Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Endothelial dysfunction and atherosclerosis: endothelin receptor antagonists as novel therapeutics. 1098 Nov 33

Benidipine hydrochloride has been developed as an antagonist for the L-type calcium channel and is used as an anti-hypertensive drug. But recent studies have reported that benidipine exerts not only antihypertensive actions but also anti-hypertrophic actions on cardiac muscles. Endothelin-1 (ET-1), one of the endogenous pathological humoral factors of cardiovascular diseases such as hypertension and heart failure, has a strong vasoconstrictive action and could induce hypertension and cardiac hypertrophy. So, it is a matter of great interest whether or not calcium antagonists can decrease cardiac hypertrophy induced by the pathological vasoactive substances such as ET-1. Thus, the present study was designed to elucidate the effects of benidipine on cardiac hypertrophy, and particularly on the interaction with ET-1, using neonatal rat cardiac myocytes (MCs) and cardiac non-myocytes (NMCs) culture systems. Cells were cultured with or without ET-1, benidipine, and nifedipine and the effects of calcium antagonists on cardiac hypertrophy were evaluated by incorporations of [3H]-leucine and [3H]-thymidine into MCs and/or NMCs. Benidipine significantly decreased the ET-1-induced increase of [3H]-leucine and [3H]-thymidine uptake into cardiac MCs and NMCs, whereas no significant effects of nifedipine were observed. Furthermore, benidipine (10(-8)M) attenuated ET-1 secretions from NMCs. In summary, benidipine at least partially decreased the cardiac hypertrophy induced by paracrine mechanisms through its attenuation of ET-1 secretions from NMCs. Benidipine could thus be a useful tool for preventing cardiac hypertrophy due to hypertension.
 ...
PMID:Possible involvement of endothelin-1 in cardioprotective effects of benidipine. 1101 4

Endothelin-1 (ET-1) not only causes potent vasoconstriction but also leads to fluid retention, both actions mediated by ET(A)- and/or ET(B)-receptors. Selective ET(A)- and combined ET(A)/ET(B)-receptor antagonists improve hemodynamics in heart failure; however, it is also important to evaluate the effects of these antagonists on urine output in heart failure. We administered an acute dose of either the selective ET(A)-receptor antagonist FR139317 (FR, n=5, 1 and 3 mg/kg) or the mixed ET(A)/ET(B)-receptor antagonist TAK-044 (TAK, n = 5, 1 and 3 mg/kg) to dogs with heart failure induced by rapid ventricular pacing. Renal hemodynamic and tubular functions were subsequently investigated. FR increased urinary excretion in association with increased renal plasma flow (RPF) and glomerular filtration rate (GFR) with no significant changes in the fractional reabsorption of water distally (FRWD). In contrast, despite increased GFR, TAK did not alter urine volume or RPF with significantly increased FRWD. The increase of GFR and RPF induced by FR was significantly larger than that of TAK. These findings indicate that ET(B)-receptor activation may result in diuresis by renal vasodilatation and reduction of water reabsorption in the distal tubules and collecting ducts. Acute ET(A)-receptor antagonism may therefore be more beneficial to diuresis than dual ET(A)/ET(B)-receptor inhibition in heart failure.
 ...
PMID:Significant roles of endothelin-A- and -B-receptors in renal function in congestive heart failure. 1107 60

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.
 ...
PMID:The role of endothelins and their receptors in heart failure. 1124 12

Endothelin-1 (ET-1) is a peptide hormone with potent vasoconstrictor properties which is synthesized and secreted predominantly by vascular endothelial cells. Its production is regulated by numerous stimuli including ischemia and hypoxia, and the enhanced levels that occur during myocardial ischemia may contribute to the progression of heart failure. We reported previously a preliminary characterization of a hypoxia-inducible factor-1 (HIF-1) binding site in the human ET-1 promoter which contributed to the activation of ET-1 expression in endothelial cells. We report here that the HIF-1 binding site alone is not sufficient for the response to hypoxia but requires an additional 50 base pairs of flanking sequence that includes binding sites for the factors activator protein-1 (AP-1), GATA-2, and CAAT-binding factor (NF-1). Mutation of any one of these sites or the HIF-1 site eliminated induction by hypoxia. Mutations of the AP-1 and GATA-2 sites, but not the HIF-1 site, were complemented by overexpressing AP-1, GATA-2, HIF-1alpha, or the activator protein p300/CBP, restoring the response to hypoxia. Binding studies in vitro confirmed physical associations among GATA-2, AP-1, and HIF-1 factors. Overexpression or depletion of p300/CBP modulated the level of ET-1 promoter expression as well as the endogenous ET-1 transcript but did not change the fold induction by hypoxia in either case. Regulation of the ET-1 promoter by hypoxia in non-endothelial cells required overexpression of GATA-2 and HIF-1alpha. The results support essential roles for AP-1, GATA-2, and NF-1 in stabilizing the binding of HIF-1 and promoting recruitment of p300/CBP to the ET-1 hypoxia response complex.
 ...
PMID:Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP. 1127 91

