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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac myocytes express two types of nitric oxide (NO) synthase, eNOS and iNOS. eNOS activity is regulated by the contractile state of the heart, while iNOS expression is induced by cytokines. Nitric oxide induced by cytokines causes negative inotropic and lethal effects on cardiac myocytes. Expression of iNOS in the myocardium is increased in patients with dilated cardiomyopathy with clinical evidence of heart failure. Several neurohumoral factors activated in chronic heart failure augment cardiac iNOS expression and could cause cardiac dysfunction and cell damage.
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PMID:Nitric oxide and cardiac failure. 937 19

The effects of exogenous and endogenous. NO on myocardial functions such as contraction, relaxation and heart rate have recently gained considerable scientific interest. .NO stimulates myocardial soluble guanylate cyclase to produce cGMP, which activates two major target proteins. A small increase in cGMP levels predominantly inhibits phosphodiesterase III, while high cGMP levels activate cGMP-dependent protein kinase. Accordingly, submicromolar .NO concentrations improve myocardial contraction, while submillimolar .NO concentrations decrease contractility. The latter action includes direct inhibitory .NO effects on ATP synthesis and voltage-gated calcium channels. Overall, the inotropic effects of exogenous .NO are small and probably of minor importance for myocardial contractility. Cardiomyocytes are capable of expressing eNOS and iNOS. Endogenous .NO has effects on myocardial contraction, similar to that of exogenous .NO. Various NOS inhibitors can substantially reduce myocardial contractility in vitro and in vivo, suggesting that basal endogenous .NO production supports myocardial contractility. There is also evidence for a .NO-dependent cardiodepressive effect of cytokines that is mediated by expression of iNOS. This is consistent with the negative inotropic effects of .NO at high concentrations. Cardiodepressive actions of endogenous .NO production may play a role in certain forms of heart failure. Finally, .NO also has an effect on heart rate. Physiologic .NO concentrations can stimulate heart rate by activating the hyperpolarization-activated inward current (If) and this effect decreases at submillimolar .NO concentrations. In summary, physiological concentrations of .NO increase contractility and heart rate under basal conditions, while high .NO concentrations induce the opposite effects.
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PMID:Regulation of basal myocardial function by NO. 1061 6

In our study the pathomechanism of sepsis-induced early myocardial depression was investigated. We determined the effects of the inducible nitric oxide synthase inhibitor and free radical scavenger mercaptoethylguanidine (MEG) on the myocardial contractility, the endothelial and inducible nitric oxide synthase (eNOS and iNOS) activities, and the activation and tissue accumulation of polymorphonuclear leukocytes in hyperdynamic endotoxemia in dogs. Group 1 served as endotoxemic control. Mean arterial pressure and cardiac output were measured, myocardial contractility was estimated from the end-systolic pressure-diameter relationship. The eNOS, iNOS and myeloperoxidase activities were determined on myocardial biopsy samples, and the free radical-producing capacity of granulocytes was measured from separated cells. The effect of MEG on the in vitro free radical production of isolated granulocytes was measured by chemiluminometry. Endotoxin induced a hyperdynamic circulatory reaction and significant myocardial depression. The myocardial eNOS activity was significantly increased 4 h after induction of endotoxemia and remained elevated, the iNOS activity was increased only 8 h after endotoxemia induction. The free radical-producing capacity and the myocardial accumulation of the granulocytes were significantly increased. In group 2, MEG treatment selectively inhibited the iNOS activity, prolonged the hyperdynamic circulatory reaction, prevented myocardial depression and decreased the activation and tissue accumulation of granulocytes. The compound dose-dependently decreased the in vitro activation of previously resting granulocytes. Our study demonstrates that iNOS do not contribute to the early cardiac failure in endotoxemia. MEG selectively inhibits iNOS in vivo, but its beneficial effects are rather related to the decreases in leukocyte and free radical-mediated myocardial dysfunction during early endotoxemia.
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PMID:Prevention of early myocardial depression in hyperdynamic endotoxemia in dogs. 1063 69

