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)

Myocardial adenine nucleotides (nicotinamide adenine nucleotides included), glutathione, catecholamines (DOPA, dopamine, noradrenaline, adrenaline) and some enzymes in correlation were investigated in dogs with cardiac failure induced by bilateral iliac arteriovenous fistulas, and unilateral (left) heart vagotomy was also studied for its influence on the changes in the myocardial amounts of these compounds occuring in this pathological circumstance. The cardiac failure in arteriovenous fistula was characterized by the following myocardial metabolic aspects: (I) no change in the amount of proteins (although an important cardiac hypertrophy was present); (II) decreases in the amounts of adenine nucleotides (especially ADP and ATP), without significant variations in the adenosine concentration, accompanied by increases in the concentrations of nicotinamide adenine nucleotides (in both their oxidized and reduced forms) in the heart mitochondria; (III) no change in the amounts of oxidized and reduced glutathione and in the activity of NADH2-dependent glutathione reductase; (IV) a very significant increase in the activity of MAO without significant influences on the levels of the studied catecholamines. The partial vagal denervation of the heart was found to attenuate substantially the changes in the amounts of adenine nucleotides and nicotinamide adenine nucleotides in the myocardial mitochondria and to facilitate the action of MAO on noradrenaline leading to a significant decrease in its myocardial level.
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PMID:Role of the vagus nerves and catecholamines in the production mechanism of the myocardial failure induced by arteriovenous fistulas. 21 43

The angiotensin AT(1) and AT(2) receptors have been cloned and characterised. Both are members of the serpentine receptor superfamily coupled to G proteins, but there is only 32% homology between the AT(1) and AT(2) receptors. The typical pharmacological features of AT(1) receptors are their selective affinity for biphenylimidazoles (typified by losartan) and their insensitivity to tetrahydroimidazopyridine (such as PD123319). In contrast, the AT(2) receptor has the opposite sensitivity for these two ligands. Genes located on chromosome 3 and X, respectively, encode the human AT(1) and AT(2) receptors. The signalling pathways of AT(1) and AT(2) are totally different. In addition to the classical signal transduction mechanisms (phospholipases C, D, A, voltage-dependent calcium channels and adenylate cyclase), the AT(1) receptor stimulates the phosphorylation of several tyrosine-containing proteins such as Jak 2, Stat 1 and mitogen-activated protein kinases. It also activates the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The AT(1) receptor is responsible for the majority of the effects of angiotensin II: vasoconstriction, sodium re-absorption, cell proliferation, extracellular matrix formation, inflammatory response and oxidative stress. The AT(2) receptor is expressed abundantly in fetal tissues but at low density in adults. It is, however, upregulated in various pathological circumstances such as heart failure. In contrast to the AT(1) receptor, the signalling pathway of the AT(2) receptor does not induce an increase in inositol triphosphate and diacylglycerate formation with calcium mobilisation. Activation of the AT(2) receptor stimulates an intracellular mechanism involving various Tyr (tyrosine) and Ser (serine)/Thr (threonine) phosphatases, nitric oxide/cyclic guanosine monophosphate (cGMP) and phospholipase A(2). The effect of the AT(2) receptor counterbalances that of the AT(1) receptor: inactivation of mitogen-activated protein kinase (MAP), antiproliferation, promotion of apoptosis, opening of delayed-rectifier K(+) channels, closing of T-type Ca(2+) channels, stimulation of nerve differentiation and regeneration. It has been hypothesised that stimulation of the AT(2) receptor is part of the mechanism of action of the AT(1) receptor antagonists.
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PMID:[AT(1) and AT(2) angiotensin II receptors: key features]. 1203 84

