UMLS:C0018801 - FACTA Search

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

Cardiac endothelial nitric oxide synthase (ecNOS) was suppressed and inducible NOS (iNOS) enhanced at the decompensated heart failure stage in 18-week-old Dahl salt-sensitive (DS) hypertensive rats to which a high-salt diet had been administered from the age of 6 weeks. Nicorandil (NIC) enhanced ecNOS by activating Adenosine triphosphate-sensitive potassium channels (K-ATP channels) in the normal rat left ventricle. In this study, left ventricular hypertrophy, remodeling, function, cardiac ecNOS, and iNOS were compared between NIC and isosorbide dinitrate (ISDN) treatments in DS hypertensive rats with congestive heart failure. We examined DS hypertensive rats of 18 weeks of age to which 8% NaCl had been administered from the age of 6 weeks, and to which subdepressor doses of NIC (6 mg/kg/d), ISDN (6 mg/kg/d), and vehicle (CON) were administered from the age of 11 weeks. Contractility (Ees), stiffness (Eed), left ventricular end-diastolic volume, and left ventricular end-systolic volume were measured by conductance catheter and micromanometer on the basis of the pressure-volume relationship, and mRNA and protein levels of ecNOS and iNOS in the left ventricle were measured by reverse transcription-polymerase chain reaction and Western blot analysis at 18 weeks. LV mass index and LV dimensions were smaller in the NIC and ISDN groups than in the CON group (P < 0.01), and the first parameter was lower in the NIC than in the ISDN group (P < 0.01). Ees was also better maintained in the NIC and ISDN groups than in the CON group (NIC: 3349 +/- 649; ISDN: 2950 +/- 577, P < 0.05 vs. NIC; CON: 1424 +/- 375 mL/mmHg, P < 0.01 vs. treatments). Eed was exacerbated only in the ISDN group. NIC enhanced whereas ISDN suppressed ecNOS mRNA and protein levels (NIC 2.0-fold and 1.8-fold, ISDN 0.70-fold and 0.8-fold vs. CON; P < 0.01, respectively). However, no intragroup differences in iNOS mRNA or protein levels were observed for the 3 groups. More significant improvements in cardiac function and LV hypertrophy regression were observed in an NIC group than in an ISDN group of DS hypertensive rats. Activation of the K-ATP channel seems to induce this beneficial effect, which may be mediated in part by enhanced ecNOS expression in the heart in DS hypertensive congestive heart failure rat model.
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PMID:Nicorandil but not ISDN upregulates endothelial nitric oxide synthase expression, preventing left ventricular remodeling and degradation of cardiac function in Dahl salt-sensitive hypertensive rats with congestive heart failure. 1677

Enhanced iNOS (inducible nitric oxide synthase) activity may contribute to vascular dysfunction in patients with heart failure. In the present study, we aimed to determine whether iNOS activity contributes to the maintenance of vascular tone in patients with symptomatic heart failure with the use of the highly selective iNOS inhibitor 1400W {N-[3-(aminomethyl)benzyl] acetamidine}. Bilateral forearm blood flow was measured using venous occlusion plethysmography in 12 patients with New York Heart Association class II-IV heart failure and eight matched healthy control subjects during intra-brachial infusion of 1400W (0.1-1 micromol/min), L-NMMA (N(G)-monomethyl-L-arginine; a non-selective NOS inhibitor; 2-8 micromol/min) and noradrenaline (control vasoconstrictor; 60-480 pmol/min). In both patients and controls, intra-brachial infusion of L-NMMA and noradrenaline caused a dose-dependent reduction in infused forearm blood flow (P<0.05 for both): peak reduction of 32+/-6% and 37+/-4% during L-NMMA and 52+/-6% and 49+/-5% during noradrenaline respectively (P values were not significant when patients were compared with controls). In contrast, 1400W had no effect on blood flow at 1 micromol/min [-3+/-4% in patients (95% confidence intervals, -11 to 5%) and 3+/-8% in controls; P value was not significant]. In conclusion, we have demonstrated that intrabrachial selective iNOS inhibition does not influence forearm blood flow in patients with heart failure. We conclude that iNOS activity does not contribute to peripheral vascular tone in patients with symptomatic heart failure.
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PMID:Inducible nitric oxide synthase activity does not contribute to the maintenance of peripheral vascular tone in patients with heart failure. 1680 56

