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 effects of tributylin chloride (TBT) on vascular smooth muscle responses to norepinephrine, nitroprusside (SNP) and atrial natriuretic peptide (ANP) were studied in isolated aortic rings of rats. TBT did not interfere with norepinephrine-induced contraction or SNP-induced vasorelaxation. However, TBT produced a dose-dependent inhibition of ANP-induced vasorelaxation. Inhibition was not observed with inorganic tin chloride, SnCl2. The inhibition of vasorelaxation was accompanied by a parallel inhibition of ANP-induced cGMP generation. SNP-induced generation of cGMP was not affected by TBT. TBT did not interfere with binding of ANP to its receptor in bovine adrenal glands suggesting that the effects of TBT were mediated by direct interaction with membrane-bound guanylate cyclase.
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PMID:The effect of tributyltin chloride on vascular responses to atrial natriuretic peptide. 133 19

Pretreatment of rat hepatocytes with low-dose nitrogen oxide (addition of SNAP in vitro or induction of nitric oxide synthase in vitro or in vivo) imparts resistance to killing and decrease in aconitase and mitochondrial electron transfer from a second exposure to a higher dose of SNAP. Induction of this resistance is prevented by cycloheximide, indicating upregulation of protective protein(s). Ferritin levels are increased as are non-heme iron-NO EPR signals. Tin-protoporphyrin (SnPP) prevents protection, suggesting involvement of hsp32 (heme oxygenase) and/or guanylyl cyclase (GC). Cross-resistance to H2O2 killing is also observed, which is also prevented by cycloheximide and SnPP. Thus, hepatocytes possess inducible protective mechanisms against nitrogen oxide and reactive oxygen toxicity.
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PMID:Nitrogen oxide-induced autoprotection in isolated rat hepatocytes. 758 41

1. Carbon monoxide (CO), produced by haem oxygenase through degradation of haem, has been claimed to be a neuromessenger and a possible regulator of vascular tone. We examined whether the haem oxygenase inhibitor, zinc protoporphyrin-IX (ZnPP) and other porphyrins affect the relaxation evoked by various agents in the rat isolated aorta. 2. Pretreatment with ZnPP (0.1 mM) virtually abolished the relaxation evoked by vasoactive intestinal peptide (VIP) and atrial natriuretic peptide (ANP). ZnPP also evoked a rightward shift of the concentration-response curve for the relaxation induced by acetylcholine. 3. In contrast, ZnPP did not affect the relaxation evoked by forskolin and 3-morpholino-sydnonimine, agents which directly activate adenylate and guanylate cyclase, respectively. 4. Although, less effective than ZnPP, tin protoporphyrin-IX (SnPP; 0.1 mM) and protoporphyrin-IX (PP; 0.1 mM) also attenuated the VIP-evoked relaxation. 5. The elevation of cyclic AMP and cyclic GMP levels evoked by VIP and ANP, respectively, were abolished by pretreatment with ZnPP (0.1 mM). 6. ZnPP, SnPP and PP did not affect the contraction evoked by phenylephrine. 7. The results show that ZnPP inhibits relaxation induced by VIP, ANP and acetylcholine, probably by interfering with membrane receptor-coupled signal transduction pathways. This inhibition does not seem to be dependent upon inhibition of haem oxygenase. The lack of specificity of the haem oxygenase inhibiting metalloporphyrins makes them less suitable as pharmacological tools in the investigation of a messenger role for CO.
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PMID:Inhibition by zinc protoporphyrin-IX of receptor-mediated relaxation of the rat aorta in a manner distinct from inhibition of haem oxygenase. 764 74

Carbon monoxide (CO) is a product of the enzyme heme oxygenase (HO; EC 1.14.99.3). In vascular smooth muscle cells, exogenously administered CO increases cyclic guanosine 3',5'-monophosphate (cGMP), which is an important regulator of vessel tone. We report here that smooth muscle cells produce CO via HO and that it regulates cGMP levels in these cells. Hypoxia, which has profound effects on vessel tone, significantly increased the transcriptional rate of the HO-1 gene resulting in corresponding increases of its mRNA and HO enzymatic activity. In addition, under the same conditions, rat aortic and pulmonary artery smooth muscle cells accumulated high levels of cGMP following a similar time course to that of HO-1 production. The increased accumulation of cGMP in smooth muscle cells required the enzymatic activity of HO, since it was abolished by a specific HO inhibitor, tin protoporphyrin. In contrast, N omega-nitro-L-arginine, a potent inhibitor of nitric oxide (NO) synthesis, had no effect on cGMP produced by smooth muscle cells, indicating that NO is not responsible for the activation of guanylyl cyclase in this setting. Furthermore, conditioned medium from hypoxic smooth muscle cells stimulated cGMP production in recipient cells and this stimulation was completely inhibited by tin protoporphyrin or hemoglobin, an inhibitor of CO production and a scavenger of CO, respectively. This report shows that HO-1 is expressed by vascular smooth muscle cells and that its product, CO, may regulate vascular tone under physiologic and pathophysiologic (such as hypoxic) conditions.
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PMID:Smooth muscle cell-derived carbon monoxide is a regulator of vascular cGMP. 787 3