In the present report we investigated the differential expression of three types of nitric oxide synthase (NOS) in the left ventricle after myocardial infarction in rats. One, 3, 7, 14, 28 and 56 days (n=6-12 for each group) after ligation of a coronary artery, tissue samples were obtained from infarcted and non-infarcted tissues. The mRNA and protein levels of neuronal (n) NOS, endothelial (e) NOS and inducible (i) NOS were sequentially determined by semi-quantitative reverse transcription-polymerase chain reaction and Western blotting. Progressive left ventricular dilatation and gradual reduction in fractional shortening were confirmed by echocardiography. The expression levels of nNOS were significantly increased 1, 3 and 7 days post-infarct compared to those of sham-operated rats in both the infarcted (P<0.01) and non-infarcted regions (P<0.01). Immunohistochemical analysis showed that nNOS was localized in nerve fibers in the left ventricle and that the number of positive fibers after myocardial infarction had increased compared to that in sham-operated rats. With regard to eNOS, no significant changes in expression levels were detected between infarcted hearts and sham-operated controls. The level of iNOS expression peaked three days post-infarct and then decreased in the infarcted tissue, whereas it increased one day post-infarct, peaked at 14 and 28 days post-infarct and was still elevated in the chronic stage in the ventricular septum. iNOS immunoreactivity was detected in spared cardiomyocytes and macrophages in the infarcted region, and in cardiomyocytes in the ventricular septum. The expressions of three types of NOS were differentially regulated and iNOS produced in the non-infarcted region may contribute to the progression of heart failure after myocardial infarction in rats.
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PMID:Differential expression of three types of nitric oxide synthase in both infarcted and non-infarcted left ventricles after myocardial infarction in the rat. 1148 84

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

Angiotensin-converting enzyme inhibitors (ACEi) reduce cardiovascular morbidity and mortality by improving coronary perfusion, reducing ventricular hypertrophy and remodeling, and preventing progression of coronary atherosclerosis. However, the cellular mechanisms underlying the beneficial effects of ACEi are not fully understood. We studied the in vivo effects of ACE inhibition with perindopril on cellular expression of ACE, AT(1) receptors and 2 nitric oxide synthase (NOS) isoforms, endothelial (eNOS) and inducible NOS (iNOS), in human blood vessels using quantitative in vitro autoradiography and immunocytochemistry. Seven patients with ischemic heart disease were treated with perindopril (4 mg/d) for up to 5 weeks before elective coronary bypass surgery, whereas controls did not receive the ACEi (n=7). Perindopril decreased plasma ACE by 70% and the plasma angiotensin II to angiotensin I ratio by 57% and reduced vascular ACE to approximately 65% of control levels in both endothelium and adventitia. By contrast, AT(1) receptor binding in vascular smooth muscle cells was increased by 80% in patients treated with perindopril as confirmed by immunocytochemistry. eNOS was expressed primarily in endothelial cells, whereas little iNOS expression occurred in vascular smooth muscle cells of untreated patients. Both eNOS and iNOS expression seemed to increase during perindopril treatment. These results suggest that suppression of angiotensin II formation in the vascular wall and increased expression of eNOS and iNOS during ACE inhibition may be beneficial in reversing endothelial dysfunction in patients with cardiovascular disease. Because vascular AT(1) receptor expression is increased during chronic ACE inhibition, more clinical studies are required to determine whether it is necessary to combine ACE inhibitors and AT(1) receptor antagonists in clinical management of heart failure, coronary heart disease, and hypertension
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PMID:Perindopril alters vascular angiotensin-converting enzyme, AT(1) receptor, and nitric oxide synthase expression in patients with coronary heart disease. 1236 66

Nitric Oxide Synthases (NOSs) are a group of related proteins that produce nitric oxide (NO). In mammals, there are three known members of this gene family: nNOS (NOS1), iNOS (NOS2) and eNOS (NOS3). Each has been disrupted by targeted gene ablation in mice and the corresponding phenotypes examined. These mice have allowed an examination of the contribution of each NOS in a variety of experimental models and continue to provided insights into the patho-physiological role of NOS and NO. With increasing sophistication, murine transgenic approaches continue to offer a wealth of information, and invaluable tools to further study the NOS system. The focus of this review will be an examination of the tools available, and the insights gained from studies done on murine NOS genetic models in the context of heart failure.
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PMID:The role of NOS in heart failure: lessons from murine genetic models. 1237 25

