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)

The effects of various muscarinic antagonists on acetylcholine (ACh)-induced pulmonary oedema were studied in isolated perfused rabbit lungs. ACh induced a dose-dependent increase in the capillary filtration coefficient (Kf,c). This effect has been previously related to the activation of the capsaicin-sensitive nerve fibres and the release of substance P. Atropine, pirenzepine (M1-selective antagonist) and 4-DAMP (M3-selective antagonist) altered this response, producing a dose-dependent shift to the right of the ACh concentration-Kf,c response curve. By contrast, the M2-selective antagonist AFDX-116 shifted the ACh concentration-response curve to the left. Atropine, pirenzepine and 4-DAMP also significantly reduced the capsaicin-induced increase in the Kf,c, while AFDX-116 enhanced it. We conclude that multiple muscarinic receptor subtypes are present in the rabbit lung, located on the C-fibres, and are involved in the ACh-induced pulmonary oedema. M1 and M3 receptors seem to stimulate the release of neuropeptides from C-fibres, whereas M2 receptors have an inhibitory effect on these fibers.
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PMID:Multiple muscarinic receptor subtypes mediating pulmonary oedema in the rabbit. 782 37

The present study was designed to examine some of the pharmacological properties of venom from the stonefish (Synanceja trachynis), with particular reference to the presence in the venom of pain-producing/enhancing substances. Stonefish venom (1-6 micrograms/ml) produced concentration-dependent contractile responses in guinea-pig isolated ileum. No tachyphylaxis, or reduction in responses with time, was observed to venom (3 micrograms/ml) in ileum. The response to venom (3 micrograms/ml) was not significantly affected by the histamine antagonist mepyramine (0.5 microM), or a preceding anaphylactic response. Mecamylamine, 5HT-desensitization or EXP3174 failed to have any significant effect on responses to venom (3 micrograms/ml). Responses to venom (3 micrograms/ml) were significantly inhibited by the cyclooxygenase inhibitor indomethacin (5 microM), the leukotriene D4 receptor antagonist FLP55712 (1 microM), the thromboxane A2 receptor antagonist GR32191B (1 microM), the muscarinic receptor antagonist atropine (10 nM) and the neurokinin-1 receptor antagonist CP96345 (0.1 microM). Venom (6 micrograms/ml) produced contractile responses in the rat isolated vas deferens which were abolished by the alpha 1-adrenoceptor antagonist prazosin (0.3 microM) and significantly potentiated by the neuronal uptake inhibitor DMI (1 microM). However, noradrenergic transmitter depletion with reserpine (5 mg/kg, i.p.) did not significantly inhibit responses to venom (6 micrograms/ml). Histamine fluorometric and phospholipase A2 assays failed to detect significant quantities of either substance in the venom. These results suggest that stonefish venom may cause the release of acetylcholine, substance P, and cyclooxygenase products, or contain components which act at these receptors. The venom also appears to contain a component which is a substrate for neuronal uptake and has a direct action at alpha 1-adrenoceptors.
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PMID:Pharmacological studies of stonefish (Synanceja trachynis) venom. 784 90