Reactive oxygen species (ROS) released acutely in large amounts have been traditionally implicated in the cell death associated with myocardial infarction or reperfusion injury. These ROS can be released from the cardiac myocyte mitochondria, xanthine oxidase, and the phagocytic nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase. Interestingly, the chronic release of ROS has been recently linked to the development of left ventricular hypertrophy and heart failure progression. The chronic release of ROS appears to derive from the nonphagocytic NAD(P)H oxidase and mitochondria. Experimental data are accumulating suggesting that the release of ROS is required for the normal, physiologic activity of cardiac cells, but abnormal activation of the nonphagocytic NAD(P)H oxidase in response to neurohormones (angiotensin II, norepinephrine, tumor necrosis factor-a) has been shown to contribute to cardiac myocyte hypertrophy. Furthermore, the fibrosis, collagen deposition, and metalloproteinase activation involved in the remodeling of the failing myocardium are dependent on ROS released during the phenotypic transformation of fibroblasts to myofibroblasts associated with progression of end-stage heart failure. Future studies are necessary to identify the sources, mechanisms of activation of NAD(P)H oxidases, and downstream signaling targets implicated in the progression of chronic heart failure.
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PMID:Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure. 1204 81

Reactive oxygen species have an important pathogenic role in organ damage. We investigated the role of oxidative stress via nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase in the kidney of the Dahl salt-sensitive (DS) rats with heart failure (DSHF). Eleven-week-old DS rats fed an 8%-NaCl diet received either vehicle or imidapril (1 mg/kg per day) for 7 weeks. The renal expression of the NAD(P)H oxidase p47phox and endothelial NO synthase were evaluated. In DSHF rats, associated with increased renal angiotensin II, mRNA and protein expression of NAD(P)H oxidase p47phox were enhanced with an increase in renal lipid peroxidation production (0.33+/-0.03 versus 0.22+/-0.01 nmol/mg protein, P<0.05) and urinary excretion of hydrogen peroxide (26.9+/-6.6 versus 9.5+/-2.1 U/mg creatinine, P<0.01) compared with levels in Dahl salt-resistant rats. The endothelial NO synthase expression was decreased in the kidney. Treatment with imidapril reduced renal angiotensin II and NAD(P)H oxidase expression and the oxidative products (kidney lipid peroxidation product: 0.16+/-0.02, P<0.001; urinary hydrogen peroxide: 3.1+/-0.2, P<0.01 versus DSHF rats). Imidapril significantly decreased albuminuria and reduced glomerulosclerosis without changes in the blood pressure. In conclusion, DSHF rats showed increased oxidative stress in the kidney via NAD(P)H oxidase. Blockade of local angiotensin II with subpressor dose of imidapril inhibited NAD(P)H oxidase and prevented renal damage.
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PMID:Angiotensin II and oxidative stress in Dahl Salt-sensitive rat with heart failure. 1246 66

We previously reported on the use of enzymatic analysis to impair fatty acid metabolism followed by reduced myocardial energy content, leading to severe heart failure in adriamycin (ADR)-treated rats. The aim of this study is to investigate whether impaired myocardial energy metabolism can also be detected by other methods; i.e. measuring mitochondrial complex I activity and myocardial 125I-15-(p-iodophenyl)-3-(R,S)- methylpentadecanoic acid (BMIPP) accumulation in ADR-treated rats. Eight-week-old male Sprague-Dawley rats received 6 intraperitoneal injections of ADR (total 15 mg/kg: group ADR) or saline (control group) over 2 weeks. Left ventricular (LV) ejection fraction was assessed using echocardiography at 3- and 6-weeks after ADR injection (3 weeks and 6 weeks, respectively). Myocardial fatty acid utilization was assessed at 3 weeks and 6 weeks. The myocardial counts of BMIPP were measured after intravenous BMIPP (370 kBq) injection, and 125I counts were measured to calculate the uptake ratio. The enzymatic activity of complex I was assessed by monitoring the oxidation of nicotinamide-adenine-dinucleotide-disodium-salt (NADH). In rats treated with ADR, significant decrease in LV ejection fraction was observed only at 6 weeks compared to control (72.5 vs. 84.5%, p < 0.01). LV ejection fraction at 3 weeks was identical between group ADR and control (81.8 vs. 84.4%). However, at 3 weeks, complex I activity was already reduced significantly in group ADR as compared to control group (p = 0.03), but the reduction in BMIPP accumulation was not (p = 0.15). Our data indicated that reduced complex I activity in a phenomenon occurred in early phase of ADR-induced cardiomyopathy, and it might play an important role in the progression of ADR-induced heart failure.
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PMID:Mitochondrials complex I activity is reduced in latent adriamycin-induced cardiomyopathy of rat. 1287 Jun 75

