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)

Transplantations of the heart are in recent years the therapeutic method in severe cardiac failure. One of the complications in the long-term follow-up of patients is the development of hypertension. The incidence of hypertension in patients treated with cyclosporin and prednisone is 70-90%. In the development of hypertension participates in addition to classical mechanisms (renin angiotensin system, fluid volume and peripheral resistance) also the negative effect of cardiac denervation, cyclosporin immunosuppression, corticoids and nephropathy. The nocturnal drop of pressure and pulse rate is lacking. Mechanisms of cyclosporin induced hypertension:enhancement of the vasoconstricting effect of endothelin 1, reduced NO production, activation of neurohumoral vasoconstrictors, increased calcium level in cytosols, increased thromboxane A production, reduced production of vasodilatating prostaglandins and activation of the sympathicus. The prerequisite of treatment are efforts to maintain the lowest possible effective cyclosporin level and if possible discontinue corticoids during the first year. The drug of first choice are calcium antagonists among others for their preventive effect on the vasculopathy of the graft. Other recommended groups of drugs are ACE inhibitors and diuretics.
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PMID:[Hypertension after heart transplantation]. 1095 83

Endothelins (ET) comprise a group of substances which are produced and have regulatory functions in different systems of the organism. The main cardiovascular ET is ET-1 which is so far the most potent vasoconstrictor substance. In the pathophysiology of cardiac insufficiency ET-1 promotes cardiac hypertrophy, is involved in vasoconstriction, delayed relaxation and reduced left ventricular contractility. The ET-1 level correlates with pulmonary vascular hypertension. By vasoconstriction of renal arteries ET leads to volume retention. Big-ET is a very efficient neurohumoral marker in the diagnosis of developed cardiac failure which can lead to more accurate prognostic stratification. ET-1 is probably important for assessment of the diagnosis of cardiac insufficiency only in severe cardiac failure. The favourable effect of ET block in cardiac insufficiency was proved for the non-selective ETA/ETB blocker and selective ETA blocker. The selective ETB blocker has an adverse haemodynamic effect in treatment of heart failure but by suppression of aldosterone it can prevent fluid retention. In the treatment of cardiac failure blockers of endothelin converting enzyme seem perspective as they reduce adversely activated neurohumoral factors.
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PMID:[Endothelins and chronic cardiac insufficiency]. 1095 66

The role of endothelins (ET) in blood pressure elevation remains controversial. Data supporting involvement of the ET system in different forms of genetic and experimental hypertension in the rat has appeared in the literature in recent years. Production of endothelin (ET)-1 may be enhanced in several experimental rat models of hypertension. Examples of these exhibiting increased preproendothelin-1 mRNA or peptide in the vasculature include salt-sensitive forms like deoxycorticosterone (DOCA)-salt hypertension, DOCA-salt treated spontaneously hypertensive rat (SHR) and Dahl salt-sensitive rats, and other models like stroke-prone SHR, angiotensin II-infused rats and fructose-fed rats, and possibly 1-kidney 1 clip (1-K 1C) Goldblatt hypertensive rats. SHR, 2-kidney 1 clip (2-K 1C) Goldblatt hypertensive rats and chronic N(omega)-nitro-L-arginine methyl ester (L-NAME)-treated hypertensive rats do not appear to exhibit an ET-1 component. Significant vascular growth, and a hypotensive response and regression of vascular growth after treatment with an ET antagonist demonstrate the endothelin-dependency present in some hypertensive models. Severity of high blood pressure elevation, salt-sensitivity and insulin resistance may be common denominators of involvement of the ET system in hypertension. ET antagonism in hypertension may result in regression of vascular damage, prevention of stroke and renal failure and improvement of heart failure. Whether the same is true in human hypertension remains to be established.
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PMID:Endothelin: role in experimental hypertension. 1097 78

