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)

Endothelins (ET) are a family of peptides with potent biological properties. Endothelial cells produce exclusively ET-1 while other tissues produce ET-2 and ET-3. The production of ET requires an increase in intracellular Ca2+. This increase can be induced by physical chemicals (i.e. hypoxia) or receptor-operated stimuli (i.e. thrombin, angiotensin II, arginine vasopressin, transforming growth factor beta 1, interleukin-1). Most of ET is released abluminally towards vascular smooth muscle and less luminally. The main vascular effect of ET are vasodilation (transient), profound and sustained vasoconstriction as well as proliferation of vascular smooth muscle. These biological effects are mediated by distinct receptors. Three ET receptors have been cloned, i.e. ETA-, ETB- and ETC-receptors. In vascular tissue ETA-receptors are expressed on vascular smooth muscle and responsible for vasoconstriction. ETB-receptors are expressed on endothelium and linked to nitric oxide and/or prostacyclin release. Activation of these receptors explains the transient vasodilation with intraluminal application of ET. Vascular smooth muscle cells can express ETB-receptors which contribute to ET-induced vasoconstriction particularly at lower concentrations. The role of the recently cloned ETC-receptor in the vasculature is still uncertain. ET production is increased (as judged from circulating plasma levels) in vascular disease and atherosclerosis in particular, in myocardial infarction and heart failure, pulmonary hypertension and renal disease. ET production is increased in arterial hypertension remains controversial. Non-peptidic ET antagonists have been developed which either block ETA- receptors or ETA- and ETB-receptors simultaneously. The advantage of ETA-receptors is that they leave the endothelium-dependent vasodilation to ET (via ETB-receptor) intact. However, ETB-mediated contraction remains unaffected by these antagonists. In contrast ETA-/ETB-antagonists fully prevent ET-induced vasoconstriction, however, they also inhibit the endothelial effects of the peptide. ET antagonists interfere with the effects of ET in isolated vascular tissue (including that obtained from humans) as well as in vivo. In humans, ETA as well as ETA-/ETB-antagonists inhibit endothelin-induced vasoconstriction. Hence in summary ET are a family of potent peptides with profound effects in the vasculature. Several studies suggest a role of ET in cardiovascular disease. The newly developed ET-antagonists are potent and selective tools to delineate the (patho-)physiological roles of ET and may become a new class of cardiovascular drugs.
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PMID:Endothelin and endothelin antagonists: pharmacology and clinical implications. 771 86

This study examined the potential role of ET-1 and the contribution of protein kinase C (PKC) in the desensitization of the ET-1 transmembrane signaling pathway in the left circumflex coronary artery (CCA) of a dog model of congestive heart failure (CHF). In the CCA of the rapid ventricular pacing-overdrive dog model of CHF, elevated plasma endothelin levels were associated with a decrease in the basal accumulation of inositol phosphates and ET-1 mediated activation of phosphatidylinositol (PI) turnover (P < 0.05). To assess whether elevated plasma ET-1 levels may have contributed to the diminished ET-1 responsiveness in the heart failure dogs, ET-1 generation of inositol phosphates was measured following a one hour pretreatment of normal coronary artery rings with 0.1 nM ET-1. As compared to non-treated rings, ET-1 pretreatment resulted in a 33% decrease of ET-1 (10 nM) production of inositol phosphates. To evaluate the role of PKC in this process, normal coronary rings pretreated for a period of one hour with the phorbol ester, phorbol 12-myristate 13-acetate (PMA, 1 microM), resulted in a similar attenuation (36%) of ET-1 production of inositol phosphates. In the presence of the protein kinase C inhibitor staurosporine, both the agonist and phorbol ester induced decreases in ET-1 mediated PI turnover were reversed. Staurosporine even potentiated (75%) ET-1 induced PI turnover despite ET-1 and PMA pretreatments. These results suggest that agonist-induced desensitization of ET-1 mediated PI turnover can occur and is at least one of the possible mechanisms contributing to the desensitization of the ET-1 transmembrane signaling pathway in the pacing-overdrive model of heart failure in the dog.
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PMID:Regulation of the endothelin-1 transmembrane signaling pathway: the potential role of agonist-induced desensitization in the coronary artery of the rapid ventricular pacing-overdrive dog model of heart failure. 826 60

