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

We investigated the time course of the expression of cardiac and renal endothelin systems in tachycardia-induced heart failure in dogs. Eleven beagles underwent rapid pacing at a progressively increased rate over a period of 5 wk, with a weekly clinical examination, echocardiography, measurement of circulating and urinary endothelin-1 (ET-1), and myocardial and renal tissue biopsies. Real-time quantitative PCR was used for determinations of tissue prepro-ET-1 (ppET-1), ET-1-converting enzyme (ECE-1), and ETA and ETB receptor mRNA. Cardiac and renal tissue ET-1 contents were evaluated by immunostaining and measured by radioimmunoassay at autopsy. Rapid pacing caused a progressive increase in end-systolic and end-diastolic ventricular volumes (P < 0.05) from week 2 together with a decrease in ejection fraction and in mean velocity of circumferential shortening (P < 0.05) from week 1. These changes were tightly correlated to myocardial ppET-1 and renal ETA receptor mRNA and less so to myocardial ECE-1 mRNA, and they occurred before any increase in plasma and urinary ET-1 (P < 0.05 from week 4) and clinical signs of heart failure. Renal ppET-1 did not change. Both cardiac and renal ET-1 peptide contents were increased at autopsy. We conclude that tachycardia-induced heart failure in dogs is characterized by an early activation of the cardiac and renal tissue endothelin systems, which occurs before any changes in circulating and urinary ET-1 and is closely related to altered ventricular function.
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PMID:Early activation of cardiac and renal endothelin systems in experimental heart failure. 1461 13

Endothelins are a family of three peptides of 21 amino acids with strong vasoconstrictor effects. The three peptides are encoded by three different genes and derived from precursors (" big endothelins") which are cleaved by metalloproteases, named endothelin-converting enzyme. Two receptors have been cloned, ET-A and ET-B which bind the three endothelins with various affinities. The diverse expression pattern of the endothelin system (ET) components is associated with a complex pharmacology and its counteracting physiological actions. New modulators of the ET system have been described : retinoic acid, leptin, prostaglandins, hypoxia. Endothelins can be considered as regulators working in paracrine and autocrine fashion in a variety of organs in different cellular types. The ET system has beneficial and detrimental roles in mammals. The different components have been shown to be essential for a normal embryonic and neonatal development, for renal homeostasis and maintenance of basal vascular tone. They are involved in physiological and tumoral angiogenesis. They affect the physiology and pathophysiology of the liver, muscle, skin, adipose tissue and reproductive tract. The endothelin system participates in the development of atherosclerosis as well as pulmonary hypertension, and mediates cardiac remodeling in heart failure. Elaboration of new animal models (knock-out, pathophysiological models em leader ) will allow the clear genetic dissection of physiological and pathophysiological roles of the endothelin system.
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PMID:[What is the role of endothelin system?]. 1506 80

Aldosterone has recently been implicated in the pathogenesis of heart failure. The purpose of the present study was to determine the effect of endothelin-1 (ET-1) and angiotensin II (Ang II), two potent vasoconstrictors that are also involved in heart failure, on aldosterone secretion by human adrenocortical carcinoma NCIH295R cells grown in 96-well plates. Ang II stimulated the production of aldosterone dose-dependently in serum-free medium, and the presence of serum drastically decreased aldosterone secretion. In contrast, ET-1-stimulated aldosterone production absolutely required serum. Under optimal conditions, ET-1 was more effective than Ang II as an aldosterone secretagogue. In a suboptimal condition of 2.5% serum, ET-1 and Ang II at 1 microM produced 63 and 76 pmol aldosterone/mg protein, respectively, while 230 pmol aldosterone/mg protein was generated upon coincubation with ET-1 and Ang II. The effect of ET-1 was inhibited dose-dependently by the selective ETA receptor antagonist BQ-123 with an IC50 of 23 nM, but the selective ETB receptor antagonist RES-701 had no effect up to 10 microM. These results suggest that ET-1 and Ang II stimulated aldosterone secretion synergistically in NCIH295R cells and that the effect of ET-1 was mediated via the ETA receptor subtype.
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PMID:Synergistic stimulation of aldosterone production in human adrenocortical carcinoma NCI-H295R cells by endothelin-1 and angiotensin II. 1583 3

