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)

Arterial vessels express one or more heme oxygenase (HO) isoenzymes that catalyze the metabolism of heme to carbon monoxide (CO) and biliverdin. Carbon monoxide promotes vasorelaxation through mechanisms that, depending on the vessels, involve activation of soluble guanylate cyclase, stimulation of calcium-activated potassium channels, or diminished synthesis of constrictor mediators, such as, endothelin and 20-HETE. Inhibitors of HO elicit vasoconstriction in vivo and in isolated pressurized arterioles. Inhibitors of HO also enhance myogenic vasoconstriction, as well as the constriction induced by phenylephrine in several vessels. The blood pressure of awake rats is increased by acute treatment with HO inhibitors, a response that is accompanied by attenuation of baroreflex activity. All in all, it would appear that a product of HO activity manufactured by arterial vessels, presumably CO, promotes vasodilation and decreases the reactivity of vascular smooth muscle to myogenic stimuli and constrictor agonists. In doing so, CO of vascular origin may contribute to the implementation of antihypertensive mechanisms. Carbon monoxide produced in central nervous system structures, for example, the nucleus tractus solitarii, also appears to support a blood pressure-lowering mechanism linked to inhibitory modulation of baroreceptor reflex activity.
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PMID:Vasoregulatory function of the heme-heme oxygenase-carbon monoxide system. 1141 67

To elucidate pathophysiological roles of heme oxygenase (HO)-1 in regulation of vascular tone in vivo, we have developed and characterized transgenic (Tg) mice that overexpress HO-1 site specifically in vascular smooth muscle cells (VSMCs). The Tg mice were generated by use of human HO-1 cDNA under the control of SM22-alpha promoter. The HO-1 gene overexpression was demonstrated by Northern blot analysis and coincided with increases in the protein expression in VSMCs and total HO activities. Tg mice exhibited a significant increase in arterial pressure at various ages and displayed impaired nitrovasodilatory responses in isolated aortic segments versus nontransgenic littermates while enhancing their nitric oxide (NO) production. The pressure of Tg mice was unchanged by systemic administration of either N(omega)-nitro-L-arginine or SNP. Furthermore, the isolated aorta in these mice exhibited lesser extents of NO-elicited cGMP elevation via soluble guanylate cyclase (sGC), while exhibiting no notable downregulation of sGC expression. Such impairment of the NO-elicited cGMP increase was restored significantly by tin protoporphyrin IX, an HO inhibitor. On the other hand, 3-(5'-hydroxymethyl-2' furyl)-1-benzyl-indazol (YC-1), an NO-independent activator of sGC, increased cGMP and relaxed aortas from Tg mice to levels comparable with those from nontransgenic mice, which indicates that contents of functionally intact sGC are unlikely to differ between the two systems. These findings suggest that site-specific overexpression of HO-1 in VSMCs suppresses vasodilatory response to NO and thereby leads to an elevation of arterial pressure.
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PMID:Vascular smooth muscle cell-directed overexpression of heme oxygenase-1 elevates blood pressure through attenuation of nitric oxide-induced vasodilation in mice. 1144 Sep 78

Previous investigations have shown that NO-producing nitric oxide synthase (NOS)-1 and CO-generating heme oxygenase (HO-2) are associated with the sarcolemma of skeletal muscle fibers in many mammalian species. Despite numerous roles ascribed to NO and possibly also CO in skeletal muscle, a specific receptor for both gases has hitherto not been found in myofibers. Therefore, in the present work the appearance of the alpha1, beta1 and beta2 subunits of soluble guanylate cyclase (sGC), the most commonly known receptor for NO and potentially also CO, was analysed in mammalian skeletal muscles using immunoblotting and immunohistochemistry. Immunoblotting with an antibody against the beta1 subunit of sGC revealed a band of 70 kDa corresponding to the molecular weight of this protein. Immunohistochemistry with antibodies against the alpha1, beta1 and beta2 sGC subunits showed that the larger part of positivity was present in the sarcolemma region of skeletal muscle fibers and colocalized with NOS-1 mainly in type II myofibers and with HO-2 in type I and type II myofibers. For the first time, sarcolemmal association of sGC and its colocalization with NOS-1 generating the sGC-activator NO and with HO-2 producing the potential sGC upregulator CO have been demonstrated in the present study. These results enable a better understanding of the role of NO and CO in myofibers and suggest a so far unknown molecular mechanism for the interaction of sGC with the sarcolemma.
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PMID:Association of soluble guanylate cyclase with the sarcolemma of mammalian skeletal muscle fibers. 1148 73

