Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The possible mechanism underlying the vasorelaxant effect of emodin isolated from a Chinese herb, was investigated in this study. Emodin dose dependently relaxed isolated vascular rings of human internal mammary artery and saphenous vein, rabbit thoracic aorta, abdominal aorta and mesenteric artery, and rat thoracic aorta. There were no differences in the sensitivity (IC50) and maximal relaxation between intact and endothelium-denuded preparations of rat aorta. In the presence of emodin (10 microM), the contractile responses of rat aorta to phenylephrine, serotonin and potassium chloride were depressed. The relaxation response to acetylcholine was attenuated by emodin, whereas that to isoproterenol was unaffected. The relaxation response to emodin was inhibited by free radical scavengers, superoxide dismutase, catalase and mannitol, and guanylate cyclase inhibitors, methylene blue and hemoglobin. Catalase was the most effective scavenger. Quinacrine (phospholipase A2 inhibitor), indomethacin (cyclooxygenase inhibitor) and nordihydroguaiaretic acid (NDGA, lipoxygenase inhibitor) potentiated the relaxation induced by emodin. NDGA was the most effective potentiator. Exposure of aortic rings to emodin (10 microM) increased the basal level of guanosine 3',5'-cyclic monophosphate (cGMP). It is suggested that the vasorelaxant effect of emodin may be mainly due to cGMP accumulation as a result of guanylate cyclase activation by free radicals and/or hydrogen peroxide generated from semiquinone.
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PMID:Vasorelaxant effect of emodin, an anthraquinone from a Chinese herb. 166 13

This study evaluates the role of intracellular levels of Ca2+ [Ca2+]i in cyclic GMP formation mediated by muscarinic and histamine receptors in the mouse neuroblastoma clone N1E-115. Muscarinic agonists activated the turnover of phosphoinositides with a relative maximal response similar to that observed previously for cyclic GMP formation. Carbamylcholine induced a transient increase in inositol trisphosphate with a time course similar to that of cyclic GMP formation. In cells loaded with the fluorescent Ca2+ probe fura-2/acetoxymethyl ester, carbamylcholine as well as histamine induced a rapid and transient rise in [Ca2+]i. The time course of the changes in [Ca2+]i induced by agonists as well as by ionomycin closely paralleled that of cyclic GMP formation. Chelation of [Ca2+]i by loading of N1E-115 cells with quin 2/acetoxymethyl ester inhibited cyclic GMP formation induced by agonists in a dose-dependent manner. When cyclic GMP formation induced by agonists was assayed after the cells were exposed to 3 mM ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) for 2 min, the formation of cyclic GMP was not inhibited significantly; however, it was completely abolished after 30-min exposure to EGTA. Treatment of cells with phospholipase A2 had no effect on resting [Ca2+]i and only slightly increased cyclic GMP formation, in spite of the induction of a marked release of [3H]arachidonate. Moreover, the formation of cyclic GMP induced by ionomycin was inhibited by the addition of phospholipase A2. Melittin contaminated with phospholipase A2 activity induced a rapid and sustained increase in cyclic GMP formation, as well as unesterified [3H]arachidonate release. However, after inactivation of the phospholipase A2 activity of melittin, its ability to stimulate cyclic GMP formation was enhanced. Our data indicate that receptor agonists stimulate cyclic GMP formation in N1E-115 cells by activating the formation of inositol trisphosphate, which is followed by the release of Ca2+ from intracellular stores. The evidence obtained does not support a major role for arachidonate release in receptor-mediated activation of guanylate cyclase. Conversely, it is consistent with an inhibitory role for arachidonic acid or its metabolites in this process.
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PMID:Role of intracellular Ca2+ mobilization in muscarinic and histamine receptor-mediated activation of guanylate cyclase in N1E-115 neuroblastoma cells: assessment of the arachidonic acid release hypothesis. 197 74

