses to exogenously-administered SP, although NKA-induced bronchoconstriction was attenuated. Glibenclamide (25 mg/kg i.v.) partially reversed the NANCe-inhibitory effects of levcromakalim (0.1 mg/kg i.v.) and RP52891 (0.25 mg/kg i.v.) and fully reversed their hypotensive effects. We have shown that levcromakalim and RP52891 inhibit bronchoconstrictor responses to NANCe nerve stimulation. This involves the opening of a glibenclamide-sensitive K(+)-channel and may represent effects at a pre-junctional site on NANCe neurones to reduce transmitter release.
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PMID:Effects of levcromakalim and RP52891 on NANCe nerve-mediated changes in pulmonary dynamics evoked by vagal stimulation in the guinea-pig. 821 74

We examined the effect of ibudilast, an antiasthma drug, on neurogenic microvascular leakage in guinea-pig airways by measuring extravasation of Evans blue dye. After intravenous pretreatment with atropine (1 mg/kg) and propranolol (1 mg/kg), bilateral vagal stimulation significantly increased nonadrenergic noncholinergic (NANC)-mediated leakage of dye in the trachea (Tr), the main bronchi (MB), and the central (cIPA) and peripheral (pIPA) intrapulmonary airways. Ibudilast (1.0 to 100 micrograms/kg given intravenously) did not affect basal leakage, but it significantly inhibited NANC-mediated plasma extravasation in a dose-dependent manner, with a maximal inhibition of 74.0% (Tr, p < 0.05), 89.1% (MB, p < 0.05), 91.4% (cIPA, p < 0.01), and 84.3% (pIPA, p < 0.05) at 100 micrograms/kg. Plasma extravasation induced by exogenous substance P (1 microgram/kg given intravenously) was not inhibited by ibudilast. Glibenclamide, an inhibitor of ATP-sensitive potassium channels, blocked the inhibitory effect of ibudilast. We conclude that ibudilast inhibits neurogenic leakage by prejunctional inhibition of neuropeptide release from airway sensory nerve terminals via an ATP-sensitive potassium channel.
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PMID:Antiasthma drug, ibudilast, inhibits neurogenic plasma extravasation in guinea-pig airways. 834 8

I.v. bolus injections of vasoactive intestinal polypeptide (VIP) (0.3 or 1 microg/kg), calcitonin gene-related peptide (CGRP) (0.3 microg/kg) or substance P (0.1 microg/kg) to anesthetized rats reduced blood pressure, accompanied by slight increases in heart rate. Cromakalim (0.3 microg/kg/min) infused i.v. significantly potentiated the depressor responses to VIP and CGRP, but not those to substance P and acetylcholine (ACh) (0.1 microg/kg). Glibenclamide (20 mg/kg, i.v.) significantly inhibited not only the depressor responses to VIP and CGRP, but also the augmentation of the effects of the two agents by cromakalim. These results suggest that the depressor responses to VIP and CGRP are mediated in part through K(ATP) channel activation.
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PMID:Possible involvement of K(ATP) channel activation in depressor responses to vasoactive neuropeptides in rats. 954 Dec 88