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)

1. Myocardial injury caused by ischaemia and reperfusion comes from multiple pathogenic events, including endothelial damage, neutrophil extravasation into tissue, mast cell activation, and peroxidation of cell membrane lipids. These events are followed by myocardial cell alterations resulting eventually in cell necrosis. An enhanced formation of reactive oxygen species is widely accepted as a stimulus for tissue destruction and cardiac failure. 2. In this study, we have investigated the cardioprotective effects of M40403 in myocardial ischaemia-reperfusion injury. M40403 is a low molecular weight, synthetic manganese containing superoxide dismutase mimetic (SODm) that selectively removes superoxide anion. Ischaemia was induced in rat hearts in vivo by ligating the left anterior descending coronary artery. Thirty minutes after the induction of ischaemia, the ligature was removed and reperfusion allowed to occur for at least 60 min. M40403 (0.1-1 mg kg(-1)) was given intravenously 15 min before ischaemia. 3. The results obtained in this study showed that M40403 significantly reduced the extent of myocardial damage, mast cell degranulation and the incidence of ventricular arrhythmias. Furthermore, M40403 significantly attenuated, in a dose-dependent manner, neutrophil infiltration in the myocardium as well as the associated induction of lipid peroxidation. Calcium overload seen post-reperfusion of the ischaemic myocardium was also reduced by M40403. 4. Immunohistochemical analysis for nitrotyrosine revealed a positive staining in cardiac tissue taken after reperfusion: this was attenuated by M40403. Moreover reperfused cardiac tissue sections showed positive staining for P-selectin and for anti-intercellular adhesion molecule (ICAM-1) in the vascular endothelial cells. M40403 treatment markedly reduced the intensity and degree of P-selectin and ICAM-1 in these tissues. No staining for nitrotyrosine, P-selectin or ICAM-1 was found in cardiac tissue taken at the end of the ischaemic period. 5. Overall, M40403 treatment reduced the morphological signs of myocardial cell injury and significantly improved survival. 6. Taken together, these results clearly indicate that M40403 treatment exerts a protective effect against ischaemia-reperfusion-induced myocardial injury, supporting a key role for superoxide anion in reperfusion injuries. This suggests that synthetic enzymes of SOD such as M40403, offer a novel therapeutic approach for the treatment of ischaemic heart disease where superoxide anion plays a dominant role.
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PMID:Protective effects of M40403, a selective superoxide dismutase mimetic, in myocardial ischaemia and reperfusion injury in vivo. 1211 Jun 15

The exact mechanisms by which NO mediates its neuromodulatory effects within the central control of cardiovascular functions are still unclear. Both excitatory and inhibitory actions of NO in different regions of the brainstem have been reported, and that it could be caused by direct actions of NO on neurones and/or by NO-mediated changes in local cerebral blood flow. Microinjection studies suggest that direct modulation of neuronal activity by NO through cyclic 3'-5' guanosine monophosphate (cGMP)-dependent mechanisms predominates. In contrast, endogenous NO produces. only minor changes in local cerebral blood flow, and potentiation of NO-dependent vasodilation with an inhibitor of phosphodiesterase V (PDE5i) has no significant effect on sympathetic activity. Activation of the NO-system in the lower brain stem modulates various central and reflex-activated neuronal pathways. To a large extent, this appears to be mediated by NO-induced GABA- and glutamate-release within the ventrolateral medulla (VLM) and the nucleus of the solitary tract (NTS). In addition, NO has been shown to reduce local generation of angiotensin II (AII) in all areas. Recent studies suggest that the NO-mediated modulation of autonomic function is severely impaired in cardiovascular diseases. Possibly in conjunction with AII, which triggers and promotes superoxide radical generation, chronic oxidative stress (COS) could act as a key mediator of this process. Evidence supporting this hypothesis comes from studies on pigs that were chronically treated with organic nitrates to pharmacologically induce COS. In these animals, microinjection of superoxide dismutase into the rostral VLM (RVLM) diminished sympathetic activity by up to 70%, whereas peroxynitrite, a key mediator of NO-related oxidative stress, had excitotoxic effects. Antagonism of neuronal COS may therefore represent a novel approach to counteract neurohumoral activation in diseases such hypertension, obesity and heart failure.
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PMID:Mechanisms of action of nitric oxide in the brain stem: role of oxidative stress. 1214 34