Endothelins (ETs) are potent vasoconstrictor peptides and are associated with several disease states like pulmonary hypertension, systemic hypertension and heart failure. Endothelin-1 (ET-1) is the first member of the family and it has the receptor subtypes known as ETA and ETB. The receptors ETA and ETB are attractive new therapeutic targets for diseases associated with elevated ET-1 levels. Several studies have thus led to the discovery of selective ETA receptor antagonists as well as non-selective ETA/ETB antagonists. The preclinical and clinical studies have clearly established that these antagonists are effective in the treatment of essential hypertension, pulmonary hypertension, heart failure and atherosclerosis. The advances in this area have resulted in the FDA approval of the orally active dual antagonist Bosentan for pulmonary hypertension in 2001. This review highlights the synthesis and structure-activity of the endothelin receptor antagonists and covers the literature in this area up to 2001.
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PMID:Endothelin receptor antagonists: an overview of their synthesis and structure-activity relationship. 1585 28

This article describes the pharmacological properties and the overall preclinical and clinical profiling of bosentan (Ro 47-0203), a non-peptide endothelin receptor antagonist with oral activity. Bosentan is a combined and competitive antagonist of both ETA and ETB receptors that is selective for the endothelin system. In vitro and in vivo, bosentan potently antagonises the vascular response elicited by the endothelins. Preclinical efficacy is demonstrated in a variety of pathological models including pulmonary and essential hypertension, renal failure of ischaemic and nephrotic origin and cerebral vasospasm following subarachnoid haemorrhage. Effects are particularly marked in experimental models of heart failure (HF) where bosentan acts as a potent vasodilator that improves overall left ventricular performance. After chronic treatment, bosentan also improves survival in rats with HF. As a result of the first encouraging clinical results that show pulmonary and systemic vasodilation, long-term studies are ongoing in the treatment of congestive heart failure (CHF).
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PMID:The pharmacology of bosentan. 1599 23

The endothelin (ET) system consists of 3 ET isopeptides, several isoforms of activating peptidases, and 2 G-protein-coupled receptors, ETA and ETB, that are linked to multiple signaling pathways. In the cardiovascular system, the components of the ET family are expressed in several tissues, notably the vascular endothelium, smooth muscle cells, and cardiomyocytes. There is general agreement that ETs play important physiological roles in the regulation of normal cardiovascular function, and excessive generation of ET isopeptides has been linked to major cardiovascular pathologies, including hypertension and heart failure. However, several recent clinical trials with ET receptor antagonists were disappointing. In the present review, the authors take the stance that ETs are mainly and foremost essential regulators of cardiovascular function, hence that antagonizing normal ET actions, even in patients, will potentially do more harm than good. To support this notion, we describe the predominant roles of ETs in blood vessels, which are (indirect) vasodilatation and ET clearance from plasma and interstitial spaces, against the background of the subcellular mechanisms mediating these effects. Furthermore, important roles of ETs in regulating and adapting heart functions to different needs are addressed, including recent progress in understanding the effects of ETs on diastolic function, adaptations to changes in preload, and the interactions between endocardial-derived ET-1 and myocardial pump function. Finally, the potential dangers (and gains) resulting from the suppression of excessive generation or activity of ETs occurring in some cardiovascular pathological states, such as hypertension, myocardial ischemia, and heart failure, are discussed.
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PMID:Cardiovascular endothelins: essential regulators of cardiovascular homeostasis. 1645 92

Endothelins (ETs) exert a persistent constrictor effect on the vessels via an increase in intracellular Ca2+ concentration due to the activation of Na+/H+ and Na+/Ca2+ exchangers of the vascular smooth muscle fibres. They also produce a transient dilator effect via the activation of endothelial nitric oxide synthase mediated by protein kinase B/Akt. ETA and ETB2 receptors are involved in vasoconstriction, whereas transient vasodilatation depends on the activation of ETB1 receptors. Depending on animal species and experimental conditions, ETs can also play a role in cardiac muscle contraction and induce either an increase or a decrease in contractility. It is likely that only ETA, and not ETB, receptors are involved in the ET-induced increase in myocardial contractility. As in the case of vasoconstriction, this inotropic effect depends on an increase in intracellular Ca2+ concentration induced by Na+/H+ and Na+/Ca2+ exchangers. Activation of the Na+/H+ exchanger is stimulated by protein kinase C, which is activated by diacylglycerol released in response to ET activity. It has also been proposed that the positive inotropic effect can occur without the contribution of the Na+/Ca2+ exchanger, if the cell alkalinisation produced by the Na/H exchanger improves myofibrillar Ca2+ sensitivity. A reduction in contractility has been attributed to the involvement of the Gi protein/protein kinase G pathway or to the activation of protein kinase C without an increase in intracellular Ca2+ concentration or in myofibrillar Ca2+ sensitivity. The chronic effect of ETs on the myocardium results in hypertrophy and prevention of apoptosis, two processes that are together responsible for the contradictory effect of ETs in heart failure.
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PMID:Effect of endothelins on the cardiovascular system. 1693 76

