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)

We investigated the effect of the putative beta 3 agonist BRL 35135 on non-adrenergic non-cholinergic (NANC) contractions in guinea-pig bronchial strips. BRL 35135 (10(-9) to 10(-6) M) did not alter the baseline tension but reduced NANC contractions induced by electrical field stimulation (EFS) in a concentration-dependent fashion without having a significant effect on the contraction induced by substance P (10(-6) M). BRL 35135 (10(-6) M) also reduced the contraction induced by capsaicin (10(-7) M). Likewise, BRL 37344 (10(-9) to 10(-6) M) reduced NANC contractions induced by EFS in a concentration-dependent fashion. While BRL 37344 up to concentrations of 10(-8) M did not alter the contraction induced by SP (10(-6) M), BRL 37344 (10(-8) M) significantly inhibited NANC contractions induced by EFS and capsaicin (10(-7) M), (P less than 0.01). The inhibitory effect of BRL 35135 (10(-6) M) on NANC contractions induced by EFS was not significantly altered by the non-selective beta-adrenoceptor antagonists, propranolol and pindolol (P greater than 0.10), by the beta 1-selective antagonists, atenolol and metoprolol (P greater than 0.20) (10(-8) to 10(-6) M), or by the alpha-adrenoceptor antagonist, phentolamine (10(-7) to 10(-5) M) (P greater than 0.50). These results suggest that beta 3 agonists exert a prejunctional inhibitory action on NANC contractions.
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PMID:Evidence that an atypical beta-adrenoceptor mediates the prejunctional inhibition of non-adrenergic non-cholinergic contraction in guinea-pig bronchi. 132 25

A potassium (K+) channel activator, BRL 38227, inhibited goblet cell secretion in guinea-pig trachea induced by either electrical stimulation of the vagus nerves or acute inhalation of cigarette smoke, two stimuli which activate both cholinergic nerves and capsaicin-sensitive sensory nerves. BRL 38227 failed to inhibit methacholine- or substance P-induced goblet cell secretion which suggests that K+ channel activators inhibit neurogenic goblet cell secretion via a prejunctional effect on cholinergic and sensory nerves.
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PMID:K+ channel activator inhibition of neurogenic goblet cell secretion in guinea pig trachea. 138 99

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

5-HT3 receptors may be present on primary afferent neurons containing substance P (SP), neurokinin A (NKA) or calcitonin gene-related peptide (CGRP). We investigated the release of SP-, NKA- and CGRP-immunoreactivities (IR) from rat spinal cord slices. Thirty mM potassium chloride caused an increased outflow of all three peptides, i.e. 140-190% of spontaneous release. This release was slightly enhanced in the presence of 3 x 10(-5) M 5-hydroxytryptamine (5-HT). In contrast, a significant inhibition of potassium-evoked, but not of basal NKA-IR and CGRP-IR release was observed when 10(-7) M BRL 43694 or ICS 205-930, two specific 5-HT3 receptor antagonists, were superfused together with 5-HT. In conclusion, 5-HT may facilitate the evoked release of peptides from central terminals of primary sensory neurons via 5-HT3 receptors.
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PMID:5-HT3 receptor antagonists inhibit sensory neuropeptide release from the rat spinal cord. 171 37

The effect of a potassium channel activator, cromakalim (BRL 34915), on excitatory nonadrenergic noncholinergic (e-NANC) and cholinergic neural bronchoconstriction was studied in guinea pigs. We monitored airway opening pressure as an index of airway caliber. After atropine (1 mg/kg iv.) and propranolol (1 mg/kg iv.), bilateral vagal stimulation evoked an e-NANC response. Cromakalim did not alter basal airway caliber, but reduced the e-NANC response to vagal stimulation in a dose-dependent manner, with a maximal inhibition of 71.9 +/- 9.2% (mean +/- S.E.) at 400 micrograms/kg i.v. (P less than .01). Pretreatment with phentolamine (2.5 mg/kg i.v.) had no effect on the inhibitory response produced by cromakalim but glibenclamide (25 mg/kg iv.), an inhibitor of ATP-sensitive potassium channels, blocked its effect. Cromakalim had no inhibitory effect on exogenous substance P (5-25 micrograms/kg i.v.)-induced bronchoconstriction. In animals depleted of tachykinins by capsaicin (50 mg/kg s.c.) pretreatment, cromakalim had an inhibitory effect on both vagalcholinergic and exogenous acetylcholine (0.3-2 micrograms/kg i.v.)-induced bronchoconstriction, although the inhibitory effect was significantly greater on neural stimulation. We conclude that potassium channels modulate both e-NANC and cholinergic neurotransmission, and to a lesser extent acetylcholine-induced bronchoconstriction in guinea pig airways.
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PMID:A potassium channel activator modulates both excitatory noncholinergic and cholinergic neurotransmission in guinea pig airways. 210 38