The effect of angiotensin-converting enzyme (ACE) inhibition and endothelin A (ET ) receptor antagonism alone and in combination on endothelial vasomotor dysfunction in chronic heart failure (CHF) was compared. Vasoreactivity and superoxide anion formation were determined in aortic rings from Wistar rats with experimental CHF 12 weeks after extensive myocardial infarction compared with sham-operated animals. Rats were treated with placebo, with the ET receptor antagonist LU 135252 (30 mg/kg/d), with the ACE inhibitor trandolapril (0.3 mg/kg/d), or with a combination of LU 135252 and trandolapril. Infarct size was similar among the groups. In the placebo group, the concentration-response curve of the endothelium-dependent, acetylcholine-induced relaxation was significantly shifted to the right and the maximum relaxation was attenuated (R 53 +/- 3%) compared with the sham placebo group (R 72 +/- 3%). Treatment with LU 135252 as well as trandolapril significantly improved acetylcholine-induced maximum relaxation (LU 135252 66 +/- 4%, trandolapril 67 +/- 4%, p < 0.05 versus CHF placebo). In addition to R (LU 135252/trandolapril 70 +/- 4%), combination therapy also improved the pathologic rightward shift (p < 0.05). Increased O production in CHF was significantly reduced in all treatment groups. The increased relaxation elicited by exogenous superoxide dismutase in CHF was reduced to normal values by monotherapy and further attenuated by combination treatment. Although monotherapy with the ACE inhibitor trandolapril and the ET receptor antagonist LU 135252 improved endothelial dysfunction in experimental CHF, combination therapy was more effective.
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PMID:Angiotensin-converting enzyme inhibition and endothelin antagonism for endothelial dysfunction in heart failure: mono-or combination therapy. 1235 22

Angiotensin II (Ang II) has profound effects in the central nervous system (CNS), including promotion of thirst, regulation of vasopressin secretion, and modulation of sympathetic outflow. Despite its importance in cardiovascular and volume homeostasis, angiotensinergic mechanisms are incompletely understood in the CNS. Recently, a novel signaling mechanism for Ang II involving reactive oxygen species (ROS) has been identified in a variety of peripheral tissues, but the involvement of ROS as second messengers in Ang II-mediated signaling in the CNS has not been reported. The hypothesis that superoxide is a key mediator of the actions of Ang II in the CNS was tested in mice using adenoviral vector-mediated expression of superoxide dismutase (AdSOD). Changes in blood pressure, heart rate, and drinking elicited by injection of Ang II in the CNS were abolished by prior treatment with AdSOD in the brain, whereas the cardiovascular responses to carbachol, another central vasopressor agent, were unaffected. In addition, Ang II stimulated superoxide generation in primary CNS cell cultures, and this was prevented by the Ang II receptor (Ang II type 1 subtype) antagonist losartan or AdSOD. These results identify a novel signaling mechanism mediating the actions of Ang II in the CNS. Dysregulation of this signaling cascade may be important in hypertension and heart failure triggered by Ang II acting in the CNS.
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PMID:Superoxide mediates the actions of angiotensin II in the central nervous system. 1245 82