Both nitric oxide (NO) and carbon monoxide (CO) are vessel wall-derived messenger molecules that cause platelet inhibition and vasodilation by activating guanylyl cyclase in target cells. Since vascular smooth muscle cells (SMCs) are exposed to shear and tensile stresses, this study examined the effects of these hemodynamic forces on the enzymes that generate NO and CO in SMCs. Monolayers of cultured rat aortic SMCs were subjected to shear stress using a modified cone and plate viscometer, or cyclic elongational stretch using a compliant silastic culture membrane. Shear stress stimulated time-dependent increases in mRNA and protein for inducible heme oxygenase-1 (HO-1), the enzyme which forms CO as a byproduct of heme degradation. The threshold level of shear necessary to induce HO-1 expression was between 5 and 10 dynes/cm2. In contrast, shear stress did not stimulate inducible NO synthase (iNOS) expression. Cyclic stretch also induced the expression of HO-1 but not of iNOS mRNA. Exposure of vascular SMCs to shear stress stimulated the production and release of CO as demonstrated by the CO-dependent increase in intracellular cGMP levels in coincubated platelets. In addition, ADP-stimulated aggregation was inhibited in platelets exposed to sheared SMCs but not in platelets exposed to untreated control SMCs. Treatment of sheared SMCs with the HO-1 inhibitor, tin protoporphyrin-IX, blocked the antiaggregatory effect of the cells, whereas the iNOS inhibitor, methyl--arginine, had no effect. These results indicate that hemodynamic forces induce HO-1 gene expression and CO production in vascular SMCs, and that SMC-derived CO inhibits platelet aggregation. Thus, CO is a novel endogenous vessel wall-derived messenger molecule that may be selectively induced by hemodynamic forces to inhibit platelet reactivity and preserve blood fluidity at sites of vascular injury.
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PMID:Hemodynamic forces induce the expression of heme oxygenase in cultured vascular smooth muscle cells. 923 6

Carbon monoxide (CO) is an endogenously produced gas sharing many properties with nitric oxide (NO), notably activating soluble guanylate cyclase and relaxing blood vessels. The brain can generate high quantities of CO from a constitutive enzyme, haem oxygenase (HO-2). To determine whether CO is involved in the regulatory mechanisms of cerebral blood flow (CBF), two conditions associated with a reproducible CBF increase were studied in rats: epileptic seizures induced by kainate, and hypercapnia. The HO inhibitor tin protoporphyrin (Sn-PP) did not modify the basal level of CBF, significantly reduced the increase in CBF during status epilepticus, and did not affect the cerebrovascular response to hypercapnia. It is concluded that CO participates in the regulation of CBF in specific conditions, notably those associated with glutamate release.
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PMID:Carbon monoxide regulates cerebral blood flow in epileptic seizures but not in hypercapnia. 969 25

Nitric oxide (NO) is a free radical produced actively by mammalian cells, including neurons. Low levels of NO can function in intercellular signaling, but high levels are cytotoxic. This cytotoxic potential suggests that cells at risk for NO damage, such as neurons, might have NO resistance mechanisms to prevent cell death, and adaptive resistance to NO-releasing compounds has been reported for some non-neuronal cell types. Here we show that immortalized mouse motor neurons (NSC34 cells) respond to sub-lethal fluxes of pure NO by activating adaptive resistance mechanisms that counteract cytotoxic NO exposure. This adaptive NO resistance is reversible and is paralleled by the induction of the oxidative stress enzyme heme oxygenase 1 (HO-1). An inhibitor of both HO-1 and heme-dependent guanylate cyclase (tin-protoporphyrin IX) greatly sensitized NO-pretreated NSC34 cells to the NO challenge. However, readdition of cyclic GMP (in the form of the 8-bromo derivative) restored rather little resistance, and a more selective guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxaline-1-one (at 10 microM), did not have the sensitizing effect. Therefore, the inducible HO-1 pathway contributes substantially to adaptive NO resistance, while cyclic GMP seems to play at most a small role. A similar adaptive resistance to NO was observed in primary rat spinal chord motor neurons. The activation of NO resistance in motor neurons may counteract age- or disease-related neurodegeneration.
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PMID:Adaptive resistance to nitric oxide in motor neurons. 1023 42

