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)

Nitric oxide (NO) mediates neurogenic relaxations of gastrointestinal (GI) smooth muscle. NO synthase (NOS) inhibitors also alter neurogenic contractions, suggesting NO modulates excitatory neurotransmitter release. In circular muscle-myenteric plexus preparations, guanethidine and either scopolamine or CP-96,345, a neurokinin-1 (NK1) receptor antagonist, were used to isolate nonadrenergic, noncholinergic (NANC) or cholinergic contractions, respectively. NOS inhibitors and hemoglobin potentiated neurogenic NANC but not cholinergic contractions and did not affect NK1 receptor agonist [substance P methyl ester (SPME)]-induced contractions. Sodium nitroprusside (SNP), a NO donor, attenuated NANC and cholinergic neurogenic contractions, but cholinergic contractions were less sensitive to SNP. SNP partially attenuated SPME-induced contractions, and apamin reduced inhibition of NANC contractions by SNP. Bethanechol responses were not affected by SNP. These data indicate NANC but not cholinergic contractions are inhibited by endogenous NO, suggesting differential regulation of release of tachykinins and acetylcholine from enteric nerves. NK1 receptor-but not muscarinic receptor-activated postjunctional pathways are also inhibited by NO. Therefore, prejunctional and postjunctional modulation of NANC contractions are mechanisms for inhibition of GI motility by endogenous NO.
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PMID:Endogenous NO inhibits NANC but not cholinergic neurotransmission to circular muscle of guinea pig ileum. 894 6

Systemic administration of the muscarinic receptor antagonist, scopolamine, augments, whereas the muscarinic receptor agonist, oxotremorine, attenuates behaviors (locomotion and stereotypies) and preprodynorphin (PPD) and substance P (SP) gene expression in striatonigral neurons induced by the indirect dopamine receptor agonist, amphetamine (AMPH). In contrast, systemic scopolamine blocks, whereas oxotremorine augments, AMPH-stimulated preproenkephalin (PPE) gene expression in striatopallidal neurons. This study investigated the site of action of these effects by administering scopolamine and oxotremorine directly into the striatum and assessing the expression of neuropeptide mRNAs with quantitative in situ hybridization. Unilateral injection of scopolamine into the dorsal striatum augmented, and oxotremorine attenuated, AMPH (2.5 mg/kg, i.p.)-stimulated behaviors. Intrastriatal scopolamine at a concentration of 62 mM, but not 6.2 mM, increased basal levels of PPD and SP mRNAs in the dorsal striatum. In addition, both 6.2 and 62 mM scopolamine significantly augmented AMPH-stimulated PPD and SP mRNA levels. Intrastriatal infusion of 1.6 or 8.1 mM oxotremorine did not alter basal levels of striatal PPD and SP mRNAs. However, both concentrations of oxotremorine completely blocked AMPH-stimulated SP mRNA and oxotremorine at 8.1 mM blocked AMPH-stimulated PPD mRNA. In contrast, PPE induction by AMPH was blocked by 62, but not 6.2, mM scopolamine. Both concentrations of oxotremorine tended to augment basal and AMPH-stimulated PPE mRNA in the dorsal striatum but the trend was not significant. These data demonstrate an inhibition of striatonigral, and facilitation of striatopallidal, gene expression through activation of local striatal muscarinic receptors, which is consistent with the changes seen after systemic administration of muscarinic agents. Therefore, muscarinic cholinergic regulation of basal and stimulated expression of neuropeptide mRNA is processed within the striatum.
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PMID:Intrastriatal injection of a muscarinic receptor agonist and antagonist regulates striatal neuropeptide mRNA expression in normal and amphetamine-treated rats. 906 45

