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. The effects of some possible inhibitors of ectonucleotidases on the breakdown of extracellular ATP by strips of guinea-pig urinary bladder were investigated. 2. Suramin and ethacrynic acid (10 mM) both inhibited ATP breakdown significantly, and difluorodinitrobenzene (10 mM) inhibited it slightly whereas N-ethylmaleimide, adenosine 5'-(gamma-thiotriphosphate) (ATP-gamma-S) and reactive blue-2 (10 mM) were without effect. 3. The inhibitory effects of suramin on ATP breakdown were non-competitive. 4. Ethacrynic acid (1 mM) irreversibly inhibited contractions of the guinea-pig bladder induced by ATP, substance P, histamine, non-adrenergic, non-cholinergic nerve stimulation or KCl, whereas suramin (100 microM) had no inhibitory effect. 5. The results suggest that suramin might provide a starting point for the design of selective inhibitors of ectonucleotidases.
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PMID:The effects of some possible inhibitors of ectonucleotidases on the breakdown and pharmacological effects of ATP in the guinea-pig urinary bladder. 254 53

1. Four putative neurotransmitters (serotonin, substance P, ATP (alpha-beta-methylene-ATP), and vasoactive intestinal peptide, VIP) of the non-adrenergic non-cholinergic (NANC) innervation were examined for their role in the NANC excitatory neurotransmission in channel catfish intestine after adrenergic and cholinergic blockade. 2. VIP at concentrations ranging from 10(-12)M to 10(-4)M did not produce either a relaxant or a contractile response in these segments. 3. Serotonin, substance P and alpha-beta-methyl-ATP produced contractile responses in a dose-dependent manner. Their EC50 values were 5 x 10(-7)M, 5 x 10(-9)M and 5 x 10(-9)M and 5 x 10(-6)M, respectively. 4. Electrical field stimulation of the intestinal segments produced a predominant excitatory response after complete blockade of adrenergic and cholinergic divisions, suggesting a predominant NANC excitatory innervation. 5. Three types of serotonin receptor antagonists, namely methiothepin (predominantly a 5-HT1 antagonist), ketanserin (a selective 5-HT2 antagonist), methysergide and cyproheptadine (predominantly 5-HT2 blockers) and metoclopramide (a selective 5-HT3 blocker) were tested for their effectiveness against serotonin and EFS-induced contractions. Methiothepin, methysergide, cyproheptadine and metoclopramide produced significant blockade of the response to serotonin, whereas only methiothepin and cyproheptadine produced blockade of EFS-induced response. 6. Three agents tested for substance P blockade, namely spantide, 4-11 fragment of substance P, and methysergide (also a serotonin blocker), did not produce significant inhibition of the response to either substance P or EFS. 7. Suramin at a dose that blocked the ED50 concentration of ATP did not produce a significant blockade of the response to EFS suggesting that ATP-involvement in the NANC-e neurotransmission is unlikely. 8. This study confirmed the involvement of serotonin in the expression of non-adrenergic non-cholinergic excitatory response of the channel catfish intestine.
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PMID:Evidence for serotonin involvement in the NANC excitatory neurotransmission in the catfish intestine. 753 35