Congestive heart failure may be produced by a variety of disorders, including dilated cardiomyopathy, hypertension, and ischemic heart disease. We have developed experimental models of these diseases, and found gene expressions of proinflammatory cytokines increased in the hearts of these animals. Various drugs for heart failure modulate the production of cytokines in experimental models of heart failure. Pimobendan, an inhibitor of phosphodiesterase III prolonged survival, attenuated inflammatory lesions, and decreased the production of cytokines and nitric oxide. Recent studies have shown that these inhibitory effects are due to inhibition of activation of NF-kappaB. In contrast, digitalis increased the production of cytokines and exacerbated myocarditis. Interleukin-10 prolonged survival, attenuated myocardial injury, and appears promising as a treatment of heart failure due to viral myocarditis. Endothelin-1 plays an important pathophysiological role in heart failure, and treatment with an endothelin antagonist had a cardioprotective effect in experimental models of heart failure.
 ...
PMID:The role of inflammatory mediators in the failing heart: immunomodulation of cytokines in experimental models of heart failure. 1130 31

Endothelin-1 (ET-1) is elevated in chronic heart failure (CHF). In this study, we determined the effects of chronic ET-1 blockade on renal sympathetic nerve activity (RSNA) in conscious rabbits with pacing-induced CHF. Rabbits were chronically paced at 320--340 beats/min for 3--4 wk until clinical and hemodynamic signs of CHF were present. Resting RSNA and arterial baroreflex control of RSNA were determined. Responses were determined before and after the ET-1 antagonist L-754,142 (a combined ET(A) and ET(B) receptor antagonist, n = 5) was administered by osmotic minipump infusion (0.5 mg. kg(-1) x h(-1) for 48 h). In addition, five rabbits with CHF were treated with the specific ET(A) receptor antagonist BQ-123. Baseline RSNA (expressed as a percentage of the maximum nerve activity during sodium nitroprusside infusion) was significantly higher (58.3 +/- 4.9 vs. 27.0 +/- 1.0, P < 0.001), whereas baroreflex sensitivity was significantly lower in rabbits with CHF compared with control (3.09 +/- 0.19 vs. 6.04 +/- 0.73, P < 0.001). L-754,142 caused a time-dependent reduction in arterial pressure and RSNA in rabbits with CHF. In addition, BQ-123 caused a reduction in resting RSNA. For both compounds, RSNA returned to near control levels 24 h after removal of the minipump. These data suggest that ET-1 contributes to sympathoexcitation in the CHF state. Enhancement of arterial baroreflex sensitivity may further contribute to sympathoinhibition after ET-1 blockade in heart failure.
 ...
PMID:Chronic endothelin-1 blockade reduces sympathetic nerve activity in rabbits with heart failure. 1135 99

Endothelin-1 (ET-1) and adrenomedullin (ADM) are both produced in the arterial wall, but have opposing biological actions. Evidence from experimental animals suggests a functional interaction between ET-1 and ADM. We have tested this in humans. Small resistance arteries were obtained from gluteal biopsies taken from patients with chronic heart failure (CHF) due to coronary heart disease (CHD), or with CHD and preserved ventricular function. The contractile responses to big ET-1 and to ET-1 in both sets of vessels were studied in the absence (control) and presence of ADM at 20 pmol/l (low ADM) or 200 pmol/l (high ADM), using wire myography. ADM did not affect the conversion of big ET-1 into ET-1 in vessels from patients with either CHD or CHF. Low ADM did not alter the contractile response to ET-1 in vessels from patients with CHF. Low ADM was not tested in vessels from patients with CHD, but high ADM did not affect this response in arteries from these patients. High ADM did, however, significantly reduce the vasoconstrictor effect of ET-1 in vessels from patients with CHF. The maximum response, as a percentage of the response to high potassium, was 199% (S.E.M. 25%) in the control experiments (n=14), 205% (27%) in the low-ADM (n=7) studies and 150% (17%) in the high-ADM (n=6) experiments (P<0.001). Furthermore, the Hill coefficient increased from 0.57+/-0.05 in the absence of ADM to 1.16+/-0.15 in the high-ADM experiments, indicating that ADM at 200 pmol/l specifically antagonized one receptor type in vessels from patients with CHF. We conclude that there is a one-site receptor interaction between ADM and ET-1 that is specific for vessels from patients with CHF. This functional interaction between ADM and ET-1 in resistance arteries may be of pathophysiological importance in CHF.
 ...
PMID:Effect of adrenomedullin on the production of endothelin-1 and on its vasoconstrictor action in resistance arteries: evidence for a receptor-specific functional interaction in patients with heart failure. 1141 Jan 13

