Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vasculature endothelium cells and the nerve cells of several regions of the brain and the autonomous nerve system contain a nitric oxide (NO)-synthase, that forms NO from arginine. The NO-synthase is stimulated by bradykinin, histamine and acetylcholine and is especially active in the coronary and brain vessels. In the vasculature smooth muscle NO activates the guanylate cyclase: The increase in the concentration of cGMP induces a relaxation and in this way a vasodilatation. In the nerve cells NO is active as a neuromodulator. The activation of macrophages by gamma-interferon or by lipopolysaccharides induces the formation of a NO-synthase, that has other properties than the enzyme of the endothelium cells. The macrophages secrete NO and inhibit the metabolism of tumour cells, especially enzymes of the respiratory chain and of the citric acid cycle as well as the DNA-synthesis. Trinitroglycerin and amyl nitrite form with thiol-compounds S-nitroso-compounds, the decomposition of these forms NO.
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PMID:[Current knowledge on the formation of nitric oxide in endothelial cells of blood vessels, in nerve cells and macrophages as well as its significance in vascular dilatation, information transmission and damage of tumor cells]. 171 6

Thiamine (vitamin B1) is an essential nutritional component that acts as a coenzyme in the oxidative decarboxylation of alpha-keto acids. It also serves as the connection between the glycolytic cycle and the high energy-producing Krebs (or citric acid) cycle. Unlike other B vitamins, it activates the guanylate cyclase/cyclic guanosine monophosphate (GMP) system but not the adenylate cyclase system. The active coenzyme, thiamine pyrophosphate (TPP) is an antiberiberi substance. Thiamine itself is a pharmacologic antagonist of acetylcholine, which may explain the nerve lesions caused by thiamine deficiency. Liver, pork, yeast, and rice-polishings are rich in thiamine; however, several antithiamine factors are also found in common foods. For example, a thermal labile factor in the viscera of fresh water fish and tea leaves antagonizes thiamine.
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PMID:What the practicing nurse should know about thiamine. 200 9

The cytoskeletal protein dystrophin has been implicated in hereditary and acquired forms of cardiomyopathy. However, much remains to be learned about the role of dystrophin in the heart. We hypothesized that the dystrophin-deficient heart displays early alterations in energy metabolism that precede overt cardiomyopathy. We evaluated the metabolic and functional phenotype of dystrophin-deficient mdx mouse hearts at 10-12 weeks, when no major histological or echocardiographic abnormalities are reported. Ex vivo working mdx heart perfusions with stable isotopes revealed a marked shift in substrate fuel selection from fatty acids to carbohydrates associated with enhanced oxygen consumption. They also unmasked in the mdx heart: (i) compromised cardiac contractile function and efficiency, (ii) reduced cellular integrity, and (iii) exacerbated alterations in mitochondrial citric acid cycle-related parameters and in nutrient signaling pathways related to Akt. The observed shift in substrate selection cannot be explained by metabolic gene remodeling. However, mdx mice hearts showed an increased expression of the atrial natriuretic factor (anf) gene, an activator of the nitric oxide (NO)/cGMP signaling pathway and marker of cardiac remodeling, and, only as the cardiomyopathy progresses (at 25 weeks of age), an increased expression of the alpha1 subunit of soluble guanylate cyclase, which is known to negatively correlate with the activity NO/cGMP pathway. Collectively, our results highlight early metabolic and signaling alterations in the dystrophin-deficient heart, which may predispose these hearts to contractile dysfunction and sarcolemmal fragility. They also suggest the presence of a "sub-clinical" defect in the NO/cGMP pathway, which in vivo, at an early age, may be compensated by enhanced anf gene expression.
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PMID:Metabolic and signaling alterations in dystrophin-deficient hearts precede overt cardiomyopathy. 1758 24

We recently demonstrated early metabolic alterations in the dystrophin-deficient mdx heart that precede overt cardiomyopathy and may represent an early "subclinical" signature of a defective nitric oxide (NO)/cGMP pathway. In this study, we used genetic and pharmacological approaches to test the hypothesis that enhancing cGMP, downstream of NO formation, improves the contractile function, energy metabolism, and sarcolemmal integrity of the mdx heart. We first generated mdx mice overexpressing, in a cardiomyocyte-specific manner, guanylyl cyclase (GC) (mdx/GC(+/0)). When perfused ex vivo in the working mode, 12- and 20-week-old hearts maintained their contractile performance, as opposed to the severe deterioration observed in age-matched mdx hearts, which also displayed two to three times more lactate dehydrogenase release than mdx/GC(+/0). At the metabolic level, mdx/GC(+/0) displayed a pattern of substrate selection for energy production that was similar to that of their mdx counterparts, but levels of citric acid cycle intermediates were significantly higher (36 +/- 8%), suggesting improved mitochondrial function. Finally, the ability of dystrophin-deficient hearts to resist sarcolemmal damage induced in vivo by increasing the cardiac workload acutely with isoproterenol was enhanced by the presence of the transgene and even more so by inhibiting cGMP breakdown using the phosphodiesterase inhibitor sildenafil (44.4 +/- 1.0% reduction in cardiomyocyte damage). Overall, these findings demonstrate that enhancing cGMP signaling, specifically downstream and independent of NO formation, in the dystrophin-deficient heart improves contractile performance, myocardial metabolic status, and sarcolemmal integrity and thus constitutes a potential clinical avenue for the treatment of the dystrophin-related cardiomyopathies.
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PMID:Sildenafil and cardiomyocyte-specific cGMP signaling prevent cardiomyopathic changes associated with dystrophin deficiency. 1847 59

While the balance between carbohydrates and fatty acids for energy production appears to be crucial for cardiac homeostasis, much remains to be learned about the molecular mechanisms underlying this relationship. Given the reported benefits of cGMP signaling on the myocardium, we investigated the impact of its chronic activation on cardiac energy metabolism using mice overexpressing a constitutively active cytoplasmic guanylate cyclase (GC(+/0)) in cardiomyocytes. Ex vivo working GC(+/0) heart perfusions with (13)C-labeled substrates revealed an altered pattern of exogenous substrate fuel selection compared to controls, namely a 38+/-9% lower contribution of exogenous fatty acids to acetyl-CoA formation, while that of carbohydrates remains unchanged despite a two-fold increase in glycolysis. The lower contribution of exogenous fatty acids to energy production is not associated with changes in energy demand or supply (contractile function, oxygen consumption, tissue acetyl-CoA or CoA levels, citric acid cycle flux rate) or in the regulation of beta-oxidation (acetyl-CoA carboxylase activity, tissue malonyl-CoA levels). However, GC(+/0) hearts show a two-fold increase in the incorporation of exogenous oleate into triglycerides. Furthermore, the following molecular data are consistent with a concomitant increase in triglyceride hydrolysis: (i) increased abundance of hormone sensitive lipase (HSL) protein (24+/-11%) and mRNA (22+/-4%) as well as (ii) several phosphorylation events related to HSL inhibitory (AMPK) and activation (ERK 1/2) sites, which should contribute to enhance its activity. These changes in exogenous fatty acid trafficking in GC(+/0) hearts appear to be functionally relevant, as demonstrated by their resistance to fasting-induced triglyceride accumulation. While the documented metabolic profile of GC(+/0) mouse hearts is partly reminiscent of hypertrophied hearts, the observed changes in lipid trafficking have not been previously documented, and may be part of the molecular mechanism underlying the benefits of cGMP signaling on the myocardium.
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PMID:Cyclic GMP signaling in cardiomyocytes modulates fatty acid trafficking and prevents triglyceride accumulation. 1859 Sep 15