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 effects of KB-2796 (1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride), a novel calcium channel blocker, on neurogenic inflammation caused by electrical stimulation in the trigeminal ganglion and on cutaneous reactions induced by inflammatory mediators in rats, by measuring plasma extravasation. Neurogenic inflammation was inhibited by pretreatment with capsaicin (25 mg/kg, s.c.) but not indomethacin (10 mg/kg, i.p.), while phosphoramidon (2.5 mg/kg, i.v.) augmented it. KB-2796 (0.1-1 mg/kg, i.v.) significantly inhibited neurogenic inflammation in a dose dependent manner, without affecting histamine-, bradykinin- or substance P-induced cutaneous reactions. Dimetotiazine (0.3 and 1 mg/kg, i.v.), flunarizine (1 mg/kg, i.v.), mepyramine (1 mg/kg, i.v.) and sumatriptan (1 mg/kg, i.v.) significantly inhibited neurogenic inflammation. However, these compounds also showed complete or partial inhibition of histamine-, bradykinin- or substance P-induced reactions. Nifedipine (0.1 mg/kg, i.v.) did not show marked effects on neurogenic inflammation and cutaneous reactions. The present experiments indicate that neurogenic inflammation is presumably mediated not only by neuropeptides released from trigeminal nerve endings but also by secondarily released histamine, and that KB-2796 like sumatriptan may inhibit neurogenic inflammation caused by trigeminal nerve stimulation probably through inhibition of neuropeptide release but its inhibition may be distinct from the calcium blocking action of the 1,4-dihydropyridine type.
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PMID:Effects of KB-2796 on plasma extravasation following antidromic trigeminal stimulation in the rat. 950 71

We report here that serotonin (5-hydroxytriptamine, 5-HT) induces an increase in intracellular Ca2+ concentration ([Ca2+]i) in rat pheochromocytoma PC12h cells, a subclone of PC12 cells, which was detected by using Ca2+ sensitive indicator dye fura-2. The [Ca2+]i increase completely disappeared when extracellular Ca2+ was chelated with excess EGTA and potently suppressed in Na+-free buffer. Nifedipine, a voltage-dependent L-type calcium channel blocker, significantly blocked the 5-HT response. Addition of another 4 mM Ca2+ to the cell suspension attenuated the [Ca2+]i increase induced by 5-HT, whereas the nicotinic action was remarkably potentiated. Furthermore, metoclopramide, a 5-HT3 receptor antagonist, inhibited the 5-HT response in a dose dependent manner. These findings suggest that the 5-HT-induced [Ca2+]i increase involves the mediation of a voltage-dependent Ca2+ channel, evoked by membrane depolarization via the activation of cation channel-type receptors, 5-HT3 receptors. We also noted the inhibitory action of tachykinin peptides on the 5-HT response, suggesting that the cell line is useful to investigate these neuromodulatory actions in the nervous system.
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PMID:Serotonin increases cytoplasmic Ca2+ concentration in PC12h cells: effect of tachykinin peptides. 979 12

1. In isolated tissue experiments, neurokinin A (NKA) produced concentration-dependent contraction of human and guinea-pig ureter (pD2 = 6.7 and 7.2, respectively); an effect greatly reduced (>80% inhibition) by the tachykinin NK2 receptor-selective antagonist MEN 11420 (0.1 microM). The tachykinin NK1 and NK3 receptor agonists septide and senktide, respectively, were ineffective. 2. Electrical field stimulation (EFS) of the guinea-pig isolated renal pelvis produced an inotropic response blocked by MEN 11420 (0.01-1 microM). In the same preparation MEN 11420 (0.1 microM) blocked (apparent pK(B) = 8.2) the potentiation of spontaneous motor activity produced by the NK2 receptor-selective agonist [betaAla8]NKA(4-10). 3. In sucrose-gap experiments, EFS evoked action potentials (APs) accompanied by phasic contractions of human and guinea-pig ureter, which were unaffected by tetrodotoxin or MEN 11420 (3 microM), but were blocked by nifedipine (1-10 microM). NKA (1-3 microM) produced a slow membrane depolarization with superimposed APs and a tonic contraction with superimposed phasic contractions. NKA prolonged the duration of EFS-evoked APs and potentiated the accompanying contractions. MEN 11420 completely prevented the responses to NKA in both the human and guinea-pig ureter. 4. Nifedipine (1-10 microM) suppressed the NKA-evoked APs and phasic contractions in both human and guinea-pig ureter, and slightly reduced the membrane depolarization induced by NKA. A tonic-type contraction of the human ureter in response to NKA persisted in the presence of nifedipine. 5. In conclusion, tachykinins produce smooth muscle excitation in both human and guinea-pig ureter by stimulating receptors of the NK2 type only. NK2 receptor activation depolarizes the membrane to trigger the firing of APs from latent pacemakers.
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PMID:Excitatory motor and electrical effects produced by tachykinins in the human and guinea-pig isolated ureter and guinea-pig renal pelvis. 984 36