The purpose of the present study was to examine Ca2+ signaling mechanisms in Sf9 cells and to demonstrate expression and functional linkage of a mammalian receptor to changes in cytosolic free Ca2+ concentration ([Ca2+]i). Addition of p-octopamine (50 microM to fura 2-loaded Sf9 cells produced a small transient increase in [Ca2+]i from a basal level of 58 +/- 10 to 194 +/- 7.6 (SD) nM. The response to octopamine was inhibited by both cyproheptadine and chlorpromazine and was mimicked by clonidine. In contrast, [Ca2+]i did not change in response to dopamine (50 microM), substance P (50 nM), histamine (50 microM), ATP (50 microM), acetylcholine (10 or 100 microM), carbachol (10 or 100 microM), serotonin (50 microM), epinephrine (10 microM), or bradykinin (50 nM). The Ca(2+)-adenosinetriphosphatase inhibitors thapsigargin (200 nM) and 2,5-di-tert-butylhydroquinone (BHQ; 10 microM) increased [Ca2+]i to 307 +/- 13 and 137 +/- 20 nM, respectively. In contrast to BHQ, the response to thapsigargin was attenuated by La3+ or removal of extracellular Ca2+ and increased by elevation of extracellular Ca2+. These results suggest that thapsigargin but not BHQ stimulates Ca2+ influx. The rat brain muscarinic receptor (subtype M5) was incorporated into the baculovirus by homologous recombination. Addition of carbachol (100 microM) increased [Ca2+]i from 92.7 +/- 6.4 to 480 +/- 26 nM in Sf9 cells infected with recombinant virus containing the M5 receptor cDNA. The effect of carbachol on [Ca2+]i was concentration dependent with a 50% effective concentration of approximately 30 microM and was blocked by atropine (10 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ca2+ signaling in Sf9 insect cells and the functional expression of a rat brain M5 muscarinic receptor. 802 3

This study was conducted to determine whether drug-dependent changes in cytosolic Ca2+ concentration take place in the ciliary nonpigment epithelial cells of rabbits under more physiological conditions. Iris-ciliary body from pigmented rabbits in organ-culture was loaded with a Ca(2+)-sensitive fluorescent dye, fura-2, and a video-imaging system with an image analyzer was employed. Using this method fluorescence from nonpigmented epithelial cells can be analyzed without interference from fluorescence from pigmented ciliary epithelial cells. Among the drugs studied, norepinephrine and carbachol induced Ca2+ transients in the nonpigmented epithelial cells of organ-cultured ciliary processes. Epinephrine, isoproterenol, dopamine, neuropeptide Y, and substance P at the concentration of 10(-6) to 10(-3) M failed to elicit a response. The cytosolic free Ca2+ concentration of the cells in the resting state, as determined by an in vitro calibration curve, was 166 nM. The peak free cytosolic Ca2+ concentration induced by norepinephrine was about 263 nM, and that induced by carbachol was more than 1,000 nM. The carbachol-induced response was larger in magnitude and longer in duration than that induced by norepinephrine. Not uncommonly, the carbachol-induced response lasted more than 15 min. The response was diminished in both peak height and duration by chelation of extracellular Ca2+. Atropine abolished the response showing the response being mediated by a muscarinic receptor.
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PMID:Drug-dependent Ca2+ mobilization in organ-cultured rabbit ciliary processes. 852 97

The purpose of this study was to establish immortalized cell cultures of cat iris sphincter smooth muscle cells for a model investigating ocular receptors and their signal transduction pathways. Cultured cat iris sphincter muscle cells were immortalized by viral transformation with SV40 virus and the morphological and immunocytochemical properties of the normal and immortalized cells were investigated. The transformed cell clone, SV-CISM-2, was further characterized biochemically and pharmacologically. The normal muscle cells showed characteristics of smooth muscle cells, as judged by their growth and the presence of smooth muscle alpha-actin and desmin. After seven passages the normal cells ceased to proliferate. In contrast, the immortalized cells retained their proliferative ability for more than 220 population doublings over 55 passages. The transformation phenotype in these cells was confirmed by their expression of the large T-antigen, the incorporation of viral DNA into cellular DNA, growth in agarose and in low-serum medium, and complete loss of contact inhibition. The immortalized cells expressed smooth muscle alpha-actin, desmin and MLC protein. Biochemical and pharmacological studies on the SV-CISM cells revealed the presence of several functional receptors including muscarinic cholinergic, beta-adrenergic, peptidergic (substance P and endothelin). Platelet-activating factor, and prostaglandin (PG). Muscarinic stimulation of these cells resulted in: (a) a dose-dependent increase in the release of arachidonic acid (AA) and (PGs) and enhancement in the production of inositol trisphosphate (IP3); and (b) a substantial increase in MLC phosphorylation (118%), an indicator of smooth muscle contractility. The stimulatory effects of carbachol on these responses were completely blocked by atropine, a muscarinic receptor antagonist. This study constitutes the first successful immortalization of iris sphincter smooth muscle cells. The SV-CISM-2 cells can serve as an important model system for investigations on the biochemical and pharmacological properties of receptors and their signal transduction pathways in smooth muscle. The advantage of these cells over normal iris sphincter cells is that they can be propagated over many generations without alterations in their morphological, biochemical and physiological characteristics.
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PMID:Immortalization of cat iris sphincter smooth muscle cells by SV40 virus: growth, morphological, biochemical and pharmacological characteristics. 865 96