Carbon monoxide (CO) is produced by the action of the heme oxygenase (HO) complex through the oxidation of heme. CO, like nitric oxide (NO), is a molecular gas that among other actions stimulates guanylyl cyclase and increases cGMP levels in smooth muscle cells, regulating the vascular tone. Acute hypoxia generates pulmonary hypertension and increases the expression of inducible HO isoform (HO-1) in the vascular endothelium. Inhaled NO causes a potent pulmonary vasodilation. We hypothesized that inhaled CO might produce similar actions as NO on pulmonary vascular resistance (PVR). To test our contention, we studied the effects of inhaled CO (40 ppm) in the augmented PVR observed during hypoxemia. Five chronically instrumented German Merino sheep were submitted to a protocol consisting of 20 min of normoxemia (N), 20 min of isocapnic hypoxemia (H20), 20 min of isocapnic hypoxemia plus CO 40 ppm (H40), and 20 min of recovery (R). In the control protocol, we did not administer inhaled CO. Arterial gases and pH, percentage of carboxyhemoglobin (COHb), systemic and pulmonary arterial pressure, systemic and pulmonary vascular resistance, and cardiac output were measured during each period. During H20 period, there was a significant increase in cardiac output and PVR in sheep submitted to both protocols. The sheep treated with inhaled CO (H40 + CO) showed a modest but significant decrease (16%) in the elevated PVR. Our data indicate that inhaled CO decreases pulmonary vascular resistance associated with acute hypoxemia in adult sheep.
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PMID:Low-dose inhaled carbon monoxide reduces pulmonary vascular resistance during acute hypoxemia in adult sheep. 1168 17

Spinal cord tissue contains two enzyme systems capable of producing monoxide gases which in turn are linked to the stimulation of soluble guanylate cyclase, nitric oxide synthase (NOS) which produces NO and heme oxygenase (HO) which produces CO. Reports from several laboratories link these two enzyme systems to pain of inflammatory and neuropathic etiologies. Additional studies have demonstrated that the activation of the NOS system by morphine limits the spinal analgesic action of this drug. In this study we first employed the hot plate model of pain to demonstrate that the NOS inhibitor L-NAME and the HO inhibitor Sn-P potentiate the analgesic actions of intrathecally administered morphine while having no intrinsic analgesic action at the doses used. We then determined that L-NAME loses its ability to potentiate morphine in nNOS null-mutant mice, while Sn-P no longer potentiates morphine in mice lacking a functional HO-2 gene. The intrathecal injection of the cGMP analog 8-Br cGMP caused hyperalgesia in the hot plate assay. Focusing on the possible involvement of cGMP metabolism, we documented that morphine stimulates cGMP production in a spinal cord slice model in a concentration dependent and naloxone reversible manner. Both L-NAME and Sn-P were potent inhibitors of morphine-stimulated cGMP production. Buffer containing either CO or the NO donor compound SNAP stimulated cGMP production as well. In spinal cord slices from either nNOS or HO-2 null-mutant animals morphine did not stimulate cGMP production. Taken together our data suggest that spinal monoxide generation modifies the acute analgesic actions of morphine.
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PMID:Spinal cord nitric oxide synthase and heme oxygenase limit morphine induced analgesia. 1168 80

Endogenous carbon monoxide (CO) shares with nitric oxide (NO) a role as a putative neural messenger in the brain. Both gases are believed to modulate CNS function via an increase in cytoplasmic cGMP concentrations secondary to the activation of soluble guanylate cyclase (sGC). Recently CO and NO were proposed as a possible mediator of febrile response in hypothalamus. NO has been reported to activate both the constitutive and inducible isoform of the cyclooxygenase (COX). Thus, we investigated whether CO arising from heme catabolism by heme oxygenase (HO) is involved in the febrile response via the activation of COX in the hypothalamus. PGE2 which is a final mediator of febrile response released from primary cultured hypothalamic cells was taken as a marker of COX activity. PGE2 concentration was measured with EIA kits. Exogenous CO (CO-saturated medium) and hemin (a substrate and potent inducer of HO) evoked an increase in PGE2 release from hypothalamic cells, and these effects were blocked by methylene blue (an inhibitor of sGC). And membrane permeable cGMP analogue, dibutyryl-cGMP elicited significant increases in PGE2 release. These results suggest that there may be a functional link between HO and COX enzymatic activities. The gaseous product of hemin through the HO pathway, CO, might play a role through the modulation of the COX activity in the hypothalamus.
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PMID:Effects of heme oxygenase system on the cyclooxygenase in the primary cultured hypothalamic cells. 1179 44