1. In the presence of atropine (1 microM), guanethidine (3 microM), indomethacin (3 microM), apamin (0.1 microM) and L-nitroarginine (L-NOARG, 30 microM), electrical field simulation (EFS) produced a nonadrenergic, noncholinergic (NANC) excitatory junctional potential (e.j.p.), action potentials and contraction of the circular muscle of the guinea-pig proximal duodenum, recorded by the single sucrose gap technique. 2. The selective tachykinin (TK) NK1 receptor antagonist, GR 82,334 (30 nM-3 microM) produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. and contraction. Similarly, the selective NK2 receptor antagonists, MEN 10,627 (30 nM-3 microM) and GR 94,800 (100 nM-10 microM), both produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. and contraction. GR 82,334 inhibited the electrical and mechanical NANC responses to EFS in an almost parallel manner, while MEN 10,627 and GR 94,800 were more effective in inhibiting the mechanical than the electrical response to EFS. 3. Activation of the NK1 or NK2 receptor by the selective agonists, [Sar9]substance P (SP) sulphone and [beta Ala8]neurokinin A (NKA) (4-10), respectively (0.3 microM each), produced depolarization, action potentials and contractions. GR 82,334 selectively inhibited the responses to [Sar9]SP sulphone, without affecting the responses to [beta Ala8]NKA (4-10). MEN 10,627 and GR 94,800 inhibited or abolished the responses to [beta Ala8]NKA (4-10), without affecting the responses to [Sar9]SP sulphone. 4. Nifedipine (1 microM) abolished the action potentials and contraction produced either by EFS or by the TK receptor agonists [Sar9]SP sulphone or [beta Ala8]NKA (4-10). 5. In the presence of nifedipine, the NANC e.j.p. produced by EFS was biphasic: in the majority of strips tested (21 out of 29) an early fast phase of depolarization was followed by a second slow component. The combined administration of GR 82,334 and GR 94,800 (3 microM each) reduced both components, the slow phase being inhibited to a greater extent than the fast phase. 6. The P2 purinoreceptor antagonist, suramin (100 microM) reduced the fast phase of the e.j.p. produced by EFS in the presence of nifedipine, without affecting the slow phase. The combined administration of suramin, GR 82,334 and GR 94,800 produced a nearly complete blockade of the e.j.p. produced by EFS in the presence of nifedipine. 7. When tested in the absence of apamin and L-NOARG, EFS induced a NANC inhibitory junction potential (i.j.p.) followed by an e.j.p., and the selective P2Y receptor agonist, adenosine-5'-O-(2-thiodiphosphate) (ADP beta S, 10 microM), produced membrane hyperpolarization. After addition of apamin and L-NOARG, the ij.p. was blocked, and EFS produced a pure NANC e.j.p.; ADPPS produced depolarization, action potentials and contraction.8. Suramin (100 microM) blocked the depolarization, action potentials and contractions produced by ADP beta S in the presence of apamin and L-NOARG, without affecting the responses produced by the NK1receptor agonist, [Sar9}SP sulphone.9. We conclude that NK1 and NK2 receptors cooperate in producing NANC excitation and contraction of the circular muscle in the guinea-pig proximal duodenum. Activation of either TK receptor produces membrane depolarization and both receptors contribute to generate action potentials which are essential for producing muscle contraction, via nifedipine-sensitive calcium channels. It appears that endogenous ATP chiefly acts as an inhibitory transmitter but, after blockade of NANC inhibitory mechanism(s),ATP may act as a fast signalling excitatory transmitter.
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PMID:Evidence that tachykinin NK1 and NK2 receptors mediate non-adrenergic non-cholinergic excitation and contraction in the circular muscle of guinea-pig duodenum. 754 17

The frequency of spontaneous action potentials of locus coeruleus neurons was recorded extracellularly in pontine slices of the rat brain. The adenosine 5'-triphosphate (ATP) analogues alpha,beta-methylene ATP (alpha,beta-meATP) and 2-methylthio ATP increased the firing rate with a similar potency, while uridine 5'-triphosphate (UTP) was inactive. Diadenosine 5'-pentaphosphate (Ap5A), diadenosine 5'-tetraphosphate (Ap4A) and diadenosine 5'-triphosphate (Ap3A) all facilitated the firing. When equimolar concentrations were compared, Ap5A had the largest effect followed by Ap4A and Ap3A. Suramin markedly inhibited responses to alpha,beta-meATP and 2-methylthio ATP; the effect of Ap4A was only slightly depressed by suramin. Pyridoxalphosphate-6-azophenyl-2,4-disulfonic acid (PPADS) strongly antagonized alpha, beta-meATP, but failed to alter the effects of 2-methylthio ATP and Ap4A. Reactive blue 2 weakly antagonized alpha,beta-meATP and did not interfere with 2-methylthio ATP and Ap4A. Moreover, suramin depressed responses to (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA), but not to substance P. PPADS failed to affect the AMPA- and NMDA-induced increases in firing. Hence, locus coeruleus neurons may possess receptors for adenosine nucleotides (P2X and P2Y purinoceptors) and dinucleotides (P2D purinoceptors); receptors for uridine nucleotides (P2U purinoceptors or pyrimidinoceptors) are probably absent.
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PMID:Pharmacological characterization of P2 purinoceptor types in rat locus coeruleus neurons. 898 62

