Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-Arginine crosses the cell membrane primarily through the system y(+) transporter. The aim of this study was to investigate the role of L-arginine transport in nitric oxide (NO) production in aortas of rats with heart failure induced by myocardial infarction. Tumor necrosis factor-alpha levels in aortas of rats with heart failure were six times higher than in sham rats (P < 0.01). L-Arginine uptake was increased in aortas of rats with heart failure compared with sham rats (P < 0.01). Cationic amino acid transporter-2B and inducible (i) nitric oxide synthase (NOS) expression were increased in aortas of rats with heart failure compared with sham rats (P < 0.05). Aortic strips from rats with heart failure treated with L-arginine but not D-arginine increased NO production (P < 0.05). The effect of L-arginine on NO production was blocked by L-lysine, a basic amino acid that shares the same system y(+) transporter with L-arginine, and by the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Treatment with L-lysine and L-NAME in vivo decreased plasma nitrate and nitrite levels in rats with heart failure (P < 0.05). Our data demonstrate that NO production is dependent on iNOS activity and L-arginine uptake and suggest that L-arginine transport plays an important role in enhanced NO production in heart failure.
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PMID:Increased L-arginine uptake and inducible nitric oxide synthase activity in aortas of rats with heart failure. 1115 87

Proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), are elevated during cardiopulmonary bypass (CPB), heart failure, and inflammatory cardiac and systemic diseases. Elevated TNF-alpha has been linked to diminished cardiac function, decreased systemic vascular resistance, as well as renal and pulmonary dysfunction. It is understood that myocardial tissues can express TNF-alpha, which results in the induction of inducible nitric oxide synthase (iNOS) leading to a significant decline in cardiac function and other direct effects. The hypothesis of this study was to determine if TNF-alpha would stimulate iNOS and its product nitric oxide (NO) similarly in immortalized macrophage and cardiac myocytes. Cultured macrophages (RAW 264.7) and cardiac myocytes (HL-1) were placed into two treatment groups and a control. The treatments included: (1) TNF-alpha and lipopolysaccharide (LPS); and (2) LPS, TNF-alpha, interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) incubated for 8 h. The macrophage expression of iNOS increased by 365% (p < 0.01) and its product, NO, increased proportionally. The expression of iNOS in the cardiac myocyte did not increase with TNF-alpha and LPS. However, with the addition of IFN-alpha and IL-1beta iNOS increased to 140% of control (p < 0.05). Myocyte cGMP and NO did not increase significantly with TNF-alpha treatment. This study suggests that HL-1 myocyte iNOS cannot be induced by TNF-alpha, unlike macrophage iNOS. Furthermore, the resultant cardiac dysfunction, secondary to proinflammatory cytokines effects, is regulated via diverse pathways.
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PMID:Comparison of tumor necrosis factor-alpha effect on the expression of iNOS in macrophage and cardiac myocytes. 1119 10

Nitric oxide (NO) has been shown to decrease cardiac performance, induce global hypotension, and generate oxygen free-radicals. Nitric oxide is produced from the conversion of L-arginine to L-citrulline by inducible nitric oxide synthase (iNOS) and is a component of many cellular second messenger systems. It is not clearly understood if NO and iNOS are compensatory mechanisms or pathological processes in heart failure, and this study was designed to understand better inhibition of iNOS in a cell culture model. Inhibitors of iNOS were compared for in vitro capability of inhibiting the production of NO. Ethanol and S-methylisothiourea (MITU) were applied to macrophage populations in 120 microM and 1 microM, 100 and 10 nM for an 8-h incubation. Level of iNOS expression was measured in the ethanol-treated populations using an anti-iNOS primary antibody with a fluorescent labeled secondary antibody. Serum nitrites were measured in both treatment groups by the nonenzymatic Griess method to determine enzyme function. Our data indicate that ethanol demonstrates a stimulation and simultaneous inhibition of iNOS during an 8-h incubation. No dose-dependent correlation between amount of serum nitrites produced and ethanol treatment was observed. However, MITU demonstrated a clear inhibition of iNOS at 120 microM with a serum nitrite value of 25.7002 +/- 0.0647, with control values of 24.3421 microM. Lower concentrations of MITU also demonstrated no correlation. Although both agents display inhibitory effects upon iNOS, MITU seems to have no apparent simultaneous stimulation and may hold more potential as a post-translational inhibitor of iNOS.
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PMID:In vitro comparison of inhibitors of inducible nitric oxide synthase in a macrophage model. 1119 55