Reactive oxygen species (ROS) play a role in cardiovascular diseases such as heart failure and hypertension. Furthermore, increasing evidence has accumulated suggesting that ROS can also be formed subsequent to the stimulation of various receptors, thus functioning as second messengers. The objective of the present study was to elucidate the role of intracellular-generated ROS in the inotropic and chronotropic effects of the alpha1- and beta-adrenoceptor and the ET-receptor stimulation in isolated rat atria. In addition, we investigated whether the MAPKerk pathway is involved in the ROS-provoked rise of contractile force. For this purpose hydrogen peroxide was applied, which is known to serve several endogenous functions as a second messenger. Moreover, hydrogen peroxide readily crosses cell membranes, which thus allows to mimic the intracellular formation. Preincubation of atria with EUK 8 (400 microM), a cell permeable superoxide dismutase- and catalase-mimetic, reduced the positive inotropic effect upon alpha1-adrenoceptor and ET-receptor stimulation. The responsiveness to beta-adrenoceptor stimulation remained unaffected by this pretreatment. The chronotropic effects were not altered by preincubation with EUK 8. In contrast to the MAPK(p38) inhibitor SB203580 (2 and 10 microM), the two MKKmek inhibitors PD98059 (30 and 100 microM) and U0126 (10 microM) significantly attenuated the positive inotropic response to hydrogen peroxide in isolated rat left atria. In addition, inhibition of the Na+/H+ exchange (NHE) by cariporide (1 microM) counteracted ROS-provoked increase of contractile force. From the present study we conclude that the inotropic responses to alpha1-adrenoceptor and ET-receptor stimulation are, at least partially, caused by intracellular-formed ROS, that subsequently may activate the MAPKerk pathway and the NHE.
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PMID:The influence of endogenously generated reactive oxygen species on the inotropic and chronotropic effects of adrenoceptor and ET-receptor stimulation. 1273 26

Skeletal muscle disuse with space-flight and ground-based models (e.g., hindlimb unloading) results in dramatic skeletal muscle atrophy and weakness. Pathological conditions that cause muscle wasting (i.e., heart failure, muscular dystrophy, sepsis, COPD, cancer) are characterized by elevated "oxidative stress," where antioxidant defenses are overwhelmed by oxidant production. However, the existence, cellular mechanisms, and ramifications of oxidative stress in skeletal muscle subjected to hindlimb unloading are poorly understood. Thus we examined the effects of hindlimb unloading on hindlimb muscle antioxidant enzymes (e.g., superoxide dismutase, catalase, glutathione peroxidase), nonenzymatic antioxidant scavenging capacity (ASC), total hydroperoxides, and dichlorohydrofluorescein diacetate (DCFH-DA) oxidation, a direct indicator of oxidative stress. Twelve 6 month old Sprague Dawley rats were divided into two groups: 28 d of hindlimb unloading (n = 6) and controls (n = 6). Hindlimb unloading resulted in a small decrease in Mn-superoxide dismutase activity (10.1%) in the soleus muscle, while Cu,Zn-superoxide dismutase increased 71.2%. In contrast, catalase and glutathione peroxidase, antioxidant enzymes that remove hydroperoxides, were significantly reduced in the soleus with hindlimb unloading by 54.5 and 16.1%, respectively. Hindlimb unloading also significantly reduced ASC. Hindlimb unloading increased soleus lipid hydroperoxide levels by 21.6% and hindlimb muscle DCFH-DA oxidation by 162.1%. These results indicate that hindlimb unloading results in a disruption of antioxidant status, elevation of hydroperoxides, and an increase in oxidative stress.
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PMID:Hindlimb unloading increases oxidative stress and disrupts antioxidant capacity in skeletal muscle. 1282 51