1) Eicosanoids are a family of polyunsaturated 20-carbon fatty acids and their metabolites. The metabolites are produced by three enzymatic pathways: the cyclooxygenase pathway, giving prostaglandins (PGs), the lipoxygenases and the epoxygenases pathways. Arachidonic acid (C20:4) is the most common fatty acid precursor in mammalian cells, where it is incorporated, as an ester, into the membrane lipid complex. 2) The eicosanoids have a variety of effects on several cell activities, including secretion, muscle contraction, cell growth and differentiation. The type of effect--stimulation or inhibition--depends on the metabolite, its concentration, the metabolic activity of the cell and the involvement of other humoral factors. 3) The message may be transmitted via a specific membrane receptor to a specific transduction system: the adenyl or guanyl cyclase system and mobilization of free cytosolic Ca2+, or via the participation of membrane ion channels. Depending on which is involved, the eicosanoid message applies to the cell in which it was synthesized or to neighboring cells (autocrine or paracrine action). 4) The eicosanoids, especially the PGs, take part in many reproductive processes; in the hypothalamic-pituitary axis, particularly through the synaptic modulation by PGE2 (stimulation of LHRH secretion and inhibition of noradrenaline secretion); in the ovary: follicle maturation and luteolysis; in the oviducts: gamete migration; in the uterus: ovum implantation and parturition. 5) PGs seem to have a variety of species-dependent effects on the normal onset of labor. In sheep there is an increase in fetal cortisol, a drop in the progesterone/estradiol ratio and increased PG synthesis. In women, there is an increase of phospholipase A2 activity in amnios and uterus with an increase of PGE2 in the first tissue and of PGF2 alpha in the second one. 6) The PGs from the seminal fluid have several actions. They effect fertility by acting on the female genital tract or on the spermatozoa. PGE1 and PGE2 influence the fertilization capacity. PGs also effect the process of ejaculation (inhibition of the stimulatory effect of noradrenaline). Finally, they effect the immune responses: PGEs and 19 hydroxy PGEs immuno-suppressive characteristics.
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PMID:[Prostaglandins and reproduction. I. Physiological aspects]. 201 23

The mechanism by which serotonin (5-HT3) receptors mediate a rise in cyclic-GMP level was investigated in a neuronal cell line. Inhibitors of phospholipase A2 (mepacrine) and of lipoxygenase (eicosatetraynoic acid or nordihydroguaiaretic acid) suppressed the action of serotonin. On the other hand, inhibition by hemoglobin indicates a role for nitric oxide which could be in part responsible for the cyclic-GMP effect as an intercellular stimulant. The suppression of the serotonin effect by the arginine analogues N omega-methyl-L-arginine and canavanine is consistent with the notion that nitric oxide could be released from arginine. The serotonin-induced rise of cyclic-GMP level depends on the presence of extracellular Ca2+ with half-maximal stimulation at 0.3 mM Ca2+. The serotonin-stimulated rise of cyclic GMP was inhibited by (a) addition of inorganic blockers of Ca2(+)-permeable channels (La3+, half-maximal inhibitory concentration (IC50) 0.04 mM; Mn2+, IC50, 0.4 mM; Co2+, IC50, 0.9 mM; Ni2+, IC50, 1.2 mM) and (b) of organic blockers (diltiazem: IC50, 6 microM, methoxyverapamil: IC50, 3 microM and (c) intracellular application of the Ca2+ chelator bis-(O-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (IC50, 2 microM). Thus, two pathways for the activation of soluble guanylate cyclase by serotonin are possible: (a) via lipoxygenase products of arachidonic acid and/or (b) via nitric oxide or a related nitroso compound. Serotonin mediates a rise of cytosolic Ca2+ activity due to entry of extracellular Ca2+. It still has to be investigated which step depends on a rise of cytosolic Ca2+ activity that appears to be a prerequisite for activation of guanylate cyclase.
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PMID:Mechanism of stimulation of cyclic-GMP level in a neuronal cell line mediated by serotonin (5-HT3) receptors. Involvement of nitric oxide, arachidonic-acid metabolism and cytosolic Ca2+. 216 57