An injury to the heart due to myocardial infarction (MI) may progress to heart failure. Among factors, whose interactions promote remodeling of ischemic myocardium, the increased expression of tumor necrosis factor alpha (TNFalpha), inducible nitric oxide synthase (iNOS) and Vascular Endothelial Growth Factor (VEGF) was found. However, little is known about the temporal and spatial relation between expression of iNOS, cytokine TNFalpha, and growth factor VEGF during pathological process of development of heart failure after the myocardial infarction. Male Sprague-Dawley rats were used for experimental myocardial infarction. The procedure was performed by anterolateral thoracotomy and snearing LAD with the metal clip. The hemodynamic measurements were done with the Langendorff preparation converted into a working heart system. The hemodynamic parameters were recorded at day 6, 11, 28, 40 and the myocardium for gene expression was collected at day 1, 4, 11, 28, 40. Control group was sham operated rats. The VEGF, TNFalpha, iNOS, and GAPDH genes were detected by RT-PCR assay from samples taken at border zone of myocardial infarction. Expression of isoform VEGF120 was found at day 1 and 4 after MI, whereas isoforms VEGF164 and VEGF188 along with expression of TNFalpha and iNOS was found at day 1, 4, 11, 28, 40. No expression of examined genes was detected in the myocardium of control rats. The expression of studied factors was parallel with development of heart failure after myocardial infarction assessed by hemodynamic measurements. These findings confirm the postulated involvement of TNFalpha, iNOS and growth factor VEGF in the remodeling of the myocardium and development of heart failure after experimental myocardial infarction.
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PMID:Relation between expression of TNF alpha, iNOS, VEGF mRNA and development of heart failure after experimental myocardial infarction in rats. 1132 12

The benefit effects of nitric oxide (NO) donors in acute heart failure have led to the development of vasodilators as treatment of chronic heart failure. However, the mechanisms involved in the effects of NO are complex and still discussed. In chronic heart failure, the eNOS downregulation in vascular endothelium explains the alteration of endothelial function. In addition, in the myocardium, cytokines induce the expression of inducible nitric oxide synthase (iNOS) which increase NO production by myocytes and surrounding cells. This excess of NO production, associated with anion superoxide synthesis, limits the inotropic properties of catecholamines and exert proapoptotic effects. The role of NO donors in heart failure treatment is still controversial but by reducing preload they improve patient's symptoms. Beside blockade of the renin-angiotensin system, the angiotensin converting enzyme inhibitors act via the inhibition of bradykinin degradation which increase NO levels. Finally, vascular endothelial NO expression is improved by exercise training and participates in the improvement of exercise capacity in patients with chronic heart failure involved in cardiac readaptation program.
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PMID:[Role of nitric oxide in heart failure]. 1132 16

An injury to the heart due to myocardial infarction may progress to heart failure. Among the cytokines and growth factors whose interactions promote remodeling of the heart, increased expression of tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF) has been found. However, little is known about the sequence of gene expression during the progression of heart injury. In the present study, male Sprague-Dawley rats were used for experimental myocardial infarction performed by ligation of the left anterior descending coronary artery. TNF-alpha, iNOS and VEGF expression was assessed by reverse transcription polymerase chain reaction. Localization of TNF-alpha, VEGF and iNOS protein was assessed by immunohistochemistry. An in vitro proliferation (BrdU incorporation) and differentiation (tube formation) assay of human umbilical vein endothelial cells was performed. The expression of TNF-alpha, iNOS, VEGF(164) and VEGF(188) was observed during the whole period after myocardial infarction (on days 1, 4, 11, 28 and 40), whereas VEGF(120) was found only on day 1 and 4. The most intense immunostaining for TNF-alpha was observed at the border zone. The iNOS immunostaining was initially located in the endothelium, whereas later it was also present in the walls of larger vessels. The VEGF protein was present in the border zone. No gene expression or immunostaining was detected in sham-operated rats. The in vitro experiments showed both proangiogenic (low TNF-alpha concentration, short period of incubation) and antiangiogenic (high TNF-alpha concentration, long period of incubation) effects of TNF-alpha. The expression of TNF-alpha and iNOS genes with the concomitant occurrence of a decrease in VEGF(120), VEGF(188) and VEGF(164) protein could be related to insufficient angiogenesis and may suggest the possible involvement of these events in remodeling after myocardial infarction.
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PMID:The time course of tumor necrosis factor-alpha, inducible nitric oxide synthase and vascular endothelial growth factor expression in an experimental model of chronic myocardial infarction in rats. 1139 1