Energostim is a combined drug comprising a mixture of nicotinamide adenine dinucleotide (0.5 mg), cytochrome C (10 mg), and inosine (80 mg), representing antihypoxant and antioxidant of direct action in one ampule. After pretreatment and subsequent 3-day energostim therapy of animals with 3-day toxico-allergic myocarditis (3d-TAM), the ECG was free of any rhythm disorders and showed evidence of improved conduction, restoration of the normal form of T-wave and the position of ST segment, while the content of myofibrillar fraction of creatine phosphokinase and toxic products of disturbed metabolism (degree of endotoxemia) decreased to the upper normal level. Under the action of energostim, neither pressure nor the maximum rate of pressure buildup in the left ventricle are reduced (as they do upon 3d-TAM); neither systolic and diastolic functions are disturbed, nor their coordination (r = 0.79 between dP/dtmin and dP/dtmax, p < 0.01). The restoration of contractile activity and maximum rate of relaxation of myocardial microfibrils during 3d-TAM is accompanied by an increase in the content of adenyl nucleotides, in the ATP/ADP, ADP/AMP, NAD/NADH, and NADP/NADPH ratios, and in the cytosol phosphorylation potential. The energostim-induced improvement in the energy supply system are accompanied by restoration of the ability of sarcoplasmic reticulum to efflux Ca2+. Thus, it is demonstrated that the effect of energostim is related to its ability to actively participate in intracell metabolic processes in myocardium, abolish necrotic changes and endotoxicosis, and restore homeostasis in the systems responsible for the contraction--relaxation process (thus preventing from the development of dysfunction of the left ventricle and the heart failure).
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PMID:[Cardioprotective effect of energostim in toxic allergic myocarditis]. 1518 54

Cardiac hypertrophy is a physiological adaptive response by the heart to pressure overload. However, after prolonged periods, this initial adaptive response becomes maladaptive, leading to increased mortality and morbidity from heart failure. Recently, 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been shown to inhibit cardiac hypertrophy by cholesterol-independent mechanisms. Statins block the isoprenylation and activation of members of the Rho guanosine triphosphatase (GTPase) family, such as RhoA and Rac1. Since Rac1 is a requisite component of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which is a major source of reactive oxygen species (ROS) in cardiovascular cells, the ability of statins to inhibit Rac1-mediated oxidative stress makes an important contribution to their inhibitory effects on cardiac hypertrophy.
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PMID:Statins and myocardial hypertrophy. 1523 20