(1) Increased vascular resistance in chronic heart failure (CHF) has been attributed to stimulated neurohumoral systems. However, local mechanisms may also importantly contribute to set arterial tone. Our aim, therefore, was to test whether pressure-induced myogenic constriction of resistance arteries in vitro--devoid of acute effects of circulating factors--is increased in CHF and to explore underlying mechanisms. (2) At 12 weeks after coronary ligation-induced myocardial infarction or SHAM-operations in rats, we studied isolated mesenteric arteries for myogenic constriction, determined as the active constriction (% of passive diameter) in response to stepwise increase in intraluminal pressure (20 - 160 mmHg), in the absence and presence of inhibitors of potentially involved modulators of myogenic constriction. (3) We found that myogenic constriction in mesenteric arteries from CHF rats was markedly increased compared to SHAM over the whole pressure range, the difference being most pronounced at 60 mmHg (24+/-2 versus 4+/-3%, respectively, P<0.001). (4) Both removal of the endothelium as well as inhibition of NO production (L-N(G)-monomethylarginine, 100 micro M) significantly increased myogenic constriction (+16 and +25%, respectively), the increase being similar in CHF- and SHAM-arteries (P=NS). Neither endothelin type A (ET(A))-receptor blockade (BQ123, 1 micro M) nor inhibition of perivascular (sympathetic) nerve conduction (tetrodotoxin, 100 nM) affected the myogenic response in either group. (5) Interestingly, increased myogenic constriction in CHF was fully reversed after angiotensin II type I (AT(1))-receptor blockade (candesartan, 100 nM; losartan, 10 micro M), which was without effect in SHAM. In contrast, neither angiotensin-converting enzyme (ACE) inhibition (lisinopril, 1 micro M; captopril, 10 micro M) or AT(2)-receptor blockade (PD123319, 1 micro M), nor inhibition of superoxide production (superoxide dismutase, 50 U ml(-1)), TXA(2)-receptor blockade (SQ29,548, 1 micro M) or inhibition of cyclooxygenase-derived prostaglandins (indomethacin, 10 micro M) affected myogenic constriction. (6) Sensitivity of mesenteric arteries to angiotensin II (10 nM - 100 micro M) was increased (P<0.05) in CHF (pD(2) 7.1+/-0.4) compared to SHAM (pD(2) 6.2+/-0.3), while the sensitivity to KCl and phenylephrine was not different. (7) Our results demonstrate increased myogenic constriction in small mesenteric arteries of rats with CHF, potentially making it an important target for therapy in counteracting increased vascular resistance in CHF. Our results further suggest active and instantaneous participation of AT(1)-receptors in increased myogenic constriction in CHF, involving increased sensitivity of AT(1)-receptors rather than apparent ACE-mediated local angiotensin II production.
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PMID:Myogenic constriction is increased in mesenteric resistance arteries from rats with chronic heart failure: instantaneous counteraction by acute AT1 receptor blockade. 1289 Jul 11

Increased oxidative stress and reduction in antioxidant enzymes have been suggested to be involved in the pathophysiology of congestive heart failure subsequent to myocardial infarction (MI). The objective of the present study was to characterize changes in the mRNA abundance and protein levels for the enzymatic antioxidants, superoxide dismutase (SOD), glutathione peroxidase (GSHPx) and catalase during the sequelae of congestive heart failure in rats. MI was produced by the ligation of the left coronary artery and hearts from controls and 1, 4 and 16 week PMI groups were analyzed. Losartan treatment (2 mg/ml in drinking water, daily) was started at 4 weeks and continued for 12 weeks. The mRNA levels for SOD were reduced by about 40% at 1-week PMI, were near to the control levels at 4-week PMI and at 16 weeks PMI, the levels were reduced by about 73% below the controls. GSHPx mRNA levels remained unchanged at all time points. The mRNA levels for catalase remained unchanged at 1 and 4 weeks PMI and were significantly reduced by about 44% at 16 weeks PMI as compared to the controls. The protein levels for MnSOD, CuZnSOD, GSHPx at 1 and 16 weeks remained unchanged in treated and untreated PMI groups. However, the protein levels for catalase was significantly increased in the control and PMI groups treated with Losartan. It is concluded that changes in the SOD and catalase activities during severe heart failure correlated with changes in mRNA for these enzymes. The precise mechanism/s for the improvement in antioxidant reserve and protein levels after Losartan treatment is/are unclear at this time.
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PMID:Antioxidant enzyme gene expression in congestive heart failure following myocardial infarction. 1457 98