1. By using the sucrose gap technique, we have investigated the effect of the metabolically stable P2Y receptor agonist, adenosine 5'-O-2-thiodiphosphate (ADPbetaS), on the membrane potential and tension in the circular muscle of the guinea-pig proximal colon. All experiments were performed in the presence of atropine (1 microM), guanethidine (3 microM), indomethacin (3 microM), nifedipine (1 microM), L-nitroarginine (L-NOARG, 100 microM) and of the tachykinin NK1 and NK2 receptor antagonists, SR 140333 (0.1 microM) and GR 94800 (0.1 microM), respectively. 2. ADPbetaS (100 microM for 15 s) evoked a tetrodotoxin- (1 microM) resistant hyperpolarization and contraction of the smooth muscle. In the presence of apamin (0.1 microM), the ADPbetaS-induced hyperpolarization was converted to depolarization and the contraction was potentiated while tetraethylammonium (TEA, 10 mM) did not affect significantly the response to ADPbetaS. The combined application of apamin and TEA reproduced the effect observed with apamin alone. 3. Pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acids (PPADS, 30 microM) slightly but significantly increased the ADPbetaS-induced hyperpolarization, while the contraction evoked by ADPbetaS was reduced by about 80%. Suramin (100 microM) did not affect the ADPbetaS-induced hyperpolarization but totally blocked the ADPbetaS-induced contraction. In the presence of suramin (100 microM), a small relaxation of the circular muscle was observed upon application of ADPbetaS. 4. The contraction and hyperpolarization evoked by ADPbetaS were abolished in Ca2+-free Krebs solution. The blocker of sarcoplasmic reticulum Ca2+ pump, cyclopiazonic acid (10 microM) reduced contraction and hyperpolarization induced by ADPbetaS by about 60 and 50%, respectively. 5. A comparison of our present and previous findings enables to conclude that at least 3 types of P2 receptors are present on the smooth muscle of the guinea-pig colon, as follows: (1) inhibitory P2 receptors, producing an apamin-sensitive hyperpolarization, which are activated by alpha,beta-methylene ATP (alpha,beta-meATP) and by endogenously released purines, sensitive to suramin and PPADS; (2) inhibitory P2 receptors, producing an apamin-sensitive hyperpolarization, which are activated by ADPbetaS and are resistant to suramin and PPADS; (3) excitatory P2 receptors, producing contraction, which are activated by ADPbetaS and are sensitive to suramin and PPADS. The data also support the idea of the existence of a restricted pool of specialized junctional P2 receptors producing the apamin-sensitive NANC inhibitory junction potential in response to endogenous ligand(s).
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PMID:Pharmacological evidence for the existence of multiple P2 receptors in the circular muscle of guinea-pig colon. 948 62

The well-known side effects of anticholinergic compounds used to treat urinary incontinence caused by detrusor overactivity have addressed the interest on other pharmacological intervention. The purpose of the present work was to investigate the possible changes in purinergic and cholinergic components of parasympathetic neurotransmission in obstructed rat bladders with detrusor overactivity, and to examine the effect of the association of suramin, atropine and indomethacin on nerve-mediated responses to electrical field stimulation (EFS). Mechanical responses to exogenous acetylcholine, ATP and substance P were also evaluated. Altered sensitivities to acetylcholine and to the sensory neurotransmitter substance P, but unchanged sensitivity to the stable ATP analogue alpha,beta-methyleneATP were observed in bladders from obstructed rats. Suramin and atropine inhibited purinergic and cholinergic components of the neurogenic responses evoked by EFS in detrusor strips from control and obstructed rats. Interestingly, suramin enhanced the antagonistic effect of atropine on neurogenic responses of detrusor strips at all frequencies of stimulation tested. Our results suggest that the association between an antimuscarinic drug and an antagonist of P2X purinoceptors such as suramin might be helpful to reduce the therapeutic dosage of the antimuscarinic drug, along with its side effects. This approach may be of interest in the therapy of patients with bladder incontinence caused by detrusor overactivity, which do not even respond to a maximal dosage of antimuscarinic drug.
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PMID:Altered neurogenic and mechanical responses to acetylcholine, ATP and substance P in detrusor from rat with outlet obstruction. 1681 25

In esophageal mucosa, HCl causes TRPV1-mediated release of calcitonin gene-related peptide (CGRP) and substance P (SP) from submucosal neurons and of platelet-activating factor (PAF) from epithelial cells. CGRP and SP release was unaffected by PAF antagonists but reduced by the purinergic antagonist suramin. ATP caused CGRP and SP release from esophageal mucosa, confirming a role of ATP in the release. The human esophageal epithelial cell line HET-1A was used to identify epithelial cells as the site of ATP release. HCl caused ATP release from HET-1A, which was reduced by the TRPV1 antagonist 5-iodoresiniferatoxin. Real-time PCR demonstrated the presence of mRNA for several P2X and P2Y purinergic receptors in epithelial cells. HCl also increased activity of lyso-PAF acetyl-CoA transferase (lyso-PAF AT), the enzyme responsible for production of PAF. The increase was blocked by suramin. ATP caused a similar increase, confirming ATP as a mediator for the TRPV1-induced increase in enzyme activity. Repeated exposure of HET-1A cells to HCl over 2 days caused upregulation of mRNA and protein expression for lyso-PAF AT. Suramin blocked this response. Repeated exposure to ATP caused a similar mRNA increase, confirming ATP as a mediator for upregulation of the enzyme. Thus, HCl-induced activation of TRPV1 causes ATP release from esophageal epithelial cells that causes release of CGRP and SP from esophageal submucosal neurons and activation of lyso-PAF AT, the enzyme responsible for the production of PAF in epithelial cells. Repeated application of HCl or of ATP causes upregulation of lyso-PAF AT in epithelial cells.
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PMID:ATP: a mediator for HCl-induced TRPV1 activation in esophageal mucosa. 2196 May 21