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)

Current evidence strongly suggests that coronary atherosclerosis is a common denominator in patients with stable effort angina pectoris. The concept of pathophysiology of coronary atherosclerosis is presented--angiographic and pathologic evidence now suggest presence of eccentric and irregular atherosclerotic lesions (sometimes associated with plaque rupture) and simultaneously present endothelial dysfunction increases sensitivity of vascular smooth muscles to physical and biochemical stimuli with propensity to spasm. Ischemia is due to an increased myocardial oxygen demand (increased heart rate or blood pressure) that cannot be met because of fixed coronary reserve. The organic nitrates are important drugs for the treatment of patients wit angina. The mechanism(s) of their action is presented--biotransformation and liberation of nitric oxide which stimulates guanylyl cyclase and conversion of GTP (by guanylyl cyclase) to cGMP, which causes vasodilatation but reduces platelet adhesion and aggregation too. Sublingual nitroglycerin and isosorbide dinitrate are effective in the treatment of acute episodes of angina. Long-acting nitrate preparations are effectiveness include intermittent transdermal nitroglycerin, standard formulation and sustained-release isosorbid dinitrate (but better isosorbid-5-mononitrate because of longer duration of action of action and no 1st pass hepatic metabolism) (nitrate-free interval should be of 8-10 hours duration). The place of the therapy with betablockers and calcium channel blockers in angina pectoris is presented as well and their combination with nitrates.
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PMID:[Anti-angina treatment in stable forms of angina pectoris with emphasis on nitrates]. 1564 Dec 33

Reperfusion injury is a complex process involving several cell types (endothelial cells, neutrophils, and cardiomyocytes), soluble proinflammatory mediators, oxidants, ionic and metabolic dyshomeostasis, and cellular and molecular signals. These participants in the pathobiology of reperfusion injury are not mutually exclusive. Some of these events take place during the very early moments of reperfusion, while others, seemingly triggered in part by the early events, are activated within a later timeframe. Postconditioning is a series of brief mechanical interruptions of reperfusion following a specific prescribed algorithm applied at the very onset of reperfusion. This algorithm lasts only from 1 to 3 minutes depending on species. Although associated with re-occlusion of the coronary artery or re-imposition of hypoxia in cell culture, the reference to ischemia has been dropped. Postconditioning has been observed to reduce infarct size and apoptosis as the "end games" in myocardial therapeutics; salvage of infarct size was similar to that achieved by the gold standard of protection, ischemic preconditioning. The cardioprotection was also associated with a reduction in: endothelial cell activation and dysfunction, tissue superoxide anion generation, neutrophil activation and accumulation in reperfused myocardium, microvascular injury, tissue edema, intracellular and mitochondrial calcium accumulation. Postconditioning sets in motion triggers and signals that are functionally related to reduced cell death. Adenosine has been implicated in the cardioprotection of postconditioning, as has e-NOS, nitric oxide and guanylyl cyclase, opening of K(ATP) channels and closing of the mitochondrial permeability transition pore. Cardioprotection by postconditioning has also been associated with the activation of intracellular survival pathways such as ERK1/2 and PI3 kinase - Akt pathways. Other pathways have yet to be identified. Although many of the pathways involved in postconditioning have also been identified in ischemic preconditioning, some may not be involved in preconditioning (ERK1/2). The timing of action of these pathways and other mediators of protection in postconditioning differs from that of preconditioning. In contrast to preconditioning, which requires a foreknowledge of the ischemic event, postconditioning can be applied at the onset of reperfusion at the point of clinical service, i.e. angioplasty, cardiac surgery, transplantation.
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PMID:Postconditioning--A new link in nature's armor against myocardial ischemia-reperfusion injury. 1579 29