Cholinergic stimulation has opposing effects on striatopallidal and striatonigral neurons. Most striatal projection neurons express m1 muscarinic receptor mRNA with m4 mRNA found in 40-50%. Expression of m4 mRNA is found in most preprotachykinin neurons but only a subset of preproenkephalin neurons, suggesting preferential localization of m4 receptors to striatonigral neurons. A volkensin lesion of striatonigral neurons reduced striatal m4 mRNA by 63% and m1 mRNA by only 18%, suggesting that preferential expression of m4 receptors by striatonigral neurons may contribute to their differential response.
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PMID:Expression of m1 and m4 muscarinic receptor mRNA in the striatum following a selective lesion of striatonigral neurons. 889 41

We have studied the importance of tachykinins and acetylcholine for motor stimulation of the rat duodenum in vitro. Contractions induced by transmural nerve stimulation and tachykinin receptor agonists selective for NK1, NK2 and NK3 receptors were used in combination with a neurokinin (NK)2 receptor antagonist, MEN 10,627, and atropine as a muscarinic receptor antagonist. Transmural nerve stimulation in the range 0.5-32 Hz caused frequency-dependent contractions. MEN 10,627 (10(-8), 10(-7) and 10(-6) M) dose-dependently reduced the contractile frequency-response curve (P < 0.01-0.001). Addition of atropine (10(-8) M) completely inhibited the response to transmural nerve stimulation (P < 0.001). As control, atropine alone reduced this response only by about 65%. Of the tachykinin analogues, [beta-AlaB]-neurokinin A(4-10) selective for NK2 receptors caused concentration-dependent contractions with high potency (pD2 8.01) and high efficacy, while substance P methyl ester acting on NK1 receptors had lower potency (pD2 7.94) and low efficacy, and senktide acting on NK3 receptors had a low potency (pD2 7.52) but high efficacy. With increasing concentrations of MEN 10,627 the response to [beta-AlaB]-neurokinin A(4-10) was markedly reduced (P < 0.01), while responses to substance P methyl ester and senktide were only slightly affected. Our results indicate that the physiological contractile responses of the rat duodenum are co-mediated by acetylcholine and tachykinins, for which NK2 receptors seem to be most important.
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PMID:Contractile responses of rat duodenum caused by transmural nerve stimulation: interaction between tachykininergic and cholinergic mechanisms. 889 60