Endothelin (ET-1) is found at elevated concentrations in the plasma of patients with heart failure and in animal models of cardiomyopathy. The peptide is a potent positive inotropic agent, the effects of which are mediated by increases in cytosolic Ca2+ in cardiomyocytes. The object of this study was to investigate at the cellular level, the actions of ET-1 on contractile function and on Ca2+ currents in heart-failed ventricular myocardium. Male New Zealand White rabbits (8 wks) were treated with twice weekly injections of epirubicin (4 mg/kg/wk, n = 7) or with saline (n = 7) for 6 wks, followed by a washout period of 2 wks. Ventricular cardiomyocytes were isolated from rabbit hearts using Langendorff perfusion with collagenase; contractile function was examined using a video microscopy method, and L-type Ca2+ currents were recorded using a whole-cell patch-clamp technique. ET-1 produced a concentration-dependent increase in contractile response (% increase from basal value) to a maximum at 1 nM ET-1 of 69 +/- 11% (mean +/- S.D.) in control cardiomyocytes and 33 +/- 6% in heart-failed cells. However, there was no significant change in the EC50 obtained with ET-1 for healthy (0.31 +/- 0.1 nM) and for failed cardiomyocytes (0.24 +/- 0.1 nM). The effects of ET-1 on L-type Ca2+ channels were similar with a peak amplitude at 1 nM ET-1 of -3.26 +/- 0.8 nA in control cardiomyocytes and -3.32 +/- 0.9 nA in heart-failed cells. The attenuation of the contractile response to ET-1 in heart-failed cells may reflect a desensitization of ET receptors as a consequence of elevated circulating levels of ET and was not reflected by alteration of transmembrane Ca2+ conductance. It is probable, therefore, that multiple signalling pathways are involved in the actions of ET on ventricular myocardium.
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PMID:Mechanical effects of ET-1 in cardiomyocytes isolated from normal and heart-failed rabbits. 873 41

The goal of this study was to test the hypothesis that chronic myocardial infarction potentiates agonist-induced constrictor responses of rat skeletal muscle arterioles in vivo. Eight weeks after we performed coronary artery ligation or sham (control) surgery, the spinotrapezius muscle was prepared for direct visualization of the microcirculation. Diameter of third-order arterioles (40.7 +/- 0.5 microns) to topical suffusion of angiotensin II (ANG II; 0.1-10 nM), arginine vasopressin (AVP; 0.1-10 nM), endothelin-1 (ET-1; 1.0-100 pM), and the thromboxane analog U-46619 (1.0-100 nM) was measured in both groups. Myocardial-infarcted rats exhibited enhanced arteriolar constrictor responses to ANG II and AVP compared with the responses in controls. In contrast, ET-1- and U-46619-induced constrictor responses were similar in control and myocardial-infarcted rats. Additional experiments explored the impact of NG-monomethyl-L-arginine (L-NMMA; 0.1 mM) on arteriolar reactivity. In control animals, L-NMMA potentiated ANG II- and AVP-induced vasoconstriction, achieving values similar to those observed in myocardial-infarcted rats. L-NMMA did not alter vasoconstrictor responses in rats with chronic myocardial infarction. These observations suggest that enhanced agonist-induced vasoconstriction during heart failure may reflect a loss of nitric oxide-mediated modulation of arteriolar tone.
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PMID:Enhanced constrictor responses of skeletal muscle arterioles during chronic myocardial infarction. 932 43