The link between endothelial nitric oxide synthase (eNOS) activation and vascular diameter during ischemia-reperfusion was investigated in the rat heart. After short (<30 min) and long (>45 min) time of ischemia conferred by coronary artery occlusion of the rats, reperfusion caused dilatation and constriction of arterioles, respectively. Partial oxygen pressure (pO2) measurement of the heart by the electrode confirmed the hyper-perfusion and no-reflow phenomena during reperfusion, as well as myocardial ischemia. The vascular diameter was correlated with phosphorylation of Akt and serine 1177 residue of eNOS, and formation of NO-bound guanylate cyclase (GC) by immuoflorescence study. Western blotting confirmed the phosphorylation of eNOS-Ser1177 depending on ischemia time. The constriction during reperfusion after 45 min of ischemia is supposedly caused by the inhibition of Akt-mediated eNOS-Ser1177 phosphorylation, which was suppressed by a PKC inhibitor chelerythrine, or ROS scavengers N-2-mercaptopropionyl glycine (MPG) and 4,5-Dihydroxy-1, 3-benzenedisulfonic acid disodium salt (Tiron). However, an endothelin receptor antagonist BQ123 alleviated the vasoconstriction by increasing NO availability but not eNOS-Ser1177 phosphorylation. Thus, vascular patency is correlated with eNOS-Ser1177 phosphorylation in association with ROS, and PKC during reperfusion. Endothelin inhibits vasodilatation by reducing NO availability during reperfusion.
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PMID:Endothelial NO Synthase (eNOS) phosphorylation regulates coronary diameter during ischemia-reperfusion in association with oxidative stress. 1603 23

Isolated rat hearts were perfused for 10 min with oxygenated buffer and equilibrated with carbon monoxide (CO) of 0.001% and 0.01% before the induction of 30 min global ischemia followed by 120 min of reperfusion. These concentrations of CO significantly improved the post-ischemic recovery of coronary flow (CF), aortic flow (AF), and left ventricular developed pressure (LVDP). The improvement in recovery reflected in the reduction of infarct size and the incidence of reperfusion-induced ventricular fibrillation (VF). Thus, hearts subjected to 0.001% and 0.01% of CO exposure via the perfusion buffer, infarct size was reduced from the CO-free control value of 39% +/- 5% to 21% +/- 3% (*p<0.05) and 18% +/- 4% (*p<0.05), respectively. In the presence of 0.001% and 0.01% CO, the incidence of VF was also reduced from its control value of 92% to 17% (*p<0.05) and 17% (*p<0.05), respectively. Increasing the CO exposure to 0.1% in the buffer, all hearts showed VF combined with ventricular tachycardia or bradycardia and various rhythm disturbances indicating the direct toxic effects of CO on the myocardium. The results show that cardioprotective concentrations (0.01% and 0.001%) of exogenous CO related to an increase in cGMP levels and guanylate cyclase activities.
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PMID:The role of exogenous carbon monoxide in the recovery of post-ischemic cardiac function in buffer perfused isolated rat hearts. 1630 67

Ischemic preconditioning is a powerful infarct-sparing intervention. Intensive investigations have revealed many of the signaling steps used to elicit this protection. One of the steps involves activation of nitric oxide synthase (NOS) by phosphorylation, with the production of NO and subsequent activation of guanylyl cyclase, production of cGMP, activation of protein kinase G, opening of mitochondrial KATP channels, and generation of reactive oxygen species. The latter act as second messengers to activate critical kinase cascades that trigger entrance into the preconditioned state. Thus, NO exposure before ischemia can act as a powerful preconditioning mimetic. Elevating NO just prior to or at reperfusion can still be an effective cardioprotective strategy. Activation of NOS or production of NO can be done pharmacologically with exogenous agents to trigger this cascade. Many of these strategies are already available and safe.
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PMID:Nitric oxide is a preconditioning mimetic and cardioprotectant and is the basis of many available infarct-sparing strategies. 1637 69