This study investigated the effects of pharmacological blockade or stimulation of muscarinic receptors on constitutive and amphetamine-stimulated preprodynorphin, substance P and pre-proenkephalin gene expression in rat striatum. Acute administration of the non-selective muscarinic antagonist, scopolamine (2.5, 5 and 10 mg/kg, s.c.), caused a dose-dependent increase in preprodynorphin and substance P, but not preproenkephalin, messenger RNA expression in the dorsal and ventral striatum as revealed by quantitative in situ hybridization. In contrast, acute injection of the non-selective muscarinic receptor agonist, oxotremorine (0.125, 0.25 and 0.5 mg/kg, s.c.), caused a dose-dependent increase in basal levels of preproenkephalin messenger RNA in the dorsal striatum, without causing a significant effect on constitutive striatal preprodynorphin and substance P expression. Pretreatment with scopolamine (2.5 mg/kg, s.c.) significantly augmented striatal induction of preprodynorphin and substance P messenger RNA induced by acute injection of amphetamine (1.25 and 2.5 mg/kg, i.p.), whereas scopolamine blocked amphetamine-stimulated striatal preproenkephalin expression. Pretreatment with oxotremorine (0.25 mg/kg, s.c.) significantly attenuated amphetamine (1.25 and 2.5 mg/kg, i.p.)-stimulated striatal preprodynorphin and, to a lesser degree, substance P messenger RNA expression. Oxotremorine tended to increase amphetamine-stimulated preproenkephalin messenger RNA expression, but the effect did not reach statistical significance. In addition, scopolamine increased spontaneous, and enhanced amphetamine-stimulated, behavioral activity, whereas oxotremorine attenuated amphetamine-stimulated behaviors. These data support the concept that cholinergic transmission, via interaction with muscarinic receptors, inhibits basal and D1 receptor-stimulated striatonigral dynorphin/substance P gene expression and facilitates striatopallidal enkephalin gene expression.
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PMID:Muscarinic receptors regulate striatal neuropeptide gene expression in normal and amphetamine-treated rats. 892 22

The purpose of the present study was to examine the mechanism of the stimulatory effect of substance P (SP) on cyclic AMP (cAMP) accumulation in dog iris sphincter. We found that: (1) SP increased cAMP accumulation in a time- and concentration-dependent manner, the T1/2 and EC50 values being 1.2 min and 44 nM, respectively. SP has no effect on inositol trisphosphate and muscle contraction in this tissue. (2) SP-stimulated cAMP formation was inhibited by quinacrine, a non-specific phospholipase A2 inhibitor (IC50 = 9.5 microM), and by indomethacin (Indo), a cyclooxygenase inhibitor (IC50 = 3.5 nM), in a concentration-dependent manner, suggesting that SP induces cAMP accumulation via an Indo-sensitive pathway. (3) SP-induced arachidonic acid release and SP-induced prostaglandin E2 (PGE2) release were inhibited concentration dependently by quinacrine and Indo, with IC50 values of 11 microM and 0.8 nM, respectively. (4) PGE2 (1 microM) increased cAMP formation in the sphincter muscle by 94%, and, furthermore, the PG, but not SP, stimulated the activity of adenylyl cyclase in membrane fractions isolated from this tissue. (5) Indo (1 microM) blocked the relaxing effect of SP (1 microM) in iris sphincter precontracted with carbachol (1 microM). (6) The inhibitory effect of Indo on SP-induced cAMP accumulation was species specific. Increases in cAMP represent a mechanism by which extracellular SP can regulate smooth muscle function. Thus, we conclude from these studies that in dog iris sphincter SP-induced cAMP accumulation is mediated through PGs, and that in this cholinergically innervated muscle SP via cAMP could function, in part, to modulate the physiological responses to muscarinic receptor stimulation.
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PMID:Mediation by prostaglandins of the stimulatory effect of substance P on cyclic AMP production in dog iris sphincter smooth muscle. 893 34

In addition to transmitters stored in and released from terminals of efferent nerves, transmitters of afferent nerves and their receptors are also involved in the control of lower urinary tract function. Tachykinins, such as substance P and neurokinins A and B, and other neuropeptides have been demonstrated in nerves of the the lower urinary tract and shown to be able to influence bladder function. Drugs affecting these nerves by causing release of tachykinins, and agents antagonizing tachykinin receptors, may be of therapeutic interest. New information on the alpha-adrenoceptor and muscarinic receptor subtypes mediating contraction of the human urethra and detrusor, respectively, has emerged, and may be the basis for the development of compounds with selectivity for the urethra or the bladder 'Non-classical' transmitters, such as nitric oxide, may also be of importance for bladder function. Nitric oxide derived from nerves seems to be involved in reflex relaxation of the outflow region at the start of micturition. However, nitric oxide derived from other sources may have a role in bladder disorders, such as interstitial cystitis.
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PMID:Neurotransmitters and neuroreceptors in the lower urinary tract. 894 35


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