Potassium (K+) channels are present on airway smooth muscle cells, and their activation results in hyperpolarization and relaxation. Because these effects may have therapeutic relevance to asthma, we examined the activity of the active L-enantiomer of cromakalim, BRL 38227 (lemakalim), a selective K+ channel activator, against a variety of spasmogens in human bronchi in vitro. BRL 38227 produced relaxation of bronchi with either resting tone or tone induced by histamine, carbachol, neurokinin A, or KCl (20 mM) with an efficacy (%Emax) of 60 to 80% of that of isoproterenol and an EC50 (the concentration producing 50% of the maximal response) of 0.2 to 0.6 microM. However, BRL 38227 had a significantly lower potency and efficacy against 80 mM KCl than against the other spasmogens (%Emax, 12% of isoproterenol and EC50, 7.2 microM; p less than 0.005 and p less than 0.001, respectively), supporting the view that BRL 38227 acts on K+ channels. The D-enantiomer BRL 38226 was less potent (EC50, 2.6 microM) than BRL 38227 and produced only 43% of the isoproterenol relaxation. BRL 38227-induced relaxation was significantly inhibited by the ATP-sensitive K+ channel antagonist glibenclamide (0.1 and 1 microM), with a three-fold and eight-fold shift to the right of the dose-response curve, respectively. In the presence of a maximal relaxation induced by the calcium voltage-dependent channel antagonist verapamil, BRL 38227 was able to produce an additional 37% relaxation response. Thus, BRL 38227 is an effective relaxant of human airway smooth muscle, and this activity results from an action at K+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The action of a potassium channel activator, BRL 38227 (lemakalim), on human airway smooth muscle. 212 15

Two types of 5-hydroxytryptamine (5-HT) receptor, 5-HT1P and 5-HT3, have been identified physiologically on enteric neurons impaled by intracellular microelectrodes. Activation of 5-HT1P receptors evokes a long-lasting membrane depolarization associated with an increased input resistance, whereas stimulation of 5-HT3 receptors results in a brief depolarization during which the input resistance falls. Slow excitatory postsynaptic potentials (EPSPs) in myenteric type II-hyperpolarizing afterpotential (AH) neurons have been demonstrated to be mediated by 5-HT1P receptors. The current experiments were done to determine whether the substituted benzamide, BRL 24924, is a specific antagonist at 5-HT1P receptors and can be used as a probe to investigate the role played by serotoninergic neurons in the control of gastrointestinal motility. Intracellular microelectrodes were used to analyze the effects of BRL 24924 on guinea pig myenteric neurons. Microejection of BRL 24924 mimicked neither the long-lasting nor the brief response to 5-HT; however, BRL 24924 (0.5-1.0 microM) reversibly antagonized both the long-lasting 5-HT1P receptor-mediated responses of myenteric neurons to 5-HT and 5-HT-mediated slow EPSPs. A greater than 10-fold higher concentration of BRL 24924 was required to reduce the short-lived responses mediated by 5-HT3 receptors. BRL 24924 did not affect the response of myenteric neurons to substance P. These results indicate that BRL 24924 is primarily a 5-HT1P antagonist. Unlike other 5-HT1P agonists or antagonists, BRL 24924 did not block the binding of 5-[3H]HT to 5-HT1P receptors. This observation suggests that specific antagonism of physiological responses to 5-HT by BRL 24924 may be the result of an action on the coupling of the 5-HT1P receptor to its effector mechanism. BRL 24924 (0.5-1 mg/kg) and another 5-HT1P antagonist, N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (5 mg/kg), significantly increased the rate of emptying of a 51Cr-labeled liquid meal from the murine stomach. In contrast, the 5-HT3 antagonist, ICS 205-930 (0.1-0.5 mg/kg), did not affect the rate of gastric emptying. These observations are consistent with the hypothesis that intrinsic inhibitory neurons of the murine stomach are activated by serotoninergic axons acting through 5-HT1P receptors. Antagonism of an excitatory drive to neurons in a relaxant pathway may thus explain the gastrokinetic effects of BRL 24924.
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PMID:Blockade of 5-HT-mediated enteric slow EPSPs by BRL 24924: gastrokinetic effects. 278 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 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

Intravenous administration of a K+ channel activator, BRL 38227, inhibited cigarette smoke-induced plasma exudation in guinea pig airways in vivo in a dose-dependent manner with an approximate ED50 of 6 microgram/kg. BRL 38227 also inhibited vagally induced plasma exudation and bronchoconstriction but did not inhibit substance P-induced plasma exudation or neurokinin A-induced bronchoconstriction. K+ channels modulate neurotransmission in the airways and K+ channel activators may have therapeutic potential in bronchial diseases including asthma and chronic bronchitis.
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PMID:Inhibition of neurogenic plasma exudation and bronchoconstriction by a K+ channel activator, BRL 38227, in guinea pig airways in vivo. 822 5


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