Atherosclerosis, a chronic systemic disease of the vasculature with an inflammatory component, is the primary cause of cardiovascular morbidity and mortality in industrialized countries. It is associated with the impairment of endothelium-dependent relaxation in the coronary, systemic circulation due to decreased bioavailability of nitric oxide, and increased release oxygen-derived free radicals, thus promoting vasoconstriction, leukocyte adhesion, thrombosis, inflammation, and cell proliferation. Expression of endothelin (ET)-1, a 21-amino acid peptide and major isoform of the endothelin peptide family, is produced by endothelial, vascular smooth muscle cells, and macrophages and acts through Gi-protein-coupled ET(A) and ET(B) receptors. Endothelin-1 increases in hypercholesterolemia and atherosclerosis in humans and experimental animals. This paper reviews current experimental and clinical evidence for the involvement of ET-1 in atherogenesis. Furthermore, the effects of ET receptor blockade on experimental hypercholesterolemia and atherosclerosis will be discussed. As chronic endothelin blockade inhibits fatty streak formation and improves vascular function in experimental hypercholesterolemia, hypertension, and heart failure, and as it restores nitric oxide (NO)-mediated endothelial function and reduces atheroma formation in animals with atherosclerosis, endothelin receptor blockade may therefore offer a novel approach for the treatment of atherosclerosis and its vascular complications.
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PMID:Endothelial dysfunction and atherosclerosis: endothelin receptor antagonists as novel therapeutics. 1098 Nov 33

It has been reported that at the end stage, apoptosis is involved in the progression of heart failure. It is suggested that cardiac energy metabolism is impaired during the progression of heart failure. Although the mechanism of induction of apoptosis in the failing heart varies according to the model of heart failure, it is not known whether an impairment of energy metabolism in cardiomyocytes is a primary cause of apoptosis. In this study, we applied mitochondrial inhibitors, such as rotenone, cobalt chloride and antimycin A, which inhibit mitochondrial function at different sites of the mitochondrial respiratory chain, to cardiomyocytes. All these reagents markedly decreased 3-(4,5)-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay (MTT) reduction activity, an indicator of mitochondrial function, of cardiomyocytes and greatly increased glucose consumption, suggesting that cardiac energy metabolism is switched from beta-oxidation of fatty acid to glycolysis. It was shown that after 48-72 h of treatment with each reagent, apoptosis was shown to occur by DNA laddering and increase in caspase activity. Interestingly, each reagent with a different action site greatly activated caspase-3, but not caspase-8 activity, suggesting that mitochondria are involved in induction of apoptosis. On the other hand, within 24 h of the treatment, when apoptosis of cardiomyocytes was not observed, the treated cardiomyocytes showed a marked increase in preproendothelin-1 and atrial natriuretic peptide (ANP) gene expressions. In conclusion, the present study suggests that mitochondrial dysfunction with impaired energy metabolism elevates gene expression of cardiac ET-1, an aggravating factor in heart failure, and then finally induces apoptosis in cardiomyocytes. The finding of marked increases in expression of molecular markers (ET-1 mRNA and ANP mRNA) in the failing heart, followed by apoptosis in the treated cardiomyocytes suggests that the inhibition of mitochondrial function of cultured cardiomyocytes provides a possible new in vitro model of heart failure.
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PMID:Mitochondrial dysfunction of cardiomyocytes causing impairment of cellular energy metabolism induces apoptosis, and concomitant increase in cardiac endothelin-1 expression. 1107 77

The development of pulmonary hypertension (PH) causes right-sided heart failure. We investigated whether chronic treatment with the endothelin-A- (ETA) receptor antagonist BMS-193884 in rats with monocrotaline- (MCT) induced PH improves right-sided heart failure. Administration of BMS-193884 (100mg/kg) was commenced on the day before treatment with MCT. At 19 days, hemodynamics were measured under anesthesia and hearts were removed. The right ventricular systolic pressure (RVSP), an indicator for pulmonary hypertension, was remarkably elevated in the PH group compared with the normal control group. BMS-193884 effectively prevented this elevation. The central venous pressure, an indicator for right-sided heart failure, was markedly increased in the PH group. This increase was reduced to the normal level by BMS-193884. In the failing right ventricle of the PH group, the expression of atrial natriuretic peptide (ANP) mRNA, which is a molecular marker for the failing heart, was markedly increased. BMS-193884 greatly prevented this increase. The present study suggests that ET-1 contributes to the right-sided heart failure caused by PH and that an ETA-receptor antagonist is a beneficial drug which improves both hemodynamics and cardiac gene expression in the failing right ventricle.
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PMID:Endothelin-1 and right-sided heart failure in rats: effects of an endothelin receptor antagonist on the failing right ventricle. 1107 11

