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)

4-Aminopyridine (4-AP) induced an atropine- and tetrodotoxin (TTX)-insensitive contraction (resistant contraction), in a concentration-dependent manner, in the isolated jejunum of rabbits. The failure of specific antagonists of histamine, serotonin and substance P to affect this resistant contraction ruled out the participation of histamine, serotonin and/or substance P. Antiserum against neuropeptide Y (NPY) reduced this resistant contraction in a concentration-dependent manner and inhibited the action of 4-AP totally at a high concentration (1.25% dilution) whereas normal serum lacked this ability. This suggested that the release of NPY was involved in this 4-AP-induced resistant contraction. Radioimmunoassay of NPY-like immunoreactivity in isolated synaptosomal preparations indicated that 4-AP possessed the ability to induce the release of NPY. However, guanethidine did not affect the actions of 4-AP, indicating that NPY is released mainly from non-adrenergic nerves. Our results indicate that 4-AP induces the release of NPY from non-adrenergic nerves to produce an atropine- and TTX-resistant contraction in the isolated jejunum of rabbits.
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PMID:4-Aminopyridine induces the release of neuropeptide Y (NPY) to produce an atropine- and tetrodotoxin-resistant contraction in rabbit isolated jejunum. 255 99

The role of the epithelium has been studied in the contractile responses of rat trachea. The different modulations observed are discussed in respect to vagal components of the epithelial layer. Responses of rat trachea to immunologic stimulation are shown to be dependent on the presence of the epithelium, which prolongs the relaxation stage without affecting the contractions. This prolongation is abolished by neonatal capsaicin pretreatment, whereas substance P induces a significantly greater relaxation of serotonin-precontracted intact than deepithelialized trachea. Serotonin concentration-response curves are shifted to the right in intact preparations, which is partly reversed by neonatal capsaicin pretreatment, but a hyporeactivity of the tissue exists. A relaxing factor released by the epithelium is hypothesized, possibly dependent on substance P-ergic innervation. Muscarinic cholinergic innervation slightly modulates the contractions but not the relaxations in antigen-induced responses, independently on the presence of the epithelial layer. 4-Aminopyridine induces epithelium-dependent potentiations of contractions to antigen and to serotonin, which involves acetylcholine at one step of the reaction cascade. Epithelial-dependent contracting and relaxing factors are thus suggested in rat trachea.
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PMID:Epithelial modulation of tracheal smooth muscle response to antigenic stimulation. 302 72

Repetitive preganglionic nerve stimulation increases cyclic guanosine 3':5'-monophosphate (cGMP) content in rat superior cervical ganglia by a mechanism requiring Ca++ but resistant to blockade by cholinergic receptor antagonists. Similarly, 45Ca-uptake during prolonged preganglionic nerve stimulation is unaffected by hexamethonium or atropine. These findings indicate that nerve stimulation increases cGMP accumulation and 45Ca-uptake by a noncholinergic mechanism Substance P, met-enkephalin and luteinizing hormone-releasing factor have little or no effect on cGMP content. By contrast, bethanechol causes a 3-fold increase in cGMP content and postganglionic cell firing. Thus, as reported by others, muscarinic receptor activation increases ganglionic cGMP[. 4-Aminopyridine causes an increase in cGMP of resting ganglia that requires Ca++ and the nerve terminal is blocked by tetrodotoxin but unaffected by atropine or hexamethonium. Ouabain also increases ganglionic cGMP content by a process that requires Ca++ and the nerve terminals. Like preganglionic nerve stimulation, 4-aminopyridine and ouabain cause cGMP accumulation in the nerve terminals or in the ganglion cells as a consequence of releasing a noncholinergic transmitter. The uptake of Ca++ by ganglion cells is not an adequate stimulus for cGMP accumulation because the nicotinic receptor agonist dimethylphenylpiperazinium increases 45Ca-uptake but has no effect on cGMP formation in ganglia.
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PMID:Cyclic guanosine 3':5'-monophosphate accumulation and 45Ca-uptake by rat superior cervical ganglia during preganglionic stimulation. 611 99

1. Intracellular recordings were made in intact and in acutely dissociated vagal afferent neurones (nodose ganglion cells) of the ferret to investigate the effects of substance P(SP). 2. In current-clamp recordings, SP (100 nM) applied by superfusion hyperpolarized the membrane potential (7 +/- 0.7 mV; mean +/- S.E.M.; n = 105) and decreased the input resistance in 80% of the neurones. With voltage-clamp recording, SP produced an outward current of 3 +/- 0.2 nA (n = 10). 3. The SP current was concentration dependent with an estimated EC50 of 68 nM. The SP-induced hyperpolarization or current was mimicked by the tachykinin receptor NK1 agonist Ac-[Arg6, Sar9, Met(O2)11]SP(6-11) (ASM-SP; 100 nM; n = 10) and blocked by the NK1 antagonist CP-96,345 (10 nM; n = 6), but not by the NK2 antagonist SR48968 (100 nM; n = 4). No measurable change in membrane potential or input resistance was observed with application of either [beta-Ala8]neurokinin A or senktide, selective NK2 and NK3 receptor agonists, respectively (100 nM; n = 3 for each agonist). 4. The reversal potential (Erev) for the SP outward current was -85 +/- 2.5 mV (n = 4). The Erev for the SP response shifted in a Nernstian manner with changes in extracellular potassium concentration. Alterations in extracellular sodium or chloride concentrations had no significant effect on the Erev for the SP response (n = 3 for each ion). 5. Nominally Ca(2+)-free external solution abolished the SP response. Removal of magnesium from the extracellular solution had no effect on the response. 6. Caesium (100 microM), barium (1 mM), tetraethylammonium (TEA; 5 mM), apamin (10 nM) and 4-aminopyridine (4-AP; 4 mM) each completely prevented the SP response (n > or = 3 for each). 7. These results indicate that SP, via an NK1 receptor, can induce a Ca(2+)-dependent outward potassium current which hyperpolarizes the resting membrane potential of vagal afferent somata.
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PMID:Substance P hyperpolarizes vagal sensory neurones of the ferret. 873 1