1. In neural tissue, leukaemia inhibitory factor (LIF) is an important trophic cytokine. In this investigation, we determined if LIF was present in human and guinea-pig airways and examined the role of this cytokine in modulating airway responses to endogenous and exogenous tachykinins as well as muscarinic receptor and beta-adrenoceptor stimulation. 2. The presence of LIF in both human and guinea-pig airways was determined by immunohistochemistry. Guinea-pig tracheal explants were incubated in CRML-1066 media containing LIF (0.5, 5 or 50 ng ml-1) for periods of 3, 6, 24 and 48 h. Tracheal rings were then transferred to organ baths for measurement of isometric force in response to carbachol, capsaicin, the neurokinin1 (NK1) receptor agonist [Sar9,Met(O2)11]-substance P (SP), the NK2 receptor agonist neurokinin A (NKA) and isoprenaline. 3. LIF immunoreactivity was observed primarily in basally situated cells in the airway epithelium of both large and small airways. Less intense immunoreactivity was observed in vascular endothelium and glandular epithelium. 4. Treatment with LIF (0.5 ng ml-1) for 3 and 6 h significantly increased contractile responses to capsaicin by 42% and 43%, respectively, compared to time controls, whereas higher concentrations of LIF (5 and 50 ng ml-1) enhanced capsaicin-induced contractions only after 6 h. After 24 h, responses to capsaicin were not significantly different from 0 h control. Contractile responses to capsaicin following exposure to LIF at any concentration for 24 h were not significantly different from relative time control values. 5. Responses to [Sar9,Met(O2)11]-SP, carbachol and isoprenaline were not influenced by time in culture or by exposure to LIF for up to 48 h. Contractile responses induced by NKA were not influenced by 3 or 6 h exposure to LIF, but at 24 and 48 h the mean maximum contractile responses to NKA were significantly increased by 33% and 35%, respectively, compared to control. 6. These results demonstrate that LIF is present in guinea-pig and human airway epithelium, and modulates airway responses to tachykinins. In the acute setting LIF augments the capsaicin-induced release of endogenous tachykinins, whilst in the longer term (> 24 h), LIF increases airway smooth muscle responses to tachykinins via an NK2 receptor selective mechanism. We conclude that LIF may be an important effector molecule in the response of airways to injury or inflammation.
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PMID:Localization of leukaemia inhibitory factor to airway epithelium and its amplification of contractile responses to tachykinins. 913 95

The selective M4 muscarinic receptor toxin, MT3, was used in vivo to evaluate the role of M4 receptors in cholinergic inhibition of neuropeptide mRNA expression in striatonigral neurons. Unilateral injection of the muscarinic toxin 3 (0.04-4 nmol) into the dorsal striatum of chronically-cannulated rats elevated basal levels of preprodynorphin, substance P and preproenkephalin mRNAs in the ipsilateral dorsal striatum as revealed by quantitative in situ hybridization. Pretreatment with muscarinic toxin 3 also augmented amphetamine (2.5 mg/kg, i.p.)-stimulated preprodynorphin and substance P expression in the dorsal striatum in a manner similar to that observed after the muscarinic antagonist, scopolamine. Since muscarinic toxin 3 has a much greater affinity for muscarinic M4 receptors than for other subtypes, it is possible that muscarinic toxin 3, by interacting with the muscarinic M4 subtype, regulates basal and/or dopamine-stimulated striatal neuropeptide gene expression.
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PMID:The muscarinic toxin 3 augments neuropeptide mRNA in rat striatum in vivo. 934 26

Primary cultures of human bronchial epithelial cells (HBE-cells) were established to measure granulocyte-macrophage colony stimulating factor (GM-CSF) release. HBE-cells showed a basal GM-CSF release (82+/-20 ng/well/24 h; 30 donors), which was increased by interleukin-1 beta(IL-1beta, 1 ng/ml) by 270%. This effect was blocked by 1 microM dactinomycin or 10 microM cycloheximide, i.e. the stimulatory effect of IL-1beta depended on de-novo synthesis. Histamine (100 microM) and acetylcholine ( 100 nM) stimulated GM-CSF release more than two-fold above the baseline. Nicotine (1 microM) increased GM-CSF release to a similar extent, and this effect was prevented by 30 microM (+)-tubocurarine. The stimulatory effect was attenuated or even lost with high agonist concentrations (10 microM acetylcholine; 100 microM nicotine) suggesting receptor desensitization. The muscarinic receptor agonist oxotremorine did not affect GM-CSF release. Serotonin, substance P and calcitonin-gene related peptide had no effect on GM-CSF release. In conclusion, acetylcholine can trigger GM-CSF release from human airway epithelial cells via stimulation of nicotinic receptors.
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PMID:Acetylcholine and nicotine stimulate the release of granulocyte-macrophage colony stimulating factor from cultured human bronchial epithelial cells. 960 35

