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

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

Despite obvious participation of endothelins in pathogenesis of heart failure therapeutic approaches to the use of endothelin receptor antagonists remain to be elucidated. Experimental heart failure caused by prolonged infusion of norepinephrine is associated with diminished endothelin induced coronary constricting effect of stimulation of ET(A) receptors and inversion of coronary dilating effect of stimulation of these receptors. The latter effect is mediated by smooth muscle ET(B)-receptors and is indicative of functional derangement of vascular control by endothelial cells. The use of selective ET(A)-antagonist is effective on early stages of heart failure while on later stages administration of nonselective ET(AB)-antagonist produces more pronounced effect.
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PMID:[Changes of activity of the endothelial system in experimental heart failure]. 1609 38

Endothelin receptor antagonists (ERAs) have been developed to block the effects of endothelin-1 (ET-1) in a variety of cardiovascular conditions. ET-1 is a powerful vasoconstrictor with mitogenic or co-mitogenic properties, which acts through the stimulation of 2 subtypes of receptors [endothelin receptor subtype A (ETA) and endothelin receptor subtype B (ETB) receptors]. Endogenous ET-1 is involved in a variety of conditions including systemic and pulmonary hypertension (PH), congestive heart failure (CHF), vascular remodeling (restenosis, atherosclerosis), renal failure, cancer, and cerebrovascular disease. The first dual ETA/ETB receptor blocker, bosentan, has already been approved by the Food and Drug Administration for the treatment of pulmonary arterial hypertension (PAH). Trials of endothelin receptor antagonists in heart failure have been completed with mixed results so far. Studies are ongoing on the effects of selective ETA antagonists or dual ETA/ETB antagonists in lung fibrosis, cancer, and subarachnoid hemorrhage. While non-peptidic ET-1 receptor antagonists suitable for oral intake with excellent bioavailability have become available, proven efficacy is limited to pulmonary hypertension, but it is possible that these agents might find a place in the treatment of several cardiovascular and non-cardiovascular diseases in the coming future.
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PMID:Endothelin receptor antagonists. 1621 61

Mixed connective tissue disease is a disease entity characterized by overlapping symptoms of lupus erythematosus (LE), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM) and rheumatoid arthritis (RA). Diagnostic criteria include high titers of antibodies against U1RNP as well as the presence of at least 3 of 5 of the following clinical features: edema of hands, synovitis, myositis, Raynaud phenomenon and acroscierosis. In terms of the pathogenesis, genetic as well as infectious (viral) factors appear to play a role. The acceptance of MCTD as a distinct disease entity is controversial. Terms such as "undifferentiated connective tissue disease" or "overlapping syndromes" are not helpful. One-quarter of MCTD patients transform into LE, while one-third progress to SSc. Therapeutic recommendations are glucocorticoids in combination with immunosuppressive agents and endothelin receptor antagonists. Double blind studies are not available. The prognosis is relatively good. Causes of death include pulmonary hypertension, infections and both pulmonary and cardiac failure.
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PMID:[MCTD--mixed connective tissue disease]. 1635 Oct 11