We have examined the effects of the tachykinin substance P on the action potential of lamprey mechanosensory dorsal cells. Substance P increased the spike duration and reduced the afterhyperpolarization. These effects were mimicked by stimulation of the dorsal root, which contains tachykinin-like immunoreactive fibres. The tachykinin antagonist spantide II blocked the effects of both substance P and dorsal root stimulation. The spike broadening was voltage-dependent, and was due to the reduction of a 4-aminopyridine-sensitive potassium conductance. The spike broadening was mimicked by G-protein activators and blocked by the G-protein inhibitor GDPbetaS. Pertussis toxin did not block the effects of substance P. The spike broadening was blocked by the protein kinase C and cAMP-dependent protein kinase inhibitor H7, and by the specific protein kinase C antagonist chelerythrine, but not by the cAMP and cGMP-dependent protein kinase inhibitor H8. The phorbol ester phorbol 12,13-dibutyrate mimicked and blocked the effects of substance P, supporting the role of protein kinase C in the spike modulation. The adenylate cyclase activator forskolin and the cAMP agonist SpcAMPs mimicked but did not block the effects of substance P on the spike duration, suggesting that protein kinase A also modulates the dorsal cell action potential, but that substance P acts independently of this pathway. Substance P also increased the excitability of the dorsal cells. This effect was blocked by 4-AP, PDBu and chelerythrine, but not by H8, suggesting that the increase in excitability shares the same intracellular and effector pathways as the spike broadening.
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PMID:Substance P modulates sensory action potentials in the lamprey via a protein kinase C-mediated reduction of a 4-aminopyridine-sensitive potassium conductance. 942 Nov 67

We examined the role of K+ channels in the endothelium-dependent relaxation which is resistant to nitric oxide (NO) synthase inhibition in porcine coronary artery. In the presence of 0.2 mM NG-nitro-L-arginine (L-NNA), a potent inhibitor of NO synthase, 10 nM substance P (SP) added to 9,11-dideoxy-11alpha,9alpha-epoxymethano-prostaglandin F2alpha (U46619) contractures elicited a relaxation. The L-NNA-resistant relaxation induced by SP was strongly inhibited by 5 mM tetrabutylammonium chloride (TBA), a non-specific inhibitor of K+ channels. Interestingly, 4-aminopyridine (4-AP, 1 mM), a relatively specific inhibitor of voltage-sensitive K+ channels, shortened the duration of SP response, but it had no effect on the peak of SP response. Although 4-AP has also been shown to inhibit Ca2+-activated K+ channels, the shortening effect of 4-AP in SP response was observed in the presence of 1 microM apamin, an inhibitor of small conductance Ca2+-activated K+ channels, or 100 nM charybdotoxin, and inhibitor of large conductance Ca2+-activated K+ channels. Moreover, although SP stimulates both L-NNA-resistant relaxation and endothelium-derived NO-dependent relaxation (EDNO) in porcine coronary arteries, a low concentration of 4-AP (1 mM) affected only the L-NNA-resistant response, but not the EDNO response. These are the first results to show that the L-NNA-resistant relaxation induced by SP, probably, endothelium-derived hyperpolarizing factor(s) (EDHF) response, is dependent on voltage-dependent K+ channels in porcine coronary artery.
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PMID:The endothelium-dependent, substance P relaxation of porcine coronary arteries resistant to nitric oxide synthesis inhibition is partially mediated by 4-aminopyridine-sensitive voltage-dependent K+ channels. 958 20

Recent studies revealed that a new compound, KW-7158 [(2S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide], can depress the excitability of afferent pathways from the urinary bladder and reduce bladder overactivity induced by chemical irritation of the urinary tract with xylene, an agent that sensitizes capsaicin-sensitive, C-fiber afferent nerves. In the present experiments, we examined the mechanisms that might underlie the depressant effect of KW-7158 on primary afferent neurons by studying the actions of the compound on ion channels and firing in dissociated dorsal root ganglion (DRG) cells from adult rats using whole cell patch-clamp techniques. KW-7158 increased transient, A-type K+ currents at concentrations ranging from 50 nM to 1 microM (20-50% increases). Similar effects were seen in fast blue identified bladder afferent neurons. Low concentrations of KW-7158 shortened the action potential duration, produced a 5- to 10-mV hyperpolarization, and inhibited repetitive firing induced by either 4-AP (50 microM) or substance P (0.5 microM) in phasic firing DRG neurons. Above 1 microM, KW-7158 elicited a smaller enhancement of A-type K+currents and in high concentrations inhibited the currents. Tetraethylammonium (5-60 mM) and verapamil (50 microM), which block noninactivating K+ currents, did not prevent the facilitatory effects of KW-7158. High concentrations of 4-AP (5 mM) inhibited A-type K+ currents and prevented the facilitatory effect of KW-7158 on the remaining currents. These data suggest that KW-7158 enhances A-type K+ currents in DRG neurons. Because A-type K+ channels regulate afferent neuron excitability and firing properties, KW-7158 is a promising new compound for treatment of hyper-reflexic bladder conditions.
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PMID:KW-7158 [(2S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide] enhances A-type K+ currents in neurons of the dorsal root ganglion of the adult rat. 1501 May 2