Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 intrathecal (i.t.) administration of either N-methyl-D-aspartate (NMDA, 10 fmol to 10 pmol) or L-arginine (1 pmol to 10 nmol), but not D-arginine (1 pmol to 10 nmol), produced a rapid, transient, dose-dependent facilitation (maximal response of 30.9 +/- 6.0% and 33.7 +/- 1.5%, respectively) of the nociceptive tail-flick reflex (ED50 = 47.8 +/- 15.4 fmol and 11.4 +/- 2.7 pmol, respectively). Maximal NMDA-produced facilitation of the tail-flick reflex (1 pmol i.t.) was completely abolished by prior treatment (10 min prior) with either N omega-nitro-L-arginine methyl ester (L-NAME, 10 nmol i.t.), methylene blue (10 nmol i.t.) or DL-5-aminophosphonovaleric acid (AP5, 100 pmol i.t.). NMDA-produced facilitation was completely recovered 40 min after L-NAME, 50 min after methylene blue and 30 min after AP5. L-NAME, methylene blue or AP5 did not significantly alter baseline tail-flick latency. These results suggest that NMDA-produced facilitation of a thermal nociceptive reflex is mediated through activation of an NMDA receptor that results in an increase in endogenous nitric oxide and activation of soluble guanylate cyclase in lumbar spinal cord.
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PMID:Production of endogenous nitric oxide and activation of soluble guanylate cyclase are required for N-methyl-D-aspartate-produced facilitation of the nociceptive tail-flick reflex. 134 62

We investigated the effect of aging on atrial natriuretic peptide (ANP)-induced relaxation and cyclic GMP (cGMP) formation in the rat thoracic aorta. In the aorta from young rats (4 weeks old), removal of the endothelium, and treatment with the nitric oxide synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), the radical scavenger, hemoglobin (Hb), and the soluble guanylate cyclase inhibitor, methylene blue (MB), attenuated ANP-induced relaxation and considerably reduced ANP-stimulated cGMP formation. With increasing age of the rats, the ANP-induced relaxation and cGMP formation in endothelium-intact aorta decreased, and Hb, L-NAME and MB no longer inhibited the ANP-induced effects, irrespective of whether the endothelium was present or absent. In the arteries without endothelium, the age-associated reduction in ANP-induced relaxation was less than in arteries with endothelium. Aging also decreased the relaxation induced by the soluble guanylate cyclase activator, nitroprusside. Potentiation due to the cGMP-phosphodiesterase (cGMP-PDE) inhibitor, M&B 22948, of the ANP-induced relaxation was greater in aortas from old rats than in those from young rats, suggesting that the degradation of cGMP may be accelerated in old rats. These results suggest that the relaxant action of ANP on the thoracic aorta from young rats is in part modulated by endothelium-derived relaxing factor (EDRF/nitric oxide), which in turn activates soluble guanylate cyclase, thus elevating the cGMP level. Aging may decrease the ANP-induced relaxation and ANP-stimulated increase in cGMP level by decreasing the ability of endothelial cells to produce EDRF, by decreasing guanylate cyclase activity, and by enhancing cGMP-PDE activity.
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PMID:Possible mechanisms of age-associated reduction of vascular relaxation caused by atrial natriuretic peptide. 135 Sep 88

In dogs under light thiopentobarbital anesthesia, intracarotid injection of bradykinin (BK) causes a dose-dependent "pain response" represented by hyperpnea, bradycardia, vocalization and ipsilateral contraction of the sternocephalic muscle. These events result from the activation of primary afferent nerves located in the wall of the carotid vessels distributed mainly in occipital artery territory. We present evidence indicating that these BK-induced reflex phenomena are 1) mediated by the activation of B2 receptors; 2) potentiated by prostaglandin E2 (PGE2) and serotonin (5-HT) the latter acting via sub-type 5-HT3 receptors; 3) reduced by indomethacin and/or NG-nitroarginine, and 4) abolished by methylene blue. These results suggest that 5-HT plays a modulatory role on BK action; the latter depends on the release of prostaglandins and nitric oxide or a related compound and includes the activation of guanylate cyclase which appears to be involved in primary afferent excitation.
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PMID:Is guanylate cyclase activation through the release of nitric oxide or a related compound involved in bradykinin-induced perivascular primary afferent excitation? 135 97

The cellular mechanism of bioactivation underlying guanylate cyclase activation by organic nitrates was investigated. In cultured rat lung fibroblasts (RFL-6 cells), the inhibitor of cytochrome P-450 proadifen (0.1 mM) decreased cyclic GMP stimulation by glyceryl trinitrate (GTN, 1-100 microM) by up to 81%. Cyclic GMP stimulation by isoidide dinitrate was inhibited to a similar degree under these conditions. However, proadifen did not affect cyclic GMP stimulation by sodium nitroprusside that spontaneously releases nitric oxide. Cyclic GMP stimulation in RFL-6 cells by GTN remained unaltered in the presence of the inhibitor of glutathione S-transferase sulfobromophthalein. In the same cell type, a 24-hr pretreatment with the inducer of cytochrome P-450 3-methylcholanthrene (10 microM) augmented cyclic GMP stimulation by GTN or isoidide dinitrate by up to 102%. Cultured porcine aortic endothelial cells were found to be without a cyclic GMP response to GTN, although sodium nitroprusside produced a marked cyclic GMP elevation in these cells. The endothelial cells remained unresponsive to GTN even in the presence of N-acetylcysteine (5 mM). Moreover, in a cell-free preparation from rat liver, glutathione-dependent biotransformation of GTN was not accompanied by activation of soluble guanylate cyclase. These findings suggest that in intact cells bioactivation of, i.e., nitric oxide formation from organic nitrates is mediated by a cytochrome P-450 enzyme system rather than by glutathione S-transferase or free thiols.
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PMID:Cytochrome P-450 mediates bioactivation of organic nitrates. 135 50