A common gene variant of human extracellular superoxide dismutase (ecSOD), in approximately 5% of humans, is associated with increased risk of ischemic heart disease. The purpose of this study was to examine vascular effects of ecSOD with effects of the ecSOD variant (ecSOD(R213G)) in rats with heart failure. Seven weeks after coronary artery ligation, we studied rats with heart failure and sham-operated rats. Adenoviral vectors expressing human ecSOD, ecSOD(R213G), or a control virus were injected intravenously. In the aorta from rats with heart failure, responses to acetylcholine (69 +/- 4% relaxation, means +/- SE) and basal levels of nitric oxide (NO) (vasoconstrictor responses to a NO synthase inhibitor) were greatly impaired, and levels of superoxide and peroxynitrite were increased. Gene transfer of ecSOD restored responses to acetylcholine (92 +/- 2% relaxation) and basal levels of NO to normal and reduced levels of superoxide [from 2.3 +/- 0.2 to 0.9 +/- 0.2 relative light units per second per millimeter squared (RLU x s(-1) x mm(-2))] and peroxynitrite (from 2.4 +/- 0.2 to 0.9 +/- 0.1 RLU x s(-1) x mm(-2)) in the aorta from rats with heart failure. Gene transfer of ecSOD(R213G) produced little or no improvement. Responses to nitroprusside were not different among the groups. Expression of endogenous mRNA for SODs (CuZnSOD, MnSOD, and ecSOD) and endothelial NOS in the aorta was not different among the groups. In contrast to ecSOD, gene transfer of ecSOD(R213G) in rats with heart failure has minimal beneficial effect on oxidative stress, endothelial function, or basal bioavailability of NO. We speculate that greatly diminished efficacy of ecSOD(R213G) in protection against oxidative stress and endothelial dysfunction may contribute to increased risk of cardiovascular disease in humans with ecSOD(R213G).
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PMID:Vascular effects of a common gene variant of extracellular superoxide dismutase in heart failure. 1684 Jul 38

Pressure overload associated with hypertension is an important pathological factor leading to heart remodeling and ultimately heart failure partially due to cardiomyocyte apoptosis. Here we show that endogenous NO signaling plays a critical role in mechanical stretch-induced cardiomyocyte apoptosis. Mechanical stretch induced elevated expression of both eNOS and inducible NO synthase (iNOS) and increased synthesis of NO. A sustained increase in iNOS expression was also found in hearts of hypertensive rats in vivo. Blockade of NO signaling by inhibitors of NOS (L-NAME and AMT) or downstream guanylyl cyclase (ODQ) strongly inhibited stretch-induced apoptosis, mitochondria depolarization, and cytochrome c release, suggesting that NO is required in stretch-induced cardiomyocyte apoptosis. The expression of iNOS, but not eNOS, was blocked by L-NAME and ODQ, indicating that the iNOS induction is NO dependent. The initial elevation of NO is likely due to Ca(2+)-dependent activation of eNOS because elimination of intracellular calcium by EGTA-AM inhibited both iNOS induction and NO elevation. Other calcium signaling inhibitors (nifedipine, ryanodine, thapsigargin, and ionic gadolinium) also attenuated the initial NO elevation. These data indicate that mechanical signals initiate Ca(2+)-dependent NO synthesis, which is further amplified by activation of NO-induced iNOS expression, to regulate cardiomyocyte apoptosis.
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PMID:Nitric oxide signaling in stretch-induced apoptosis of neonatal rat cardiomyocytes. 1687 24