1. The role of tachykinin NK1 receptors in the recruitment of eosinophils to airway nerves, loss of inhibitory neuronal M2 muscarinic receptor function and the development of vagal hyperreactivity was tested in antigen-challenged guinea-pigs. 2. In anaesthetized guinea-pigs, the muscarinic agonist, pilocarpine (1-100 microg kg(-1), i.v.), inhibited vagally induced bronchoconstriction, in control, but not in antigen-challenged guinea-pigs 24 h after antigen challenge. This indicates normal function of neuronal M2 muscarinic receptors in controls and loss of neuronal M2 receptor function in challenged guinea-pigs. Pretreatment of sensitized guinea-pigs with the NK1 receptor antagonists CP99994 (4 mg kg(-1), i.p.), SR140333 (1 mg kg(-1), s.c.) or CP96345 (15 mg kg(-1), i.p.) before antigen challenge, prevented M2 receptor dysfunction. 3. Neither administration of the NK1 antagonists after antigen challenge, nor pretreatment with an NK2 receptor antagonist, MEN10376 (5 micromol kg(-1), i.p.), before antigen challenge, prevented M2 receptor dysfunction. 4. Electrical stimulation of the vagus nerves caused a frequency-dependent (2-15 Hz, 10 V, 0.2 ms for 5 s) bronchoconstriction that was significantly increased following antigen challenge. Pretreatment with the NK1 receptor antagonists CP99994 or SR140333 before challenge prevented this increase. 5. Histamine (1-20 nmol kg(-1), i.v.) caused a dose-dependent bronchoconstriction, which was vagally mediated, and was significantly increased in antigen challenged guinea-pigs compared to controls. Pretreatment of sensitized animals with CP99994 before challenge prevented the increase in histamine-induced reactivity. 6. Bronchoalveolar lavage and histological studies showed that after antigen challenge significant numbers of eosinophils accumulated in the airways and around airway nerves. This eosinophilia was not altered by pretreatment with the NK1 receptor antagonist CP99994. 7. These data indicate that pretreatment of antigen-sensitized guinea-pigs with NK1, but not with NK2 receptor antagonists before antigen challenge prevented the development of hyperreactivity by protecting neuronal M2 receptor function. NK1 receptor antagonists do not inhibit eosinophil accumulation around airway nerves.
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PMID:Effects of tachykinin NK1 receptor antagonists on vagal hyperreactivity and neuronal M2 muscarinic receptor function in antigen challenged guinea-pigs. 964 42

We have previously demonstrated that endogenous ascorbic acid is secreted into the gastric lumen by cholinergic stimulation in both conscious pylorus-ligated rats and the perfused stomach of unconscious rats, and that gastrin, a potent gastric stimulatory peptide hormone, has no effect. In the present study, the effects of some gastrointestinal peptide hormones on gastric ascorbic acid secretion were further examined in the perfused stomach of rats. An intravenous administration of cholecystokinin octapeptide (CCK-8) significantly increased gastric ascorbic acid secretion at a dose of 1.0 and 4.0 micrograms/kg, whereas the other three peptides examined, bombesin, neurotensin and substance P, showed no or little effect at the doses which were quite commonly employed for evaluation of various gastric functions. CCK-8-induced ascorbic acid secretion was reduced by pretreatment with proglumide, which is a CCK receptor antagonist, but not by pretreatment with atropine. These results indicate that gastric ascorbic acid secretion is physiologically regulated not only by muscarinic receptor-associated cholinergic stimulation but also by CCK receptor-associated humoral stimulation.
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PMID:Cholecystokinin stimulates ascorbic acid secretion through its specific receptor in the perfused stomach of rats. 982 Dec 9

1. The Ca2+ channel subtypes controlling ACh release from basal forebrain neurones and the ionic basis underlying muscarinic receptor-mediated autoinhibition were studied using skeletal myoballs to detect ACh release from individual rat basal forebrain neurones in culture. 2. Somatic Ca2+ currents evoked using a simulated action potential waveform revealed that Ca2+ entry was primarily through N-, Q- and to a lesser extent R-, T- and L-type Ca2+ channels. 3. Muscarine (10 microM) inhibited N- and Q- but not R-, T- or L-type somatic Ca2+ channels. Agonist inhibition was totally blocked by pre-treatment with pertussis toxin (500 ng ml-1). 4. ACh release from discrete sites along basal forebrain neurites (1. 2 mM extracellular Ca2+) could be largely abolished by blocking Ca2+ entry through either N-type or Q-type Ca2+ channels. Inhibition of Ca2+ entry through L- or T-type channels had no effect upon release. Following inhibition of either N- or Q-type Ca2+ channels, release could be restored to near control levels by raising [Ca2+]o. After selectively blocking N-, Q-, L- and T-type channels, low levels of release could still be evoked as a result of Ca2+ entry through R-type Ca2+ channels. 5. Muscarinic receptor activation reversibly inhibited ACh release due to Ca2+ entry through N-, Q- and R-type Ca2+ channels. In contrast, inhibition of inwardly rectifying K+ channels using Ba2+ (3-10 microM) or substance P (0.03-0.1 microM), or block of SK or BK Ca2+-activated K+ channels with apamin (100 nM) or charbydotoxin (100 nM) respectively, had no effect upon either ACh release or its modulation by muscarinic agonists. 6. These results show that ACh release from individual release sites on basal forebrain neurones is controlled by multiple Ca2+ channel subtypes with overlapping Ca2+ microdomains and that autoinhibition of release results from M2 muscarinic receptor-mediated inhibition of these presynaptic Ca2+ channels rather than as a consequence of K+ channel activation.
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PMID:The role of N-, Q- and R-type Ca2+ channels in feedback inhibition of ACh release from rat basal forebrain neurones. 992 81