We recently demonstrated that mice deficient in endothelial nitric oxide (NO) synthase (eNOS) have congenital septal defects and postnatal heart failure. However, the mechanisms by which eNOS affects heart development are not clear. We hypothesized that deficiency in eNOS impairs myocardial angiogenesis. Myocardial capillary densities were measured morphometrically in neonatal mouse hearts. In vitro tube formation on Matrigel was investigated in cardiac endothelial cells. In vivo myocardial angiogenesis was performed by implanting Matrigel in the left ventricular myocardium. Myocardial capillary densities and VEGF mRNA expression were decreased in neonatal eNOS(-/-) compared with neonatal wild-type mice (P < 0.01). Furthermore, in vitro tube formation from cardiac endothelial cells and in vivo myocardial angiogenesis were attenuated in eNOS(-/-) compared with wild-type mice (P < 0.01). In vitro tube formation was inhibited by N(G)-nitro-l-arginine methyl ester in wild-type mice and restored by a NO donor, diethylenetriamine-NO, in eNOS(-/-) mice (P < 0.05). In conclusion, deficiency in eNOS decreases VEGF expression and impairs myocardial angiogenesis and capillary development. Decreased myocardial angiogenesis may contribute to cardiac abnormalities during heart development in eNOS(-/-) mice.
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PMID:Deficiency in endothelial nitric oxide synthase impairs myocardial angiogenesis. 1238 4

Chronic unloading of the failing heart with a left ventricular assist device (LVAD) can decrease cardiac mass and myocyte size and has the potential to improve contractile function. To study the effect of chronic ventricular unloading on myocardial gene expression, a microarray (U133A, Affymetrix) profiling gene expression was compared before and after LVAD support in seven patients with idiopathic dilated cardiomyopathy and end-stage heart failure. On average, 1,374 +/- 155 genes were reported as "increased" and 1,629 +/- 45 as "decreased" after LVAD support. A total of 130 gene transcripts achieved the strict criteria for upregulation and 49 gene transcripts for downregulation after LVAD support. Upregulated genes included a large proportion of transcription factors, genes related to cell growth/apoptosis/DNA repair, cell structure proteins, metabolism, and cell signaling/communication. LVAD support resulted in downregulation of genes for a group of cytokines. To validate the array data, 10 altered genes were confirmed by real-time RT-PCR. Further study showed that the phosphoinositide-3-kinase-forkhead protein pathway and proteins related to nitric oxide synthesis, including eNOS and dimethylarginine dimethylaminohydrolase isoform 1 (DDAH1, an enzyme regulating endogenous nitric oxide synthase activity), were significantly increased during the cardiac remodeling process. Increased eNOS and DDAH1 expression after LVAD support may contribute to improved endothelial function of the failing hearts.
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PMID:Alterations of gene expression in failing myocardium following left ventricular assist device support. 1282 57

Several cell types, including cardiac myocytes and vascular endothelial cells, produce nitric oxide (NO) via both constitutive and inducible isoforms of NO synthase. NO attenuates cardiac contractility and contributes to contractile dysfunction in heart failure, although the precise molecular mechanisms for these effects are poorly defined. Adenylyl cyclase (AC) isoforms type 5 and 6, which are preferentially expressed in cardiac myocytes, may be inhibited via a direct nitrosylation by NO. Because endothelial NO synthase (eNOS and NOS3), beta-adrenergic (betaAR) receptors, and AC6 all can localize in lipid raft/caveolin-rich microdomains, we sought to understand the role of lipid rafts in organizing components of betaAR-G(s)-AC signal transduction together with eNOS. Using neonatal rat cardiac myocytes, we found that disruption of lipid rafts with beta-cyclodextrin inhibited forskolin-stimulated AC activity and cAMP production, eliminated caveolin-3-eNOS interaction, and increased NO production. betaAR- and G(s)-mediated activation of AC activity were inhibited by beta-cyclodextrin treatment, but prostanoid receptor-stimulated AC activity, which appears to occur outside caveolin-rich microdomains, was unaffected unless eNOS was overexpressed and lipid rafts were disrupted. An NO donor, SNAP, inhibited basal and forskolin-stimulated cAMP production in both native cardiac myocytes and cardiac myocytes and pulmonary artery endothelial cells engineered to overexpress AC6. These effects of SNAP were independent of guanylyl cyclase activity and were mimicked by overexpression of eNOS. The juxtaposition of eNOS with betaAR and AC types 5 and 6 results in selective regulation of betaAR by eNOS activity in lipid raft domains over other G(s)-coupled receptors localized in nonraft domains. Thus co-localization of multiple signaling components in lipid rafts provides key spatial regulation of AC activity.
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PMID:Nitric oxide inhibition of adenylyl cyclase type 6 activity is dependent upon lipid rafts and caveolin signaling complexes. 1500 69


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