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)

We attempted to identify and establish the role of cyclic nucleotide phosphodiesterase (PDE) isozymes in human basophils by using standard biochemical techniques as well as describing the effects of isozyme-selective and nonselective inhibitors of PDE. The nonselective PDE inhibitors, theophylline and 3-isobutyl-1-methylxanthine, inhibited anti-IgE-induced release of histamine and leukotriene C4 (LTC4) from basophils. This inhibition was accompanied by elevations in cAMP levels. Rolipram, an inhibitor of the low Km cAMP-specific PDE (PDE IV), inhibited the release of both histamine and LTC4 from activated basophils and increased cAMP levels in these cells. In contrast, mediator release from basophils was not inhibited by either siguazodan or SK&F 95654, inhibitors of the cGMP-inhibited PDE (PDE III) or zaprinast, an inhibitor of the cGMP-specific PDE (PDE V). SK&F 95654 failed to elevate basophil cAMP in these experiments whereas zaprinast induced significant increases in cAMP content. The inhibitory effect of rolipram on mediator release was potentiated by siguazodan or SK&F 95654, but not by zaprinast. SK&F 95654 also enhanced the ability of rolipram to increase cAMP content. Forskolin, a direct activator of adenylate cyclase, inhibited IgE-dependent release of mediators from basophils and increased cAMP levels in these cells. These effects were enhanced by rolipram, but not by SK&F 95654 or zaprinast. The cell permeant analog of cAMP, dibutyryl cAMP, inhibited mediator release from these cells, a property not shared by either dibutyryl-cGMP or sodium nitroprusside, an activator of soluble guanylate cyclase. The presence of both PDE III and PDE IV was confirmed by partially purifying and characterizing PDE activity in broken cell preparations. Overall, these data lend support to the hypothesis that cAMP inhibits mediator release from basophils and suggest that the major PDE isozyme responsible for regulating cyclic AMP content in these cells is PDE IV, with a minor contribution from PDE III. However, the finding that zaprinast caused increases in cAMP without inhibiting mediator release indicates that cAMP accumulation is not invariably linked to an inhibition of basophil activation.
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PMID:Preliminary identification and role of phosphodiesterase isozymes in human basophils. 137 72

The mast cell is the cellular basis for immediate hypersensitivity reactions. The specificity of the immediate hypersensitivity reaction is attributable to IgE molecules fixed to specific membrane receptors which, when stimulated by specific antigen, initiates the process of degranulation of the mast cell. The granules provide three separate sources of biologic activity: performed or primary mediators, newly generated or secondary mediators, and activities associated with the granular matrix. A number of biologic consequences are generated in response to these mediators and these include: increased vascular permeability, vasodilation, smooth muscle spasm, polymorphonuclear leukocyte chemotaxis, stimulation of adenylate and guanylate cyclase, superoxide radical generation, prostaglandin formation, mucous and gastric acid secretion, hypotension, tissue destruction, and mononuclear leukocyte infiltration. This pharmacopia of activities accounts for the clinical aspects of allergic diseases, suggests that the mast cell granule may be involved in the host's defense against parasitic infections, and is compatible with a suggested role of the mast cell as a widely distributed, monocellular endocrine system.
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PMID:The mast cell. 617 51

This study examined whether a clinically relevant concentration of the volatile anaesthetic halothane modifies the endothelium-dependent relaxation produced by acetylcholine (3 nM-10 microM), histamine (1 pM-0.1 microM) and anti-human immunoglobulin E (1:1000) in human isolated pulmonary arteries submaximally precontracted with noradrenaline. An inhibitor of nitric oxide formation, N(G)-nitro-L-arginine (100 microM), attenuated acetylcholine-induced relaxation but failed to inhibit histamine- and anti-human immunoglobulin E-induced relaxation. Indomethacin (2.8 microM, a cyclooxygenase inhibitor) preferentially reduced the relaxation to histamine and anti-human IgE. Halothane (2%) significantly attenuated the relaxation to acetylcholine but had no significant effect on the relaxation elicited by histamine and anti-human IgE. Halothane (2%) enhanced the basal release of prostaglandin I2 by human pulmonary arteries (control 0.31 +/- 0.04 ng mg(-1); treated tissues 0.50 +/- 0.06 ng mg(-1); n = 5; P < 0.05). Halothane (2%) did not alter the responsiveness and sensitivity of preparations to relaxants acting through activation of adenylyl cyclase (forskolin) or guanylyl cyclase (sodium nitroprusside) or by the opening of K(ATP) channels (cromakalim). In conclusion, halothane inhibits the endothelium-dependent relaxation of human pulmonary arteries to acetylcholine by interfering with the nitric oxide pathway at a site before activation of soluble guanylyl cyclase in vascular smooth muscle.
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PMID:Halothane inhibits endothelium-dependent relaxation elicited by acetylcholine in human isolated pulmonary arteries. 919 70

We report that cultured rat peritoneal cells spontaneously synthesize nitric oxide and this is associated with active suppression of mast cell secretory function. Addition of interleukin-4 (IL-4) or the nitric oxide synthase inhibitor N-monomethyl-l-arginine to peritoneal cells inhibited nitric oxide synthesis and enhanced anti-IgE-mediated mast cell degranulation, measured as serotonin release. Interferon-gamma (IFN-gamma) completely overcame the enhancement of serotonin release and suppression of nitrite production induced by IL-4. Over several experiments, with or without IL-4 and/or IFN-gamma, serotonin release correlated inversely with nitrite production. On a cell-for-cell basis, non-mast cells produced approximately 30 times more nitrite than mast cells in peritoneal cell populations, with or without IFN-gamma stimulation. The nitric oxide donor S-nitrosoglutathione inhibited anti-IgE-induced serotonin release from purified mast cells, whereas 8-bromo-cyclic GMP, the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, superoxide dismutase and the peroxynitrite scavenger uric acid, were without effect. We conclude that IL-4 and IFN-gamma reciprocally regulate mast cell secretory responsiveness via control of nitric oxide synthesis by accessory cells; the nitric oxide effect on mast cells is direct but does not involve cyclic GMP or peroxynitrite.
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PMID:Reciprocal effects of interleukin-4 and interferon-gamma on immunoglobulin E-mediated mast cell degranulation: a role for nitric oxide but not peroxynitrite or cyclic guanosine monophosphate. 1023 88

This study investigates whether relaxin (RLX), a hormone previously shown to inhibit mast cell function and to stimulate endogenous nitric oxide (NO) biosynthesis, counteracts the activation of isolated human basophils stimulated with anti-IgE or phorbol ester, and, if so, whether NO is involved. RLX reduced dose-dependently the expression of the activation marker CD63, the release of histamine and the rise of intracellular Ca2+ levels which triggers granule release by stimulated basophils. RLX also blunts the ultrastructural signs of anaphylactic granule release. The effects of RLX appear to depend upon activation of Ca2+/calmodulin-dependent NO synthase and endogenous NO production. They were reproduced by the NO donor sodium nitroprusside (SNP) and were reverted by the NO synthase inhibitor N(omega)-monomethyl-L-arginine, or by the NO scavenger oxyhemoglobin, or by blocking the NO physiological target guanylate cyclase with ODQ. In conclusion, RLX appears to play a role in down-regulating basophil function upon immunologic and nonimmunologic activation.
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PMID:Inhibitory effects of relaxin on human basophils activated by stimulation of the Fc epsilon receptor. The role of nitric oxide. 1234 56