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

Left ventricular assist device (LVAD) implantation and heart transplantation (HTx) are established therapeutic approaches in the treatment of end-stage heart failure. The postoperative humoral responses to the two treatments have not yet been compared. All patients were treated with inhaled nitric oxide (iNO) on weaning from cardiopulmonary bypass as they presented with pulmonary hypertension. We investigated atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), cGMP, endothelin (ET)-1, big endothelin (big ET), and hemodynamic parameters after LVAD implantation (15 patients; age 51 +/- 8 years) or HTx (10 patients; age 53 +/- 6 years) preoperatively, on cardiopulmonary bypass and postoperatively up to 72 hrs after cessation of iNO. Preoperatively, cardiac index (CI), pulmonary artery pressure, pulmonary capillary wedge pressure (PCWP), central venous pressure (CVP), and mean atrial pressure (MAP) were similar for both groups. Similarly, ANP, BNP, cGMP, ET-1, and big ET were comparable before surgery. Seventy-two hours after weaning from iNO, the administered epinephrine dose was higher in the HTx group (P = 0.003); whereas the CVP (P = 0.04) and pulmonary vascular resistance (PVR; P = 0.03) were lower. The following humoral parameters differed markedly: ANP (preoperatively: LVAD, 99 +/- 123 pg/ml; HTx, 197 +/- 199 pg/ml; P = 0.14; vs. 72 hrs after iNO: LVAD, 110 +/- 106 pg/ml; HTx, > 640 +/- 0 pg/ml; P = 0.003) and cGMP (preoperatively: LVAD, 4.4 +/- 5.8 pg/ml; HTx, 5.0 +/- 3.0 pg/ml; P = 0.35; vs. 72 hrs after iNO: LVAD, 8.0 +/- 10.8 pg/ml; HTx, 26.2 +/- 15.8 pg/ml; P = 0.02). Although the hemodynamic effects of both LVAD implantation and HTx in the treatment of end-stage heart failure are comparable, except for the effects on CVP and PVR, the humoral responses with respect to ANP and cGMP were strikingly different. These effects are independent of volume status, iNO, and ETs, suggesting a physiologic response to maintain circulatory homeostasis.
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PMID:Humoral and hemodynamic responses after left ventricular assist device implantation and heart transplantation. 1674 Oct 13

Whereas the right ventricle tolerates volume loads without any substantial increase of the pressure in the pulmonary circulation by recruiting capacitance vessels and capillaries, it possesses only small contractile reserves and reacts unadapted with right ventricular dysfunction. Its size and pressure load are relevant factors for prognosis of all forms of pulmonary hypertension, in particular if linked to left-sided heart failure. Differentiation of pulmonary hypertension according to the Venice classification is highly important. Right-sided ventricular heart failure worsens left ventricular hemodynamics due to reduced ejection fraction and in addition due to direct diastolic ventricular interaction in which left ventricular diastolic dysfunction increases even though the left ventricular systolic function is still intact. Right ventricular ejection fraction <40% is an important predictor of prognosis after myocardial infarction or chronic stages of left ventricular heart failure. The most important noninvasive diagnostic method is transthoracic echocardiography with determination of the Tei index and Doppler echocardiographic estimation of pulmonary artery pressure. Chronic obstructive pulmonary disease is the most frequent cause of cor pulmonale. While long-term oxygen therapy in patients with COPD and cor pulmonale and for example the administration of endothelin receptor antagonists in patients with idiopathic pulmonary hypertension is beneficial, the therapeutic use of drugs effective for left-sided heart failure is very limited in patients with right ventricular dysfunction.
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PMID:[Right heart failure and cor pulmonale]. 1762 62

Doxorubicin is a frequently used anticancer drug, but its therapeutic benefit is limited by acute and chronic cardiotoxicity, often leading to heart failure. The mechanisms underlying doxorubicin-induced cardiotoxicity remain unclear. It was previously shown in men that doxorubicin leads to increased endothelin-1 plasma levels. In addition, cardiac-specific overexpression of endothelin-1 in mice resulted in a cardiomyopathy resembling the phenotype following doxorubicin administration. We therefore hypothesized that endothelin-1 is involved in the pathogenesis of doxorubicin cardiotoxicity. In mice (C57Bl/10), we found that doxorubicin (20 mg/kg body weight, i.p.) impaired cardiac function with decreased ejection fraction, diminished cardiac output, and decreased end-systolic pressure points recorded by a microconductance catheter. This impaired function was accompanied by the up-regulation of endothelin-1 expression on mRNA and protein level. In vitro investigations confirmed the regulation of endothelin-1 by doxorubicin and indicated that the doxorubicin-mediated increase of endothelin-1 expression involves epidermal growth factor receptor signaling via the MEK1/2-ERK1/2 cascade, which was further confirmed by immunoblotting studies in the left ventricle of treated animals. Pretreatment of mice with the endothelin receptor antagonist bosentan (100 mg/kg body weight, p.o.) strikingly inhibited doxorubicin-induced cardiotoxicity with preserved indices of contractility. Moreover, bosentan pretreatment resulted in reduced tumor necrosis factor-alpha content, lipid peroxidation, and Bax expression, as well as increased GATA-4 expression. Thus, endothelin-1 plays a key role in mediating the cardiotoxic effects of doxorubicin and its inhibition may be of therapeutic benefit for patients receiving doxorubicin.
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PMID:The endothelin receptor blocker bosentan inhibits doxorubicin-induced cardiomyopathy. 1797 86