Postinfarct remodeling impairs mechanisms of ischemic preconditioning. We examined whether myocardial response to activation of the erythropoietin (EPO) receptor is modified by postinfarct remodeling. Four weeks after induction of myocardial infarction (MI) by coronary ligation in post-MI group (post-MI) or a sham operation in sham group (sham), rat hearts were isolated and subjected to 25-min global ischemia/2-h reperfusion. Infarct size was expressed as a percentage of risk area (i.e., left ventricle) from which scarred infarct was excluded (%I/R). The heart weight was 15% larger in post-MI, but there was no intergroup difference in plasma EPO levels or myocardial EPO receptor levels. EPO infusion (5 U/ml) significantly reduced %I/R from 59.9 +/- 4.1 to 36.2 +/- 4.2 in sham and from 58.1 +/- 5.0 to 35.2 +/- 4.0 in post-MI. This EPO-induced protection was sensitive to a phosphatidylinositol 3-kinase (PI3K) inhibitor, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), in sham. However, neither LY294002 nor wortmannin inhibited the EPO-induced protection in post-MI. Phosphorylation of Janus kinase 2 by EPO was attenuated and phosphorylation of Akt was not detected in post-MI. A guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one, and a mitochondrial ATP-sensitive K(+) channel (mitoK(ATP) channel) blocker, 5-hydroxydecanoate, inhibited EPO-induced protection in both sham and post-MI. Suppressor of cytokine signaling (SOCS)-1 protein level was higher by 50% in post-MI than in sham, although SOCS-3 levels were similar. These findings suggest that postinfarct remodeling disrupts cellular signaling from the EPO receptor to PI3K, presumably by increased SOCS-1. However, in the remodeled myocardium, lack of PI3K/Akt activation by the EPO receptor seems to be compensated by a mechanism upstream of the guanylyl cyclase-mitoK(ATP) channel pathway to achieve EPO-induced protection.
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PMID:Alteration in erythropoietin-induced cardioprotective signaling by postinfarct ventricular remodeling. 1637 61

Low concentrations of carbon monoxide (CO) can protect tissues against ischemia-reperfusion (I-R) injury. We have recently identified a novel class of compounds, CO-releasing molecules (CO-RMs), which exert important pharmacological activities by carrying and delivering CO to biological systems. Here, we examined the possible beneficial effects of CO liberated from CO-RMs on the damage inflicted by cold storage and I-R in isolated perfused kidneys. Hemodynamic and biochemical parameters as well as mitochondrial respiration were measured in isolated perfused rabbit kidneys that were previously flushed with CO-RMs and stored at 4 degrees C for 24 h. Two water-soluble CO-RMs were tested: (1) sodium boranocarbonate (CORM-A1), a boron-containing carbonate that releases CO at a slow rate, and (2) tricarbonylchloro(glycinato)ruthenium(II) (CORM-3), a transition metal carbonyl that liberates CO very rapidly in solution. Kidneys flushed with Celsior solution supplemented with CO-RMs (50 microM) and stored at 4 degrees C for 24 h displayed at reperfusion a significantly higher perfusion flow rate (PFR), glomerular filtration rate, and sodium and glucose reabsorption rates compared to control kidneys flushed with Celsior solution alone. Addition of 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor, prevented the increase in PFR mediated by CO-RMs. The respiratory control index from kidney mitochondria treated with CO-RMs was also markedly increased. Notably, renal protection was lost when kidneys were flushed with Celsior containing an inactive compound (iCO-RM), which had been deliberately depleted of CO. CO-RMs are effective therapeutic agents that deliver CO during kidney cold preservation and can be used to ameliorate vascular activity, energy metabolism and renal function at reperfusion.
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PMID:Treatment with CO-RMs during cold storage improves renal function at reperfusion. 1640 12