Our understanding of the role of the endothelin system in human cardiovascular physiology and pathophysiology has evolved very rapidly since the initial description of its constituent parts in 1988. Endothelin-1 (ET-1) is the predominant endothelin isoform in the human cardiovascular system and has potent vasoconstrictor, mitogenic and antinatriuretic properties which have implicated it in the pathophysiology of a number of cardiovascular diseases. The effects of ET-1 have been shown to be mediated by 2 principal endothelin receptor subtypes: ET(A) and ET(B). The development of a range of peptidic and nonpeptidic endothelin receptor antagonists represents an exciting breakthrough in human cardiovascular therapeutics. Two main classes of endothelin receptor antagonist have been developed for possible human therapeutic use: ET(A)-selective and nonselective antagonists. Extensive laboratory and clinical research with these agents has highlighted their promise in various cardiovascular diseases. Randomised, placebo-controlled clinical trials have yielded very encouraging results in patients with hypertension and chronic heart failure with more preliminary data suggesting a possible role in the treatment and prevention of atherosclerosis and stroke. Much more research is needed, however, before endothelin receptor antagonists can be considered for clinical use.
 ...
PMID:Endothelin receptor antagonists and cardiovascular diseases of aging. 1141 17

The important neuroendocrine systems involved in heart failure are reviewed with special emphasis on their possible role in pathophysiology and their relation to prognostic and diagnostic information. Plasma levels of noradrenaline (NA), renin, vasopressin, endothelin-1, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and tumour necrosis factor-alpha (TNF-alpha) are all elevated in heart failure. Activity of the sympathetic nervous system as reflected by NA is correlated to mortality and seems to possess independent prognostic information. Several studies have now documented the beneficial effect of beta-blockade in chronic heart failure (CHF). Renin seems to be a poor prognostic marker in CHF possibly because of the interference with diuretic treatment, angiotensin converting enzyme (ACE)-inhibitors and angiotensin II antagonist, and probably also because of the significance of tissue renin-angiotensin system (RAS), poorly reflected by plasma renin. On the other hand, several large-scale trials with ACE-inhibitors and angiotensin II antagonists have demonstrated reduced mortality and morbidity in CHF. Plasma vasopressin does not seem to possess prognostic information but testing of non-peptide antagonists is ongoing. Endothelin-1 seems to have independent prognostic information and endothelin receptor antagonists may represent a therapeutic possibility. The natriuretic peptides ANP and BNP are correlated to prognosis and possess independent information. Brain natriuretic peptide and N-terminal ANP seem to increase early, i.e. in asymptomatic heart failure. Plasma BNP being more stable than ANP is therefore a promising measure of left ventricular dysfunction. Increase in ANP and BNP, potentially beneficial, may be achieved by administration of neutral endopeptidase inhibitors, at present an unsettled therapeutic possibility. Several cytokines are increased in heart failure and especially TNF-alpha has drawn attention. Experimental studies suggest that TNF-alpha is important in the pathophysiology of heart failure and preliminary studies indicate that inhibition of TNF-alpha seems to be a possible therapeutic approach. Thus, neuroendocrine markers seem to (i) have a role in diagnosis and classification of heart failure, (ii) be useful in providing a 'neuroendocrine profile' which enlightens different aspects of heart failure, and therefore (iii) in the future probably will be valuable in the choice of medical treatment of the individual patient. In addition to beta-blockers, ACE-inhibitors and angiotensin II antagonists several new drugs based on neuroendocrine modification are on their way and might become important in the future.
 ...
PMID:Heart failure and neuroendocrine activation: diagnostic, prognostic and therapeutic perspectives. 1172 73


<< Previous 1 2 3 4 5 6 7 8 Next >>