A large proportion of patients with congenital heart disease (CHD), in particular those with relevant systemic-to-pulmonary shunts, will develop pulmonary arterial hypertension (PAH) if left untreated. Persistent exposure of the pulmonary vasculature to increased blood flow, as well as increased pressure, may result in pulmonary obstructive arteriopathy, which leads to increased pulmonary vascular resistance that, if it approaches or exceeds systemic resistance, will result in shunt reversal. Eisenmenger's syndrome, the most advanced form of PAH associated with CHD, is defined as CHD with an initial large systemic-to-pulmonary shunt that induces severe pulmonary vascular disease and PAH, with resultant reversal of the shunt and central cyanosis. The histopathological and pathobiological changes seen in patients with PAH associated with congenital systemic-to-pulmonary shunts, such as endothelial dysfunction of the pulmonary vasculature, are considered similar to those observed in idiopathic or other associated forms of PAH. A pathological and pathophysiological classification of CHD with systemic-to-pulmonary shunt leading to PAH has been developed that includes specific characteristics, such as the type, dimensions and direction of the shunt, extracardiac abnormalities and repair status. A clinically oriented classification has also been proposed. The prevalence of PAH associated with congenital systemic-to-pulmonary shunts in Western countries has been estimated to range between 1.6 and 12.5 cases per million adults, with 25-50% of this population affected by Eisenmenger's syndrome. Clinically, Eisenmenger's syndrome presents with multiple organ involvement, with progressive deterioration of function over time. The signs and symptoms of Eisenmenger's syndrome in the advanced stages include central cyanosis, dyspnoea, fatigue, haemoptysis, syncope and right-sided heart failure. Survival of patients with Eisenmenger's syndrome is clearly less than that of the general population, but appears to be better than that of patients with idiopathic PAH in a comparable functional class. The treatment strategy for patients with PAH associated with congenital systemic-to-pulmonary shunts and, in particular, those with Eisenmenger's syndrome is based mainly on clinical experience rather than being evidence based. General measures include recommendations for physical activity, pregnancy, infections, air travel, exposure to high altitudes and elective surgery, and that psychological assistance be provided as necessary. Phlebotomies are required only when hyperviscosity of the blood is evident, usually when the haematocrit is >65%. The use of supplemental oxygen therapy is controversial and it should be used only in patients in whom it produces a consistent increase in arterial oxygen saturation. Oral anticoagulant treatment with warfarin can be initiated in patients with pulmonary artery thrombosis and absent, or only mild, haemoptysis. The following three classes of drugs targeting the correction of abnormalities in endothelial dysfunction have been approved recently for the treatment of PAH: (i) prostanoids; (ii) endothelin receptor antagonists; and (iii) phosphodiesterase-5 inhibitors. The efficacy and safety of these compounds have been confirmed in uncontrolled studies in patients with PAH associated with corrected and uncorrected congenital systemic-to-pulmonary shunts, as well as in patients with Eisenmenger's syndrome. One randomized controlled trial reported favourable short- and long-term outcomes of treatment with the orally active dual endothelin receptor antagonist bosentan in patients with Eisenmenger's syndrome. Lung transplantation with repair of the cardiac defect or combined heart-lung transplantation are options for Eisenmenger's syndrome patients with a poor prognosis. A treatment algorithm based on the one used in the treatment of PAH patients is proposed for patients with PAH associated with corrected and uncorrected congenital systemic-to-pulmonary shunts and Eisenmenger's syndrome.
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PMID:Management of pulmonary arterial hypertension associated with congenital systemic-to-pulmonary shunts and Eisenmenger's syndrome. 1848 98


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