The present study, addressed to understand the mechanism behind the cholesterol-induced proliferative and collagen secretory activity of smooth muscle cells, revealed that cholesterol-induced smooth muscle cellular DNA synthesis and collagen secretion was mediated through its ability to amplify the intracellular cGMP signal because of the fact that Trifluoperazine (an anticalmodulin and blocker of phospholipase A2) and colchicine (an antitubulin and inhibitor of guanyl cyclase) inhibited DNA synthesis and collagen-secretory activity of smooth muscle cells by their ability to decrease the cGMP levels within smooth muscle cells. From these results we suggest that membrane cholesterol modulated phospholipase 'A2' activity may be the basic mechanism involved in cholesterol-induced proliferative and collagen-secretory activity of smooth muscle cells in vitro.
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PMID:Effect of trifluoperazine and colchicine on smooth muscle cellular proliferative and secretory activity induced by hypercholesterolemic medium in vitro. 216 85

Cyclic GMP formation and inositol phospholipid hydrolysis were studied in rat brain slices to determine if the two processes have common origins. Muscarinic cholinergic stimulation enhanced [3H]inositol phosphate ([ 3H]IP) accumulation from slices prelabelled with [3H]inositol but did not affect cyclic GMP formation in the cortex, striatum, or cerebellum. An elevated level of extracellular K+ stimulated accumulation of both cyclic GMP and [3H]IP in cortex slices. The former, but not the latter, was reduced by lipoxygenase and phospholipase A2 inhibition. Calcium channel activation enhanced and blockade reduced K+-stimulated [3H]IP formation without affecting the cyclic GMP level, and there were differences in the Ca2+ requirements for the two responses. Thus, there is no support for the concept that guanylate cyclase activation inevitably accompanies inositol phospholipid breakdown, and the evidence presented demonstrates that K+ stimulation promotes cyclic GMP and [3H]IP accumulation by different transducing pathways.
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PMID:Cyclic GMP formation and inositol phosphate accumulation do not share common origins in rat brain slices. 242 34

A brief review is given of the vasodilators that require an intact vascular endothelium to exert their relaxing effect. Then some major issues of the phenomenon of endothelium-dependent smooth muscle relaxation are discussed in more detail: The chemical structure of the endothelium-derived relaxing factor (EDRF), which mediates this type of vasodilation, is still unclear. There is agreement that EDRF is chemically unstable, but determinations of its biological half-life have yielded discrepant values (6-50 s). Recent evidence suggests that oxygen and/or activated oxygen species accelerate the evanescence of the factor. The biochemical mechanisms involved in the production of EDRF are still largely unknown. Both stimulators of phospholipase A2 and inhibitors of lysolecithin acyltransferase were found to induce EDRF-mediated relaxation, while several phospholipase inhibitors block these relaxations. These findings suggest that cleavage of phospholipids (and formation of free fatty acids and lysophosphatides) play an important role in EDRF production. EDRF-mediated relaxations are associated with increased levels of cyclic GMP in vascular smooth muscle cells. Endothelial cells were found to produce a factor that directly stimulates the enzymatic activity of soluble guanylate cyclase. This stimulating factor is likely to be identical with EDRF. The significance of the endothelium-dependent relaxing mechanism in resistance vessels is still largely unclear. In the blood-perfused hind limb of the rabbit, two irreversible inhibitors of endothelium-dependent vasodilation (gossypol and p-bromophenacyl-bromide) blocked the vasodilation induced by the endothelium-dependent agent acetylcholine, but not the response to the endothelium-independent vasodilator prostaglandin E1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Properties and mechanisms of production and action of endothelium-derived relaxing factor. 243 90