Resting neutrophils generate NO, while activation leads to the production of reactive oxygen and nitrogen species. Nowadays cardiovascular pathological conditions such as hypertension, cardiac ischemia, reperfusion and heart failure are associated with inflammation. This project explores the respiratory burst potential and NO generation status in the neutrophils, plasma, aorta, and kidneys from normotensive Wistar and spontaneously hypertensive rats (SHR). Total and protein associated nitrite content was quantitated using Griess reagent following cadmium reduction and mercuric chloride treatment respectively. NO and superoxide generation evaluated by Flowcytometry and peroxynitrite by spectrofluorimetric method. Expression of NOS isoforms was analyzed by RT-PCR. NO generation from SHR neutrophils was significantly augmented in comparison to normotensive counterparts. Neutrophils activated in response to arachidonic acid, PMA, fMLP or E. coli generated more superoxide radicals among SHR, and consequentially peroxynitrite. Expression of iNOS was significantly more in the SHR neutrophils, while that of nNOS remained unaffected. Results suggest that NO generated in SHR is utilized in scavenging superoxide radicals thereby limiting its bioavailability. Thus induction of NOS in neutrophils combined with augmented oxidative stress might influence its association with endothelium and contribute to inflammatory responses under hypertensive condition.
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PMID:Biochemical and molecular evaluation of neutrophil NOS in spontaneously hypertensive rats. 1751 16

Cardiac myocyte dysfunction is clearly identified as underlying the acute heart failure associated with bacterial infection, as well as the chronic syndrome following cardiac damage, but the mechanisms leading to dysfunction in each case are not fully established. It is thought that local hormones such as endothelin 1 (ET-1) can increase the risk of heart failure in acute or chronic conditions. In the current study, we characterize myocytes as populations and identify a novel phenotype of the ventricular cardiac myocyte that does not contract appropriately on electrical stimulation. The noncontractile cardiac myocytes were viable and had normal calcium transients. The proportion of noncontractile cardiac myocytes was increased by bacteria (gram-positive Staphylococcus aureus or gram-negative Escherichia coli). Using selective ligands or myocytes from genetically modified mice, we established that the effects of S. aureus were mediated by Toll-like receptor 2/6 and of E. coli by Toll-like receptor 4. The transition to the noncontractile phenotype was strongly inhibited by ETA antagonism but unaffected by inhibition of NOS, suggesting that ET-1 and not NO mediates this phenomenon. These results are the first to describe the characteristics of this noncontractile phenotype and the mechanisms of its induction by bacteria. Description of the myocyte population, instead of effects only on individual cells, will be more relevant to the prediction of the depression of cardiac function.
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PMID:Identification and characterization of a dysfunctional cardiac myocyte phenotype: role of bacteria, Toll-like receptors, and endothelin. 1755 48

Nitric oxide (NO) is a highly reactive, free radical signalling molecule that is constitutively released in cardiomyocytes by both the endothelial and neuronal isoforms of nitric oxide synthase (eNOS and nNOS, respectively). There are increasing data indicating that NO modulates various proteins involved in excitation-contraction coupling (ECC), and here we discuss the evidence that NO may modulate the function of the ryanodine receptor Ca(2+) release channel (RyR2) on the cardiac sarcoplasmic reticulum (SR). Both constitutive isoforms of NOS have been shown to co-immunoprecipitate with RyR2, suggesting that the channel may be a target protein for NO. eNOS gene deletion has been shown to abolish the increase in spontaneous Ca(2+) spark frequency in cardiomyocytes exposed to sustained stretch, whereas the effect of nNOS-derived NO on RyR2 function remains to be investigated. Single channel studies have been performed with RyR2 reconstituted in planar lipid bilayers and exposed to various NO donors and, under these conditions, NO appears to have a dose-dependent, stimulatory effect on channel open probability (P(open)). We discuss whether NO has a direct effect on RyR2 via covalent S-nitrosylation of reactive thiol residues within the protein, or whether there are downstream effects via cyclic nucleotides, phosphodiesterases, and protein kinases. Finally, we consider whether the proposed migration of nNOS from the SR to the sarcolemma in the failing heart may have consequences for the nitrosative vs. oxidative balance at the level of the RyR2, and whether this may contribute to an increased diastolic Ca(2+) leak, depleted SR Ca(2+) store, and reduced contractility in heart failure.
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PMID:Does nitric oxide modulate cardiac ryanodine receptor function? Implications for excitation-contraction coupling. 1800 80