Yeast silent information regulator 2 (Sir2), a nicotinamide adenine dinucleotide-dependent histone deacetylase (HDAC) and founding member of the HDAC class III family, functions in a wide array of cellular processes, including gene silencing, longevity, and DNA damage repair. We examined whether or not the mammalian ortholog Sir2 affects growth and death of cardiac myocytes. Cardiac myocytes express Sir2alpha predominantly in the nucleus. Neonatal rat cardiac myocytes were treated with 20 mmol/L nicotinamide (NAM), a Sir2 inhibitor, or 50 nmol/L Trichostatin A (TSA), a class I and II HDAC inhibitor. NAM induced a significant increase in nuclear fragmentation (2.2-fold) and cleaved caspase-3, as did sirtinol, a specific Sir2 inhibitor, and expression of dominant-negative Sir2alpha. TSA also modestly increased cell death (1.5-fold) but without accompanying caspase-3 activation. Although TSA induced a 1.5-fold increase in cardiac myocyte size and protein content, NAM reduced both. In addition, NAM caused acetylation and increases in the transcriptional activity of p53, whereas TSA did not. NAM-induced cardiac myocyte apoptosis was inhibited in the presence of dominant-negative p53, suggesting that Sir2alpha inhibition causes apoptosis through p53. Overexpression of Sir2alpha protected cardiac myocytes from apoptosis in response to serum starvation and significantly increased the size of cardiac myocytes. Furthermore, Sir2 expression was increased significantly in hearts from dogs with heart failure induced by rapid pacing superimposed on stable, severe hypertrophy. These results suggest that endogenous Sir2alpha plays an essential role in mediating cell survival, whereas Sir2alpha overexpression protects myocytes from apoptosis and causes modest hypertrophy. In contrast, inhibition of endogenous class I and II HDACs primarily causes cardiac myocyte hypertrophy and also induces modest cell death. An increase in Sir2 expression during heart failure suggests that Sir2 may play a cardioprotective role in pathologic hearts in vivo.
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PMID:Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes. 1553 38

Ca(2+) overload in myocardial cells is responsible for arrhythmia. Sodium-calcium exchanger (NCX) inhibitors are more effective than sodium-hydrogen exchanger (NHE) inhibitors with regard to modulation of Ca(2+) overload, because NCX inhibitors can directly inhibit the influx of Ca(2+) into cells. NCX is an attractive target for the treatment of heart failure and ischemia-reperfusion. We have designed and synthesized a series of N-(2-aminopyridin-4-ylmethyl)nicotinamide derivatives, based on compound 5. We have discovered a novel NCX inhibitor (23 h) with an IC(50) value of 0.12 microM against reverse NCX. The inhibitory activities of our NCX inhibitors against cytochrome P450 were also evaluated. The effects on heart failure and the pharmacokinetic profile of compound 23 h are discussed.
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PMID:Discovery of an N-(2-aminopyridin-4-ylmethyl)nicotinamide derivative: a potent and orally bioavailable NCX inhibitor. 1591 15

The incidence of ischaemic heart disease and acute myocardial infarction are greater in people with diabetes than in nondiabetic individuals. Heart disease patients with diabetes have a higher incidence of mortality during and following an acute myocardial infarction and a high risk for progression to heart failure post-infarction. The greater occurrence of ischaemic heart disease is partially due to a poorer coronary artery disease risk factor profile in diabetic patients, and, importantly, due to diabetes-induced abnormalities in the myocardium, termed 'diabetic cardiomyopathy'. The main metabolic abnormalities in the diabetic myocardium are impaired carbohydrate metabolism, specifically reduced pyruvate oxidation in the mitochondria and a greater reliance on fatty acids and ketone bodies as fuels. The healthy heart takes up glucose and lactate and converts them to pyruvate; however, in the diabetic heart there is a reduced capacity to oxidize pyruvate, and thus less glucose and lactate uptake. The defective metabolism is due to high circulating free fatty acids and ketone body concentrations in the plasma, resulting in greater acetyl-Co-enzyme A/Co-enzyme A and reduced nicotinamide adenonine dinucleotide/nicotinamide adenonine dinucleotide+ ratios in the mitochondria, and the subsequent inhibition of pyruvate dehydrogenase. Pharmacological inhibition of fatty acid oxidation during ischaemia increases myocardial pyruvate oxidation and provides clinical benefit to patients with stable angina or ischaemic left ventricular dysfunction. Recent clinical trials with trimetazidine, an inhibitor of the fatty acid beta-oxidation enzyme long chain 3-ketoacylthiolase, showed improvement in cardiac function and exercise performance in diabetic patients with ischaemic heart disease, illustrating the effectiveness of this approach in diabetes.
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PMID:Rationale for a metabolic approach in diabetic coronary patients. 1634 Mar 98


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