Nitric oxide (NO), applied by inhalation or released from NO donors, has been used to reduce the expression of cell adhesion molecules (CAM) and ameliorate other consequences of ischemia/reperfusion (I/R) injury. In this study, we have assessed the time frames of pretreatment and of the duration of the preconditioned state using human umbilical vein endothelial cells (HUVECs) and the NO donor, SNAP, in combination with cysteine. The induction of vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM) and E-selectin by the cytokines TNFalpha and IL-1beta, and by bacterial lipopolysaccharide (LPS) was reduced by SNAP/Cys preincubation (30 min, 1mM) to less than 10% of controls. This refractory state in respect to cytokine-induced CAM expression persisted for 6h after washout of the NO donor in the combination TNFalpha/VCAM, and a partial block was still observed after 8h. The effect was not mediated by the cGMP pathway, as was demonstrated by using the inhibitor of guanylyl cyclase, ODQ, and the cGMP analogue, 8-Br-cGMP. The TNFalpha-induced expression of CAM was exclusively dependent on the transcription factor NFkappaB since the inhibitor of NFkappaB activation, BAY 11-7082, completely blocked the induction. The TNFalpha-induced phosphorylation and degradation of the inhibitor of kappaB (IkappaBalpha) was suppressed for up to 8h after SNAP/Cys pretreatment. The inhibitory S-nitrosation of IkappaB kinase (IKKbeta), as assessed by the biotin-switch-procedure and immunoprecipitation, was only detectable immediately after SNAP/Cys incubation but not at later time points. In summary, a short preincubation of HUVEC with SNAP/Cys results in a persistent suppression of NFkappaB-dependent expression of CAM. The stabilization of IkappaBalpha over the same time span may be causally related to this effect.
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PMID:Nitric oxide donor-induced persistent inhibition of cell adhesion protein expression and NFkappaB activation in endothelial cells. 1650 56

Carbon monoxide (CO), an endogenous cytoprotective product of heme oxygenase type-1 regulates target thrombotic and inflammatory genes in ischemic stress. Regulation of the gene encoding early growth response 1 (Egr-1), a potent transcriptional activator of deleterious thrombotic and inflammatory cascades, may govern CO-mediated ischemic lung protection. The exact signaling mechanisms underlying CO-mediated cytoprotection are not well understood. In this study we tested the hypothesis that inhibition of mitogen-activated protein kinase-dependent Egr-1 expression may be pivotal in CO-mediated ischemic protection. In an in vivo isogeneic rat lung ischemic injury model, inhaled CO not only diminished fibrin accumulation and leukostasis and improved gas exchange and survival but also suppressed extracellular signal-regulated kinase (ERK) activation, Egr-1 expression, and Erg DNA-binding activity in lung tissue. Additionally, CO-mediated inhibition of Egr-1 reduced expression of target genes, such as tissue factor, serpine-1, interleukin-1, and TNF-alpha. However, CO failed to inhibit serpine-1 expression after unilateral lung ischemia in mice null for the Egr-1 gene. In RAW macrophages in vitro, hypoxia-induced Egr-1 mRNA expression was ERK-dependent, and CO-mediated suppression of ERK activation resulted in Egr-1 inhibition. Furthermore, CO suppression of ERK phosphorylation was reversed by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one but was insensitive to cAMP-dependent protein kinase A inhibition with H89 and NO synthase inhibition with l-nitroarginine methyl ester. This finding indicates that CO suppresses ERK in a cGMP-dependent but cAMP/protein kinase A- and NO-independent manner. Together, these data identify a unifying molecular mechanism by which CO interrupts proinflammatory and prothrombotic mediators of ischemic injury.
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PMID:Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes. 1655 42

Many effects of inhaled nitric oxide (NO) are not explained by the convention that NO activates pulmonary guanylate cyclase or is inactivated by ferrous deoxy- or oxyheme. Inhaled NO can affect blood flow to a variety of systemic vascular beds, particularly under conditions of ischemia/reperfusion. It affects leukocyte adhesion and rolling in the systemic periphery. Inhaled NO therapy can overcome the systemic effects of NO synthase inhibition. In many cases, these systemic-NO synthase-mimetic effects of inhaled NO seem to involve reactions of NO with circulating proteins followed by transport of NO equivalents from the lung to the systemic periphery. The NO transfer biology associated with inhaled NO therapy is rich with therapeutic possibilities. In this article, many of the whole-animal studies regarding the systemic effects of inhaled NO are reviewed in the context of this emerging understanding of the complexities of NO biochemistry.
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PMID:Summary: systemic effects of inhaled nitric oxide. 1656 27


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