Macrophage activation and the resulting inflammatory response may be a major component of tissue injury upon hypoxia and re-oxygenation. Activation of the haem oxygenase (HO)/carbon monoxide (CO) pathway may be an important regulator of the inflammatory response, through production of cyclic 3', 5'-monophosphate (cGMP). We have assessed whether HO contributes to the increased production of the pro-inflammatory cytokines TNF-alpha and IL-6 in re-oxygenated rat peritoneal macrophages.Hypoxia/re-oxygenation markedly increased levels of HO-1 mRNA and cGMP. The increase in cGMP was reduced by the HO-1 inhibitor tin-protoporphyrin (SnPP-9) given during re-oxygenation. Hypoxia and re-oxygenation also increased IL-6 and TNF-alpha mRNA expression, as well as IL-6 and TNF-alpha concentrations in the cell supernatant. These increases were nullified by SnPP-9 and by Methylene Blue, an inhibitor of guanylate cyclase, but were not affected by L-NNA, an inhibitor of NO synthesis. The inhibitory effect of SnPP on the synthesis of cytokines was reversed by co-administration of the stable analogue of cGMP, 8-Br-cGMP. Our results indicate that activation of haem oxygenase and of the CO/cGMP pathway is a major stimulus for the synthesis and release of pro-inflammatory cytokines in re-oxygenated macrophages. This pathway may play a central role in pathological situations in which local tissue hypoxia/re-oxygenation triggers a systemic inflammatory response, for example in patients with shock.
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PMID:Induction of haem oxygenase contributes to the synthesis of pro-inflammatory cytokines in re-oxygenated rat macrophages: role of cGMP. 1032 72

Heme oxygenase (HO)-1 catalyzes the oxidative cleavage of heme to yield equimolar amounts of biliverdin, iron, and carbon monoxide. HO-1 is a stress response protein, the induction of which is associated with protection against oxidative stress. The mechanism(s) of protection is not completely elucidated, although it is suggested that one or more of the catalytic by-products provide antioxidant functions either directly or indirectly. The involvement of reactive oxygen species in apoptosis raised the question of a possible role for HO-1 in programmed cell death. Using the tetracycline-regulated expression system, we show here that conditional overexpression of HO-1 prevents tumor necrosis factor-alpha-induced apoptosis in murine L929 fibroblasts. Inhibition of apoptosis was not observed in the presence of tin protoporphyrin, a specific inhibitor of HO activity, and in cells overexpressing antisense HO-1. Interestingly, exogenous administration of a low concentration of carbon monoxide also prevented tumor necrosis factor-alpha-induced apoptosis in L929 fibroblasts. Inhibition of tumor necrosis factor-alpha-induced apoptosis by HO-1 overexpression was reversed by 1H-(1,2, 4)oxadiazolo(4,3-a)quinoxalin-1-one, an inhibitor of guanylate cyclase, which is a target enzyme for carbon monoxide. Taken together, our data suggest that the antiapoptotic effect of HO-1 may be mediated via carbon monoxide.
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PMID:Heme oxygenase-1 inhibits TNF-alpha-induced apoptosis in cultured fibroblasts. 1066 15

Inducible heme oxygenase (HO-1) has recently been recognized as an antioxidant and cytoprotective gene. By use of Western blotting, cell viability analysis, and antisense technique, the present study investigates the involvement of HO-1 in endothelial protection induced by the clinically used nitric oxide (NO) donor molsidomine (specifically, its active metabolite 3-morpholinosydnonimine [SIN-1]) and the second messenger cGMP. In bovine pulmonary artery endothelial cells, SIN-1 and S-nitroso-N-acetyl-D,L-penicillamine (SNAP) at 1 to 100 micromol/L induced the synthesis of HO-1 protein in a concentration-dependent fashion up to 3-fold over basal levels. HO-1 induction by SIN-1 was inhibited in the presence of the NO scavenger phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide and the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazole[4, 3-a]quinoxalin-1-one. 8-Bromo-cGMP (1 to 100 micromol/L) and dibutyryl cGMP (1 to 100 micromol/L) as well as the activator of particulate guanylyl cyclase atrial natriuretic peptide (1 to 100 nmol/L) produced increases in HO-1 protein similar to those produced by SIN-1. SIN-1 and 8-bromo-cGMP increased heme oxygenase activity (bilirubin formation). Cytoprotection by NO donors was abrogated in the presence of the heme oxygenase inhibitor tin protoporphyrin IX. Pretreatment of cells with a phosphorothioate-linked HO-1 antisense oligonucleotide prevented protection by SIN-1 or 8-bromo-cGMP against tumor necrosis factor-alpha cytotoxicity, whereas sense and scrambled HO-1 were without effect under these conditions. Our results show for the first time that HO-1 is a cGMP-sensitive endothelial gene and establish conclusively a causal relationship between HO-1 induction and endothelial protection by the NO/cGMP system. By targeting cytoprotective HO-1, NO donors may therefore be expected to induce antioxidant, antiatherogenic, and anti-inflammatory effects.
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PMID:Heme oxygenase-1 is a cGMP-inducible endothelial protein and mediates the cytoprotective action of nitric oxide. 1080 35


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