Nitric oxide (NO), a potent regulator of myocardial contractility, has been implicated in the development of heart failure; however, no study exists describing the relation between expression of inducible nitric oxide synthase (iNOS), formation of NO in vivo, and cardiac contractility. We have therefore generated transgenic (TG) mice overexpressing iNOS under the cardiospecific alpha-myosin heavy chain (alpha-MHC) promoter. In vitro, iNOS activity in hearts of two transgenic lines was 260- to 400-fold above controls (wild type [WT]), but TG mice were viable and appeared normal. Ventricular mass/body weight ratio did not differ; heart rate and cardiac output as well as mean arterial blood pressure were decreased by 10%. NO(x) levels of hearts and blood of TG mice were 2.5- and 2-fold above WT controls, respectively. In the isolated heart, release of the NO oxidation products nitrate and nitrite, an index of in vivo NOS activity, was 40-fold over WT. However, cardiac hemodynamics and levels of ATP and phosphocreatine were unaltered. The high iNOS activity was associated with reduced cardiac L-arginine in TG hearts to only 15% of the WT, indicating limited substrate availability, whereas L-citrulline was 20-fold elevated. Our findings demonstrate that the heart can tolerate high levels of iNOS activity without detrimental functional consequences. The concept that iNOS-derived NO is the triggering factor in the pathomechanism leading to heart failure therefore needs to be reevaluated.
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PMID:Cardiac-specific overexpression of inducible nitric oxide synthase does not result in severe cardiac dysfunction. 1452 22

Nitric oxide regulates many aspects of myocardial function, not only in the normal heart but also in ischemic and nonischemic heart failure, septic cardiomyopathy, cardiac allograft rejection, and myocarditis. Accumulating evidence implicates the endogenous production of nitric oxide in the regulation of myocardial contractility, distensibility, heart rate, coronary vasodilation, myocardial oxygen consumption, mitochondrial respiration, and apoptosis. The effects of nitric oxide promote left ventricular mechanical efficiency, ie, appropriate matching between cardiac work and myocardial oxygen consumption. Most of these beneficial effects are attributed to the low physiologic concentrations generated by the constitutive endothelial or neuronal nitric oxide synthase. By contrast, inducible nitric oxide synthase generates larger concentrations of nitric oxide over longer periods of time, leading to mostly detrimental effects. In addition, the recently identified beta3-adrenoceptor mediates a negative inotropic effect through coupling to endothelial nitric oxide synthase and is overexpressed in heart failure. An imbalance between beta 1 and beta2-adrenoceptor and beta3-adrenoceptor, with a prevailing influence of beta3-adrenoceptor, may play a causal role in the pathogenesis of cardiac diseases such as terminal heart failure. Likewise, changes in the expression of endothelial nitric oxide synthase or inducible nitric oxide synthase within the myocardium may alter the delicate balance between the effects of nitric oxide produced by either of these isoforms. New treatments such as selective inducible nitric oxide synthase blockade, endothelial nitric oxide synthase promoting therapies, and selective beta3-adrenoceptor modulators may offer promising new therapeutic approaches to optimize the care of critically ill patients according to their stage and specific underlying disease process.
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PMID:Nitric oxide: does it play a role in the heart of the critically ill? 1180 29

Endothelial function plays a key role in the local regulation of vascular tone. Alterations in endothelial function may result in impaired release of endothelium-derived relaxing factors or increased release of endothelium-derived contracting factors. Heart failure may impair endothelial function by means of reduced synthesis and release of nitric oxide (NO) or by increased degradation of NO and increased production of endothelin-1. Endothelial dysfunction may worsen heart function by means of peripheral effects, causing increased afterload and central effects such as myocardial ischemia and inducible nitric oxide synthase (iNOS)-induced detrimental effects. Evidence from clinical studies has suggested that there is a correlation between decreased endothelial function and increasing severity of congestive heart failure (CHF). Treatments that improve heart function may also improve endothelial dysfunction. The relationship between endothelial dysfunction and heart failure may be masked by the stage of endothelial dysfunction, the location of vessels being tested, and the state of endothelial-dependent vasodilatation response.
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PMID:Vascular dysfunction and heart failure: epiphenomenon or etiologic agent? 1186 41

Increased inducible nitric oxide synthase (iNOS) expression is a component of the immune response and has been demonstrated in cardiomyocytes in septic shock, myocarditis, transplant rejection, ischemia, and dilated cardiomyopathy. To explore whether the consequences of such expression are adaptive or pathogenic, we have generated a transgenic mouse model conditionally targeting the expression of a human iNOS cDNA to myocardium. Chronic cardiac-specific upregulation of iNOS in transgenic mice led to increased production of peroxynitrite. This was associated with a mild inflammatory cell infiltrate, cardiac fibrosis, hypertrophy, and dilatation. While iNOS-overexpressing mice infrequently developed overt heart failure, they displayed a high incidence of sudden cardiac death due to bradyarrhythmia. This dramatic cardiac phenotype was rescued by specific attenuation of transgene activity. These data implicate cardiomyocyte iNOS overexpression as sufficient to cause cardiomyopathy, bradyarrhythmia, and sudden cardiac death.
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PMID:Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death. 1190 Nov 82


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