To effectively control bladder activity, and to treat urinary incontinence caused by bladder overactivity, identification of suitable targets for pharmacological intervention is necessary. Such targets may be found in the central nervous system (CNS) or peripherally. The causes of bladder overactivity are not known, but theoretically increased afferent activity, decreased inhibitory control in the CNS and/or peripheral ganglia, and increased sensitivity of the detrusor to efferent stimulation may be involved. Several CNS transmitters may modulate voiding, but few drugs with a defined CNS site of action have been developed for treatment of voiding disorders. Potentially, drugs affecting GABA, opioid, 5-HT, noradrenaline, dopamine, or glutamatergic receptors and mechanisms can be developed, but a selective action on the lower urinary tract may be difficult to obtain. Traditionally, drugs used for treatment of bladder overactivity have had a peripheral site of action, mainly the efferent neurotransmission or the detrusor muscle itself. Antimuscarinic drugs, beta-adrenoceptor agonists, alpha-adrenoceptor antagonists, drugs affecting membrane channels, prostaglandin synthetase inhibitors and several other agents have been used. However, none of them has been developed specifically for treatment of bladder disorders, and their efficacy, as judged from controlled clinical trials (where performed), is often limited. Recent information on the alpha-adrenoceptor, beta-adrenoceptor (beta 3), and muscarinic receptor subtypes of the human detrusor and outflow region can be the basis for the development of compounds with effect on bladder overactivity and with improved tolerance. New ways of decreasing acetylcholine release may represent a promising way of controlling bladder contraction. Potassium channel (KATP) openers are theoretically attractive, but the drugs available so far have targeted vascular rather than bladder smooth muscle, which has limited their clinical use. However, new drugs belonging to these groups with an interesting profile of action have been developed. Drugs decreasing afferent activity represent an attractive therapeutic approach and transmitters of afferent nerves and their receptors are possible targets for pharmacological interventions. Tachykinins, such as substance P, neurokinins A and B, and other neuropeptides have been demonstrated in nerves of the lower urinary tract and have been shown to influence bladder function. Agents affecting these nerves by causing release of tachykinins, such as capsaicin and resiniferatoxin, given intravesically can be effective in some cases of bladder overactivity, and agents antagonizing tachykinin receptors may also be of therapeutic interest. New drugs specifically directed for control of bladder activity are under development and will hopefully lead to improved treatment of urinary incontinence.
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PMID:Advances in the pharmacological control of the bladder. 1008 18

Substance P (SP) evokes bradycardia that is mediated by cholinergic neurons in experiments with isolated guinea pig hearts. This project investigates the negative chronotropic action of SP in vivo. Guinea pigs were anesthetized with urethane, vagotomized and artificially respired. Using this model, IV injection of SP (32 nmol/kg/50 microl saline) caused a brief decrease in heart rate (-30+/-3 beats/min from a baseline of 256+/-4 beats/min, n = 27) and a long-lasting decrease in blood pressure (-28+/-2 mmHg from baseline of 51+/-5 mmHg, n = 27). The negative chronotropic response to SP was attenuated by muscarinic receptor blockade with atropine (-29 +/- 9 beats/min before vs -8 +/- 2 beats/min after treatment, P = 0.0204, n = 5) and augmented by inhibition of cholinesterases with physostigmine (-23 +/- 6 beats/min before versus -74 +/- 20 beats/min after treatment, P = 0.0250, n = 5). Ganglion blockade with chlorisondamine did not diminish the negative chronotropic response to SP. In another series of experiments, animals were anesthetized with sodium pentobarbital or urethane and studied with or without vagotomy. Neither anesthetic nor vagotomy had a significant effect on the negative chronotropic response to SP (F3,24 = 1.97, P = 0.2198). Comparison of responses to 640 nmol/kg nitroprusside and 32 nmol/kg SP demonstrated that the bradycardic effect of SP occurs independent of vasodilation. These results suggest that SP can evoke bradycardia in vivo through stimulation of postganglionic cholinergic neurons.
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PMID:Substance P evokes bradycardia by stimulation of postganglionic cholinergic neurons. 1046 15


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