The present study investigates the mechanism of endothelium-dependent relaxation of vascular smooth muscle. Melittin, a polypeptide found in honeybee venom and a known activator of phospholipase A2, induced transient, endothelium-dependent relaxations of rat thoracic aortae contracted with norepinephrine. Higher concentrations of melittin induced relaxations followed by contractions. Prior incubation of melittin with trypsin abolished the changes in relaxation and contraction due to melittin. Melittin (10 micrograms/ml)-induced relaxations were associated with transiently elevated levels of cyclic GMP with a peak increase of 30-fold, which occurred 30 seconds after melittin exposure. Melittin (10 micrograms/ml) elevated cyclic AMP levels less than twofold and this effect was variable. A lower concentration of melittin (1 microgram/ml) elevated cyclic GMP levels approximately twofold, while exposure to 1 microgram/ml melittin in the presence of the cyclic GMP phosphodiesterase inhibitor, M&B 22948 (1 mM), increased cyclic GMP levels fivefold. Removal of the endothelium prevented the increased levels of cyclic GMP and cyclic AMP due to melittin. Exposure to the guanylate cyclase inhibitor, methylene blue, prevented the increased levels of cyclic GMP. Methylene blue, nordihydroguaiaretic acid, and the phospholipase A2 inhibitor, parabromophenacyl bromide, inhibited melittin-induced relaxations, while the cyclo-oxygenase inhibitor, indomethacin, was without effect. Arachidonic acid increased cyclic AMP levels but had no effect on cyclic GMP levels in the presence or absence of indomethacin. Relaxations to melittin, and to the endothelium-dependent vasodilators acetylcholine, trypsin, histamine, and the Ca2+ ionophore A23187, and/or the associated increased cyclic GMP levels, were reduced following exposure to melittin. Prior exposure to polyarginine (10 micrograms/ml), which induced endothelium-dependent relaxations that were prevented by methylene blue, also inhibited relaxations to the endothelium-dependent vasodilators. In contrast, relaxations to sodium nitroprusside were potentiated in tissues previously exposed to melittin. Removal of the endothelium by rubbing the intimal surface also potentiated relaxations to sodium nitroprusside. Scanning electron micrographs of the intimal surface demonstrated that melittin and polyarginine greatly damaged the endothelial cells. The present results suggest that polycation containing peptides induce endothelium-dependent relaxation through elevation of cyclic GMP levels within the smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of melittin on endothelium-dependent relaxation and cyclic GMP levels in rat aorta. 253 55

Uteroglobin (UG) or blastokinin is a steroid-dependent low molecular weight secretory protein in the rabbit. This protein has many immunomodulatory properties. Recently, UG has been reported to be a potent phospholipase A2 (E.C. 3.1.1.4) inhibitor and this property may explain, at least in part, the immunomodulatory/antiinflammatory effects of this protein. Although UG has been detected in many reproductive and non-reproductive tissues of the rabbit it has not been reported in the circulation of this animal. Here, we present biochemical and immunochemical evidence for the presence of a low molecular weight circulating protein with progesterone binding and phospholipase A2 inhibitory properties similar to rabbit uterine UG. The major organs which contribute UG-like protein in circulation seem to be the tracheobronchial tree and to a lesser extent the uterus. The concentration of this protein is much higher in the vicinity of these organs as compared to peripheral circulation. Phospholipase A2 (PLA2)-catalyzed reaction is the major pathway of arachidonic acid production from cell membrane phospholipids. Arachidonic acid participates in the stimulation of guanylate cyclase, adenylate cyclase, protein kinase C and release of calcium from intracellular stores. These processes are thought to be involved in cellular signal transduction. Arachidonic acid is also essential for eicosanoid synthesis and many eicosanoids (e.g. prostaglandins, leukotrienes, etc.) are proinflammatory. Thus, the UG-like protein by inhibiting PLA2 may play a vital role in the regulation of cellular signal transduction, control of inflammation and platelet aggregation.
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PMID:Detection of a uteroglobin-like phospholipase A2 inhibitory protein in the circulation of rabbits. 274 26

Characteristics of phospholipase A2 (PLA2) modulation of guanylate cyclase were evaluated. Addition of phospholipase A2 from Vipera russelli venom led to a significant increase in the activity of guanylate cyclase in various rat organs. The activation of the enzyme was selective and was only observed in the particulate fractions of tissue homogenate. The soluble guanylate cyclase from all the tissue tested exhibited lack of stimulation. The treatment of membranes with PLA2 resulted in solubilization of cyclase activity. The increase in enzyme by PLA2 was not altered by antioxidants or reducing agents. Addition of calcium ions led to further enhancement in PLA2-dependent increases in cyclic GMP formation. Peak calcium responses were observed in micromolar concentration ranges. These observations suggest a potential role for PLA2 and calcium ions in the hormonal regulation of cyclic GMP metabolism.
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PMID:Phospholipase A2 modulation of cyclic GMP metabolism: characteristics of guanylate cyclase activation. 286 36


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