Peripheral chemoreflex sensitivity is potentiated in clinical and experimental chronic heart failure (CHF). Downregulation of nitric oxide (NO) synthase (NOS) in the carotid body (CB) is involved in this effect. However, it remains poorly understood whether carbon monoxide (CO) also contributes to the altered peripheral chemoreflex sensitivity in CHF. This work highlights the effect of NO and CO on renal sympathetic nerve activity (RSNA) in response to graded hypoxia in conscious rabbits. Renal sympathetic nerve responses to graded hypoxia were enhanced in CHF rabbits compared with sham rabbits. The NO donor S-nitroso-N-acetylpenicillamine (SNAP, 1.2 microg x kg(-1) x min(-1)) and the CO-releasing molecule tricarbonyldichlororuthenium (II) dimer {[Ru(CO)(3)Cl(2)](2), 3.0 microg x kg(-1) x min(-1)} each attenuated hypoxia-induced RSNA increases in CHF rabbits (P < 0.05), but the degree of attenuation of RSNA induced by SNAP or [Ru(CO)(3)Cl(2)](2) was smaller than that induced by SNAP + [Ru(CO)(3)Cl(2)](2). Conversely, treatment with the NOS inhibitor N(omega)-nitro-L-arginine (30 mg/kg) + the heme oxygenase (HO) inhibitor Cr (III) mesoporphyrin IX chloride (0.5 mg/kg) augmented the renal sympathetic nerve response to hypoxia in sham rabbits to a greater extent than treatment with either inhibitor alone and was without effect in CHF rabbits. In addition, using immunostaining and Western blot analyses, we found that expression of neuronal NOS, endothelial NOS, and HO-2 protein (expressed as the ratio of NOS or HO-2 expression to beta-tubulin protein expression) was lower in CBs from CHF (0.19 +/- 0.04, 0.17 +/- 0.06, and 0.15 +/- 0.02, respectively) than sham (0.63 +/- 0.04, 0.56 +/- 0.06, and 0.27 +/- 0.03, respectively) rabbits (P < 0.05). These results suggest that a deficiency of NO and CO in the CBs augments peripheral chemoreflex sensitivity to hypoxia in CHF.
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PMID:Downregulation of carbon monoxide as well as nitric oxide contributes to peripheral chemoreflex hypersensitivity in heart failure rabbits. 1845 Sep 75

Oxidative stress mediated by activation of angiotensin II type-1 receptor (AT(1)R) plays a crucial role in the progression of heart failure. We investigated the effect of N-acetylcysteine (NAC) and an AT(1)R blocker on oxidative stress and left ventricular (LV) remodeling in BIO14.6 cardiomyopathy hamsters. The cardiomyopathy hamsters were treated with NAC or the AT(1)R blocker losartan for 20 weeks. Although NAC and losartan inhibited oxidative stress and upregulation of iNOS in the cardiomyopathy hamster heart, only losartan inhibited LV chamber dilation, myocardial fibrosis, and LV dysfunction in the cardiomyopathy hamster. Co-treatment with NAC abolished the protective effect of losartan against LV remodeling associated with inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt and eNOS activation. An iNOS inhibitor 1400W or a nonselective NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) exacerbated LV remodeling in the cardiomyopathy hamster. However, L-NAME but not 1400W abrogated losartan-mediated inhibition of LV remodeling. These results suggest that redox-sensitive upregulation of iNOS plays a crucial role in preventing LV remodeling in the BIO14.6 cardiomyopathy hamster. Losartan inhibits LV remodeling by switching the cardioprotective mechanism from iNOS- to eNOS-dependence, but NAC abolishes the protective effect of losartan by inhibiting redox-sensitive activation of PI3K/Akt and eNOS in the cardiomyopathy hamster.
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PMID:N-acetylcysteine abolishes the protective effect of losartan against left ventricular remodeling in cardiomyopathy hamster. 1866 99

The NO system plays an important role in pathogenesis of coronary heart disease. Disturbances of reperfusion associated with myocardial infarction and post-infarction heart failure are shown to be related to reduced synthesis and biological availability of NO. Variations of activity of three NOS isoforms (eNOS, nNOS, and iNOS) in patients with ischemic heart disease are linked to altered expression of the respective genes. They correlate with the character and severity of myocardial dysfunction. Cardiotropic effects of the above isoenzymes depend on their subcellular localization, interaction between themselves and between NO and reactive oxygen species, disturbed NO/redox balance, and other factors. Enhanced NOS activity and NO level at the premorbid stage of coronary heart disease have important implications for the prevention and treatment of this condition.
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PMID:[Nitric oxide and coronary heart disease]. 1928 Sep 86

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