Activation of the renin-angiotensin system (RAS), with ensuing aldosterone excess, detrimentally affects outcome in patients with hypertension and heart failure (HF). RAS blockade with angiotensin (Ang) 1-converting enzyme inhibitors (ACEIs) or Ang II type 1 receptor blockers (ARBs) is beneficial in such conditions. However, aldosterone secretion can persist despite these treatments. Hence, mechanisms besides Ang II acquire the role of aldosterone secretagogue. The RALES and EPHESUS studies have shown that this aldosterone "escape" or "breakthrough" is an important factor, because it is a determinant of outcome in HF patients. Endothelin (ET)-1, which stimulates aldosterone secretion via both A (ETA) and B (ETB) receptor subtypes, and which is increased in HF, is a candidate for the "aldosterone breakthrough." Moreover, the novel ET peptide ET-1(1-31) is involved in adrenocortical growth. Therefore, findings suggesting a role for the ET-1 system as an aldosterone secretagogue, along with the potential usefulness of endothelin antagonists for the prevention of "aldosterone breakthrough," are discussed.
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PMID:Aldosterone breakthrough during RAS blockade: a role for endothelins and their antagonists? 1714 26

Heart failure is a cause of pulmonary vasoconstriction and remodelling, leading to pulmonary hypertension (PH) and decreased survival. The pathobiology of PH in heart failure remains incompletely understood. We investigated pulmonary vascular function and signalling molecules in early stage PH secondary to experimental heart failure. Eight beagle dogs with overpacing-induced heart failure underwent haemodynamic assessment and postmortem pulmonary arterial reactivity, morphometry and quantification of genes encoding for factors involved in vascular reactivity and remodelling: endothelin-1 (ET-1), ETA and ETB receptors, vascular endothelial growth factor (VEGF), VEGF receptors 1 and 2 (VEGFR1 and VEGFR2), endothelial nitric oxide synthase, angiopoietin-1, bone morphogenetic protein receptors (BMPR1A and BMPR2), serotonin transporter (5-HTT) and the 5-HT(2B) receptor. Overpacing was associated with a decrease in cardiac output and an increase in pulmonary vascular pressures. However, there were no changes in pulmonary vascular resistance or in arteriolar medial thickness. There were increased expressions of genes encoding for ET-1, ETB, VEGF and VEGFR2, while expression of the other genes analysed remained unchanged. In vitro, pulmonary arteries showed decreased relaxation and increased reactivity, while systemic mammary arteries were unaffected. Early PH in heart failure is characterized by altered vasoreactivity and increased ET-1/ETB and VEGF/VEGFR2 signalling.
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PMID:Early increase in pulmonary vascular reactivity with overexpression of endothelin-1 and vascular endothelial growth factor in canine experimental heart failure. 1799 9

It is now becoming clear that two major systems namely the sympathetic nervous system and the renin-angiotensin system are activated in response to ischemic injury; these result in the elevation of plasma catecholamines and angiotensin II during the development of myocardial infarction as well as congestive heart failure. Although plasma levels of several other hormones including aldosterone, endothelin, vasopressin, natriuretic peptides, growth factors and inflammatory cytokines are also increased in heart failure, their relationship with changes in catecholamine and/or angiotensin levels as well as their significance for the induction of congestive heart failure are poorly understood. In this article we have examined the evidence regarding the role of endothelin and vasopressin in the pathogenesis of cardiac hypertrophy and congestive heart failure in addition to evaluating the significance of their antagonism by using their receptor blockade for treatment of congestive heart failure. Endothelin appears to maintain blood pressure by its vasoconstricting action whereas vasopressin primarily produces similar effect by retention of body fluid. Myocardium is also known to express both ET-A and ET-B receptors in addition to V1 and V2 receptors for vasopressin, which have been shown to induce cardiac remodeling. Out of various ET-1 receptor antagonists, which are available, a non-selective endothelin receptor antagonist, bosentan, as well as an ET-A receptor antagonist, BQ-123, seem most promising for the treatment of congestive heart failure. Likewise, vasopressin antagonists such as a non-selective antagonist, conivaptan, as well as V2 selective antagonist, tolvaptan, may prove highly valuable for the therapy of this condition. Since most of the existing interventions are helpful in treating patients with congestive heart failure only partially, there appears to be a real challenge for developing some combination therapy for the treatment of congestive heart failure.
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PMID:Potential of endothelin-1 and vasopressin antagonists for the treatment of congestive heart failure. 1976 21


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