During experimental hypertensive cardiac hypertrophy, the heart energy metabolism reverts from the normal adult type that obtains the majority of its requirement for adenosine triphosphate (ATP) from metabolism of fatty acids and oxidative phosphorylation (OXPHOS), to the fetal form, which metabolizes glucose and lactate. Mitochondrial synthesis and function require an estimated 1000 polypeptides, 37 of which are encoded by mitochondrial (mt) DNA, the rest by nuclear (n) DNA. Inherited or acquired aberrations of either mtDNA or nDNA mitochondrial genes cause mitochondrial dysfunction. Tissue expression of OXPHOS enzyme defects is often heterogeneous. As a result, cardiomyopathy and cardiac failure are frequent but unpredictable complications of mitochondrial encephalopathy, neuropathy, and myopathy. Several nuclear genes that encode mitochondrial proteins have been sequenced and specific defects associated with nuclear genes that affect mitochondrial structure and function have been linked to hypertrophic and dilated cardiomyopathies and to cardiac conduction defects. Thyroid hormone and exercise stimulate expression of a nuclear respiratory factor (NRF) that induces the nuclear gene TFAM, which encodes the mitochondrial transcription factor A that controls mitochondrial replication and transcription. TFAM-null mouse embryos lack mitochondria and fail to develop a heart. Mitochondrial dysfunction enhances the generation of radical oxygen species (ROS), which damage mtDNA, nDNA, proteins, and lipid membranes. Mice lacking the mitochondrial antioxidant enzyme manganese-superoxide dismutase (SOD) develop dilated cardiomyopathy. Palliative mitochondrial therapy with L-acetyl-carnitine and coenzyme Q10 improves cardiac function in patients with cardiomyopathy. Cure is only achievable by mitochondrial gene therapy. Experimental direct gene therapy uses vectors or targeting signal sequences to insert genes into mtDNA; indirect gene therapy employs viral or non-viral vectors to introduce genes into nDNA. Clinical repair of damaged somatic and germline genes that encode mitochondrial proteins may soon be within reach.
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PMID:Review: Mitochondrial medicine--cardiomyopathy caused by defective oxidative phosphorylation. 1458 51

Increased angiotensin II signaling in the brain has been shown to play a critical role in the excessive sympathoexcitation and development of heart failure (HF) after myocardial infarction (MI). We have recently demonstrated that reactive oxygen species mediate the actions of angiotensin II in the brain. In this study, we tested the hypothesis that increased redox signaling in central cardiovascular control regions is a key mechanism in the neurocardiovascular dysregulation that follows MI. Ligation of the left coronary artery induced a large MI and subsequent HF in adult C57BL/6 mice, as demonstrated by cardiac hypertrophy, hydrothorax, and ascites. Immunohistochemical analysis of Fos, a marker of neuronal activation, revealed a significant increase in the number of Fos-positive neurons in the paraventricular nucleus and supraoptic nucleus at 2 and 4 weeks after MI compared with sham mice. Intracerebroventricular injection of an adenoviral vector encoding superoxide dismutase (Ad-Cu/ZnSOD) caused a significant decrease in the number of Fos-positive neurons in the paraventricular nucleus and supraoptic nucleus at 2 weeks after MI compared with mice receiving either saline or a control vector (Ad-LacZ). There was also a diminished role of sympathetic drive in post-MI mice treated centrally with Ad-Cu/ZnSOD, as demonstrated by significantly attenuated falls in heart rate and mean arterial pressure to the ganglionic blocker hexamethonium and decreased urinary norepinephrine levels in these mice compared with Ad-LacZ-treated MI mice. These results suggest that superoxide plays a key role in the central activation and sympathetic hyperactivity after MI in mice and that oxygen radicals in the brain may be important new targets for therapeutic treatment of heart failure.
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PMID:Superoxide is involved in the central nervous system activation and sympathoexcitation of myocardial infarction-induced heart failure. 1468 26

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