Whilst endothelin (ET) receptor antagonism has been evaluated in post-myocardial infarction (MI) remodeling, endothelin-converting enzyme (ECE) inhibition has not been determined. In the study reported here female Sprague-Dawley rats underwent coronary artery ligation, then were randomized 24 h post-MI to either no therapy (control) or 7 days therapy with the highly selective ECE inhibitor, FR901533 (Fujisawa, Osaka, Japan) 100 mg/kg/day, by continuous subcutaneous infusion. Echocardiography [fractional shortening (FS), internal dimensions and relative wall thickness (RWT)] and invasive hemodynamics were performed before sacrifice on day 8, with subsequent cardiac immunohistochemistry. Plasma concentrations of ET-1 and big ET-1 (39 AA) were determined by enzyme-linked immunosorbent assay (ELISA). ECE inhibitor-treated rats [n = 6, infarct size (IS) 37 +/- 2%) were compared to control rats with similar size MI (n = 8, IS 38 +/- 3%). Values for sham-operated rats were: RWT 0.49 +/- 0.02; left ventricular end-diastolic diameter (LVEDD) 6.2 +/- 0.5 mm; left ventricular end-systolic diameter (LVESD) systolic3.5 +/- 0.5 mm; blood pressure (SBP) 119 +/- 4 mmHg; heart rate 340 +/- 21 bpm; and left ventricular end-diastolic pressure (LVEDP) 12 +/- 2 mmHg, FS 46 +/- 4%. ECE inhibition was confirmed by increased big ET-1 to ET-1 ratio (0.23 +/- 0.06 vs 0.05 +/- 0.02, ECE inhibitor vs control, p < 0.05). ECE inhibitor increased RWT (0.43 +/- 0.03 vs 0.35 +/- 0.02, p < 0.05) contributed to by reduced left ventricular (LV) internal dimensions (EDd 7.5 +/- 0.4 vs 7.9 +/- 0.3 mm, ESd 5.2 +/- 0.5 vs 5.6 +/- 0.3 mm, ECE inhibitor vs control respectively). There were also trends in ECE inhibitor rats to increased FS (31 +/- 4 vs 29 +/- 2%), decreased SBP (99 +/- 4 vs 104 +/- 4 mmHg), heart rate (355 +/- 28 vs 385 +/- 12 bpm) and LVEDP (23 +/- 2 vs 25 +/- 1 mmHg), all p = NS, ECE inhibitor vs control. Immunoreactive cardiac collagen I peptide was unchanged by ECE inhibitor, however, alpha-smooth muscle actin, a marker of myofibroblast activation, was decreased in the infarct zone of ECE inhibitor rats (35 +/- 4 vs 46 +/- 3%, ECE inhibitor vs control, p < 0.05). This study concludes that selective ECE inhibitor with FR901533 reduces the conversion of big ET-1 to ET-1 in post-MI rats and improves some parameters of cardiac remodeling early post-MI. However, longer-term studies are needed fully to assess the therapeutic potential of ECE inhibitor post-MI and in heart failure.
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PMID:Effect of a highly selective endothelin-converting enzyme inhibitor on cardiac remodeling in rats after myocardial infarction. 1107 22

Endothelin (ET) is a peptide composed of 21 amino acids, derived from a larger precursor, the big-endothelin, by action of the endothelin-converting enzyme (ECE) family; three isoforms of endothelin, named ET-1, ET-2 and ET-3, have been identified. Endothelin-1 is generated mainly by vascular endothelial cells and exerts various important biological actions, mediated by two receptor subtypes, ET-A and ET-B, belonging to the G protein-coupled family that have been identified in various human tissues such as the cardiac tissue. Endothelin-1 is a potent vasoconstrictive agent, has inotropic and mitogenic actions, modulates salt and water homeostasis and plays an important role in the maintenance of vascular tone and blood pressure in healthy subjects. Endothelin-1, as well as ET-A and ECE-1, also has an important role in cardiovascular development, as observed by the variety of abnormalities related to neural crest-derived tissues in mouse embryos deficient of a member of the ET-1/ECE-1/ET-A pathway. Various evidence indicates that endogenous endothelin-1 may contribute to the pathophysiology of conditions associated with sustained vasoconstriction, such as heart failure. In heart failure, elevated circulating levels of both endothelin-1 and big-endothelin-1 are observed; in failing hearts an activation of the endothelin system is found: tissue level of ET-1 is increased with respect to non-failing hearts as well as receptor density, due mainly to an upregulation of the ET-A subtype, the prevalent receptor subclass in cardiac tissue. Finally, studies in both humans and animal models of cardiovascular disease show that inhibition of the endothelin function (anti-endothelin strategy) is associated with an improvement of haemodynamic conditions; these observations indicate that endothelin receptor antagonists or endothelin-converting enzyme inhibitors may constitute a novel and potentially important class of agents for the treatment of this disease.
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PMID:The role of endothelins and their receptors in heart failure. 1124 12