Rod outer segments of retina contain guanylate cyclase activity both in the cytosol and membrane fractions. Though the activity in the cytosol is a small fraction of the total activity, it is highly activated by nitroprusside, a nitric oxide generating agent. The membrane guanylate cyclase on the other hand is unaffected by nitroprusside both before and after solubilization. The effects of nitroprusside or nitric oxide on photoreceptor function should therefore be mediated by the cytosolic and not the membrane guanylate cyclase.
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PMID:Nitroprusside-sensitive and insensitive guanylate cyclases in retinal rod outer segments. 135 82

Several low molecular weight compounds are capable of activating soluble guanylyl cyclase. Recent evidence suggests that some of these are formed under physiological conditions: the nitric oxide radical, carbon monoxide and the hydroxyl radical. Thus, multiple signal transduction pathways appear to exist that form a family of guanylyl cyclase activating factors and thereby regulate the intracellular cyclic guanosine 3',5'-monophosphate level.
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PMID:NO., CO and .OH. Endogenous soluble guanylyl cyclase-activating factors. 135 61

Three different guanylyl cyclase cell receptors are known, but others will likely be discovered within the next few years. The general function of these receptors appear to relate to the regulation of fluid volume or fluid movement. New receptors, or possibly the currently known receptors, therefore, may be discovered in areas of the body where fluid volume regulation is important. Such fluids whose volume or composition might be regulated by guanylyl cyclase receptors include synovial fluid, uterine/oviductal luminal fluid, follicular fluid, aqueous humor, cerebral spinal fluid, seminiferous tubule luminal fluid, epididymal luminal fluid, seminal plasma, and airway luminal fluid. The function of the heterodimeric forms of guanylyl cyclase appear to relate to a primary regulation of nitric oxide (or similar molecules) concentrations, which are in turn regulated by a Ca2+/calmodulin-sensitive nitric oxide synthase.
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PMID:Receptor guanylyl cyclases. 135 64

Endothelial cells (ECs) from brain microvessels respond to exogenous nitric oxide (NO) donor molecules (N-ethoxycarbonyl-3-morpholinosydnonimine and sodium nitroprusside) with large (greater than 15-fold) increases in cyclic GMP (cGMP) levels. Comparable actions of sodium nitroprusside were observed in vascular smooth muscle cells and in neuroblastoma cells. Coculturing brain capillary ECs in the presence of N1E-115 neuroblastoma cells increased their cGMP levels fourfold. A further increase was observed in the presence of 50 nM neurotensin, although brain capillary ECs lack receptor sites for neurotensin. The neuroblastoma cell-dependent formation of cGMP was suppressed by 0.1 mM L-NG-monomethylarginine, indicating that NO, produced by N1E-115 cells in response to neurotensin, activated guanylate cyclase in brain capillary ECs. Similarly, culturing brain capillary ECs in the presence of aortic ECs increased their cGMP content in a manner that was amplified by bradykinin and that was inhibited by L-NG-monomethylarginine. Bradykinin had no action in pure cultures of brain capillary ECs. It is concluded that brain capillary ECs express high levels of guanylate cyclase activity that could be activated by exogenous NO donor molecules and by NO produced by neuroblastoma cells and by aortic ECs in response to specific agonists. Brain capillary ECs are thus potential target cells for brain-derived NO.
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PMID:Activation by nitric oxide of guanylate cyclase in endothelial cells from brain capillaries. 135 91

The nearly total inhibition of development of pharmacological tolerance to an organic nitrate is reported here for the first time. The development of in vitro tolerance in the rabbit aorta to isosorbide-5-mononitrate (CAS 87-33-2) was potently inhibited by five structurally unrelated antioxidants--diaminodurol, ascorbic acid, potassium sulphite, pyrogallol and quercetin. Diaminodurol, ascorbic acid and potassium sulphite decreased, but quercetin increased, the spasmolytic activity of isosorbide-5-mononitrate. Diaminodurol, potassium sulphite, quercetin and ascorbic acid potently inhibited the spasmolytic activity of nitric oxide (NO). Quercetin also inhibited the development of in vitro tolerance to glyceryl trinitrate. It is suggested that tolerance to organic nitrates is the result of biochemical damage caused by a reactive intermediate such as NO. To test this possibility directly the effect of pretreatment with NO on the spasmolytic activity of glyceryl trinitrate (CAS 55-63-0) was examined. This pretreatment produced a small but significant tolerance to glyceryl trinitrate and to SIN-1 (3-morpholinosydnone imine), which also acts through guanylate cyclase. There was no effect on the activity of the unrelated vasodilators nitrendipine and theophylline. It is concluded that the reaction between NO and soluble quanylate cyclase is a real but minor cause of tolerance to organic nitrates. Other possible mechanisms of tolerance development are discussed.
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PMID:Total prevention of the development of in vitro tolerance to organic nitrates. Experiments with antioxidants. 135 61

The history of how we reached the goal of determining the mechanism of vasodilatation caused by non-adrenergic, non-cholinergic nerve stimulation in cerebral arteries was traced. We concluded from this project that electrical and chemical (by nicotine) stimulations evoke an increased influx of Ca2+ into nerve terminals and activate nitric oxide (NO) synthase, resulting in the synthesis and release of NO that stimulates the guanylate cyclase in smooth muscle, thereby causing the accumulation of cyclic GMP and eliciting muscle relaxation. Reviewed also are the neurally-induced inhibitory responses of extracranial arteries, intestines, etc. with respect to NO.
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PMID:[Neurotransmission and nitric oxide (NO)]. 135 95


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