The aim of this study was to determine whether an excess of nitric oxide (NO) (mimicked by addition of NO donors) might produce by itself changes in the contractile responses to acetylcholine (ACh), substance P (SP) and KCl in the longitudinal muscle of the rat ileum. We also studied the calcium handling properties of this tissue in presence of NO donors. The NO donors assayed sodium nitroprusside (SNP) and 3-morpholinosydnonimine hydrochloride (SIN-1), induced different responses. SNP caused an immediate contraction followed by a sustained relaxation, whereas SIN-1 induced an immediate relaxation followed by a contraction. Even after prolonged incubations (up to 90 min), the NO donors SNP and SIN-1 were unable to modify the ACh- and SP-concentration-response curves, as well as the response to 30 mM KCl. The nifedipine-resistant component of the ACh-induced contraction was not modified in presence of SNP. Cyclopiazonic acid (CPA) induced a contraction that was not modified when the tissue was pre-incubated with SNP. Nifedipine caused a sharp relaxation when added during the CPA-induced contraction and, when added previously, it reduced the CPA-induced contractile response. It is concluded that NO excess is not, by itself, responsible for the altered responses to KCl. ACh and SP. The contractility changes observed in the longitudinal muscle of the rat ileum during inflammation could rather be related to the presence of other inflammatory mediators.
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PMID:Lack of effect of nitric oxide on KCl, acetylcholine and substance P induced contractions in ileal longitudinal muscle of the rat. 1099 18

1. Neurokinins contribute to the neural regulation of gastrointestinal (GI) smooth muscles. We studied responses of murine colonic smooth muscle cells to substance P (SP) and NK(1) and NK(2) agonists using confocal microscopy and the patch clamp technique. 2. Colonic myocytes generated localized Ca(2+) transients that were coupled to spontaneous transient outward currents (STOCs). SP (10(-10) M) increased Ca(2+) transients and STOCs. Higher concentrations of SP (10(-6) M) increased basal Ca(2+) and inhibited Ca(2+) transients and STOCs. 3. Effects of SP were due to increased Ca(2+) entry via L-type Ca(2+) channels, and were mediated by protein kinase C (PKC). Nifedipine (10(-6) M) and the PKC inhibitor, GF 109203X (10(-6) M) reduced L-type Ca(2+) current and blocked the effects of SP. 4. SP responses depended upon parallel stimulation of NK(1) and NK(2) receptors. NK(1) agonist ([Sar(9),Met(O(2))(11)]-substance P; SSP) and NK(2) agonists (neurokinin A (NKA) or GR-64349) did not mimic the effects of SP alone, but NK(1) and NK(2) agonists were effective when added in combination (10(-10)-10(-6) M). Consistent with this, either an NK(1)-specific antagonist (GR-82334; 10(-7) M) or an NK(2)-specific antagonist (MEN 10,627; 10(-7) M) blocked responses to SP (10(-6) M). 5. Ryanodine (10(-5) M) blocked the increase in Ca(2+) transients and STOCs in response to SP (10(-10) M). 6. Our findings show that low concentrations of SP, via PKC-dependent enhancement of L-type Ca(2+) current and recruitment of ryanodine receptors, stimulate Ca(2+) transients. At higher concentrations of SP (10(-6) M), basal Ca(2+) increases and spontaneous Ca(2+) transients and STOCs are inhibited.
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PMID:Substance P modulates localized calcium transients and membrane current responses in murine colonic myocytes. 1271 23

Cisplatin-like chemotherapeutics cause vomiting via release of multiple neurotransmitters (dopamine, serotonin (5-HT), or substance P (SP)) from the gastrointestinal enterochromaffin cells and/or the brainstem via a calcium dependent process. Diverse channels in the plasma membrane allow extracellular Ca(2+) entry into cells for the transmitter release process. Agonists of 5-HT3 receptors increase calcium influx through both 5-HT3 receptors and L-type Ca(2+) channels. We envisaged that L-type calcium agonists such as FPL 64176 should cause vomiting and corresponding antagonists such as nifedipine would behave as broad-spectrum antiemetics. Administration of FPL 64176 did cause vomiting in the least shrew in a dose-dependent fashion. Nifedipine and the 5-HT3 receptor antagonist palonosetron, potently suppressed FPL 64176-induced vomiting, while a combination of ineffective doses of these antagonists was more efficacious. Subsequently, we investigated the broad-spectrum antiemetic potential of nifedipine against diverse emetogens including agonists of serotonergic 5-HT3- (e.g. 5-HT or 2-Me-5-HT), SP tachykinin NK1- (GR73632), dopamine D2- (apomorphine or quinpirole), and cholinergic M1- (McN-A-343) receptors, as well as the non-specific emetogen, cisplatin. Nifedipine by itself suppressed vomiting in a potent and dose-dependent manner caused by the above emetogens except cisplatin. Moreover, low doses of nifedipine potentiated the antiemetic efficacy of non-effective or semi-effective doses of palonosetron against vomiting caused by either 2-Me-5-HT or cisplatin. Thus, our findings demonstrate that activation of L-type calcium channels causes vomiting, whereas blockade of these ion channels by nifedipine-like antagonists not only provides broad-spectrum antiemetic activity but can also potentiate the antiemetic efficacy of well-established antiemetics such as palonosetron. L-type calcium channel antagonists should also provide antiemetic activity against drug-induced vomiting as well as other emetogens including bacterial and viral proteins.
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PMID:Broad-spectrum antiemetic potential of the L-type calcium channel antagonist nifedipine and evidence for its additive antiemetic interaction with the 5-HT(3) receptor antagonist palonosetron in the least shrew (Cryptotis parva). 2451 17


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