The present study aimed to characterize pulmonary vascular reactivity in the chicken embryo from the last stage of prenatal development and throughout the perinatal period. Isolated intrapulmonary arteries from non-internally pipped embryos at 19 days of incubation and from internally and externally pipped embryos at 21 days of incubation were studied. Arterial diameter and contractile responses to KCl, endothelin-1, and U-46619 increased with incubation but were unaffected by external pipping. In contrast, the contractions induced by norepinephrine, phenylephrine, and electric field stimulation decreased with development. No developmental changes were observed in endothelium-dependent [acetylcholine (ACh) and cyclopiazonic acid] or endothelium-independent [sodium nitroprusside (SNP)] relaxation. These relaxations were abolished by the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Endothelium-dependent relaxation was unaffected by blockade of cyclooxygenase or heme oxygenase but was significantly reduced by nitric oxide (NO) synthase inhibitors. Reduction of O2 concentration from 95 to 5% produced a marked reduction in ACh and SNP-induced relaxations. Chicken embryo pulmonary arteries show a marked endothelium-dependent relaxation that is unaffected by transition to ex ovo life. Endothelium-derived NO seems to be the main mediator responsible for this relaxation.
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PMID:Vascular reactivity in intrapulmonary arteries of chicken embryos during transition to ex ovo life. 1183 15

Previous studies have shown that heme oxygenase-1 (HO-1), a heat stress protein (HSP32), has a beneficial effect on the ischemic myocardium. The purpose of the present study was to explore whether HO-1 is involved in delayed cardioprotection provided by heat stress in vivo. Sprague--Dawley rats were pretreated with whole body hyperthermia (rectal 42 degrees C) for 15 min followed by ischemia-reperfusion 24 h later. Ischemia-reperfusion injury was induced by 45 min of coronary artery occlusion followed by a 3-h reperfusion. Myocardial injury degree was evaluated by measurement of infarct size and serum creatine kinase (CK) activity. The expression of HO-1 mRNA and protein in myocardial tissues were measured. Pretreatment with hyperthemia significantly reduced infarct size and CK release during reperfusion, which was completely blocked by pretreatment with ZnPP-9, an inhibitor of HO and methylene blue, an inhibitor of soluble guanylate cyclase. Heat stress also significantly increased the expression of HO-1 mRNA and protein, and the effect was not affected by pretreatment with methylene blue. The present results suggest that the HO-1 pathway is involved in the mediation of delayed cardioprotection by heat stress in rats.
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PMID:Heme oxygenase-1 pathway is involved in delayed protection induced by heat stress against cardiac ischemia-reperfusion injury. 1185 99

Pancreatic islets transplanted to treat autoimmune type 1 diabetes often fail to function (primary nonfunction), likely because of islet beta-cell apoptosis. We show that carbon monoxide (CO), a product of heme oxygenase activity, protects beta-cells from apoptosis. Protection is mediated through guanylate cyclase activation, generation of cyclic GMP (cGMP), and activation of cGMP-dependent protein kinases. This antiapoptotic effect is still observed when beta-cells are exposed to CO for 1 h before the apoptotic stimulus. In a similar manner, mouse islets exposed to CO for just 2 h function significantly better after transplantation than islets not exposed to CO. These findings suggest a potential therapeutic application for CO in improving islet function/survival after transplantation in humans.
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PMID:Carbon monoxide protects pancreatic beta-cells from apoptosis and improves islet function/survival after transplantation. 1191 17

Carbon monoxide and nitric oxide are two endogenously produced gases that can act as second messenger molecules. Heme oxygenase and nitric oxide synthase are the enzyme systems responsible for generating carbon monoxide and nitric oxide, respectively. Both carbon monoxide and nitric oxide share similar properties, such as the ability to activate soluble guanylate cyclase to increase cyclic GMP. It is becoming increasingly clear that these two gases do not always work independently, but rather can modulate each other's activity. Although much is known about the heme oxygenase/carbon monoxide and nitric oxide synthase/nitric oxide pathways, how these two important systems interact is less well understood. This review attempts to define the current known relationship between carbon monoxide and nitric oxide as it relates to their production and physiological function.
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PMID:Cross talk between carbon monoxide and nitric oxide. 1200 81


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