We previously reported that cardiomyocytes produce endothelin (ET)-1 and that the tissue level of ET-1 markedly increased in failing hearts in rats with chronic heart failure. Because the level of plasma ET-1 also increased progressively in patients with breast cancer who received doxorubicin (Dox; Adriamycin), which possesses cardiotoxicity, we hypothesized that ET-1 plays a role in the pathophysiology of cardiomyocytes injured by Dox. In this study, we investigated the effect of ET-1 on the cytotoxicity of Dox in primary cultured neonatal rat cardiomyocytes. The results showed that ET-1 effectively attenuated Dox-induced acute cardiomyocyte cytotoxicity (24-h incubation with Dox) evaluated by in vitro cell toxicity assay [3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay and lactate dehydrogenase release]. The cytoprotective effect of ET-1 was mediated via ET(A) receptors, because pretreatment with the ET(A)-receptor antagonist BQ123 completely suppressed the cytoprotective effect of ET-1, whereas the ET(B)-receptor antagonist BQ788 did not. The cytoprotective effect of ET-1 was abolished by pretreatment with cycloheximide or staurosporine. These results suggest that a protein molecule(s), which is synthesized de novo by the stimulation of protein kinase pathway, is involved in the cytoprotective effect of ET-1. ET-1 increased the expression of an endogenous antioxidant, manganese superoxide dismutase (Mn-SOD), in the cardiomyocytes, as demonstrated by a Western blotting analysis. Pretreatment with an antisense oligodeoxyribonucleotide of Mn-SOD markedly attenuated the cytoprotective effect of ET-1 on the Dox-induced cytotoxicity. However, under conditions of prolonged incubation with Dox (48 h), ET-1 did not affect Dox-induced cardiomyocyte cytotoxicity in culture. These results suggest that ET-1 prevents the early phase of Dox-induced cytotoxicity via the upregulation of the antioxidant Mn-SOD through ET(A) receptors in cultured cardiomyocytes.
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PMID:A novel pharmacological action of ET-1 to prevent the cytotoxicity of doxorubicin in cardiomyocytes. 1129 60

In 76 patients with heart failure (HF) (New York Heart Association [NYHA] classes I through IV) and in 15 control subjects, cardiac angiotensin II (Ang II) generation and its relationship with left ventricular function were investigated by measuring aorta-coronary sinus concentration gradients of endogenous angiotensins and in a part of patients by studying (125)I-labeled Ang I kinetics. Gene expression and cellular localization of the cardiac renin-angiotensin system components, the density of AT(1) and AT(2) on membranes and isolated myocytes, and the capacity of isolated myocytes for synthesizing the hypertrophying growth factors insulin-like growth factor-I (IGF-I) and endothelin (ET)-1 were also investigated on 22 HF explanted hearts (NYHA classes III and IV) and 7 nonfailing (NF) donor hearts. Ang II generation increased with progression of HF, and end-systolic wall stress was the only independent predictor of Ang II formation. Angiotensinogen and angiotensin-converting enzyme mRNA levels were elevated in HF hearts, whereas chymase levels were not, and mRNAs were almost exclusively expressed on nonmyocyte cells. Ang II was immunohistochemically detectable both on myocytes and interstitial cells. Binding studies showed that AT(1) density on failing myocytes did not differ from that of NF myocytes, with preserved AT(1)/AT(2) ratio. Conversely, AT(1) density was lower in failing membranes than in NF ones. Ang II induced IGF-I and ET-1 synthesis by isolated NF myocytes, whereas failing myocytes were unable to respond to Ang II stimulation. This study demonstrates that (1) the clinical course of HF is associated with progressive increase in cardiac Ang II formation, (2) AT(1) density does not change on failing myocytes, and (3) failing myocytes are unable to synthesize IGF-I and ET-1 in response to Ang II stimulation.
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PMID:Cardiac angiotensin II formation in the clinical course of heart failure and its relationship with left ventricular function. 1134 94


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