The endothelins (ET) are a family of contractile peptides made up of 21 amino acids. They are synthesised from larger precursors and they are expressed in different tissues. ET-1 is synthesised in endothelial cells by means of a specific endothelin converting enzyme and it is assumed that most of it is secreted into the basolateral compartment. It acts in a paracrine manner on the ETA and ETB2 receptors located on the surface of the vascular smooth muscle to elicit an increase in intracellular calcium and vasoconstriction. The circulating ET-1 can also activate endothelial ETC and ETB1 receptors releasing vascular smooth muscle relaxing factors, such as nitric oxide and prostacyclin. At present, it is generally accepted that ET-1 is a vasodilator in physiological conditions acting on endothelium ETB1 receptors. Nevertheless, in pathological situations such as hypertension, heart failure, acute myocardial infarction, acute renal failure and vasospastic conditions (Raynaud's disease and subarachnoid haemorrhage), ET-1 levels increase and it binds to the receptors present in vascular smooth muscle in such a way that its vasoconstrictor effect is manifested. Currently, experimental and clinical evidence exists to support the importance of the development of drugs that block the production or actions of ET for use in cardiovascular medicine, particularly in conditions in which these peptides are clearly implicated.
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PMID:Highlights on endothelins: a review. 944 24

Congestive heart failure(CHF) is associated with a marked decrease in cortical blood flow and preservation of medullary blood flow. In the present study we tested the hypothesis that changes in the endothelin (ET) and nitric oxide (NO) systems in the kidney may contribute to the altered intrarenal hemodynamics in rats with aortocaval fistula, an experimental model of CHF. Cortical and medullary blood flow were measured simultaneously by laser-Doppler flowmetry in controls and rats with compensated and decompensated CHF. As previously reported [K. Gurbanov, I. Rubinstein, A. Hoffman, Z. Abassi, O. S. Better, and J. Winaver. Am. J Physiol. 271 (Renal Fluid Electrolyte Physiol. 40): F1166-F1172, 1996], administration of ET-1 in control rats produced a sustained cortical vasoconstriction and a transient medullary vasodilatory response. In rats with decompensated CHF, cortical vasoconstriction was severely blunted, whereas ET-1-induced medullary vasodilation was significantly prolonged. This prolonged response was mimicked by IRL-1620, a specific ETB agonist, and partially abolished by NO synthase (NOS) blockade. In line with these findings, expression of ET-1, ETA and ETB receptors, and endothelial NOS (eNOS), assessed by RT-PCR, and eNOS immunoreactivity, assessed by Western blotting, was significantly higher in the medulla than in the cortex. Moreover, expression of ET-1 mRNA in the cortex and eNOS mRNA in the cortex and the medulla increased in proportion to the severity of heart failure. These findings indicate that CHF is associated with altered regulation of intrarenal blood flow, which reflects alterations in expression and activity of the ET and NO systems. It is further suggested that exaggerated NO activity in the medulla contributes to preservation of medullary blood flow in the face of cortical vasoconstriction in CHF.
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PMID:Regulation of intrarenal blood flow in experimental heart failure: role of endothelin and nitric oxide. 957 2

Endothelin-converting enzyme-1 (ECE-1) plays a substantial role in activation of the endothelin (ET) system by cleaving the precursor, big ET-1, to the active peptide ET-1. The aim of this study was to investigate whether ECE-1 mRNA expression is modified in human cardiovascular disease. ECE-1 expression was related to echocardiographic data, drug treatment, age, sex, and NYHA heart failure classification. A quantitative PCR assay (qPCR) was established to measure ECE-1 mRNA in these samples. The ECE-1 measurements were normalized over a simultaneously performed GAPDH qPCR. The results indicate a higher ECE-1 expression level in atrial tissue samples of patients who have experienced a myocardial infarction compared with those who did not (ECE-1/GAPDH: 5.81 +/- 0.76 fg/ng; n = 21 vs. 3.20 +/- 0.51 fg/ng; n = 22; p = 0.007). The transverse diameter of the left atrium over 37 mm was associated with a lower ECE-1 expression (ECE-1/GAPDH: 3.11 +/- 0.69 fg/ng; n = 18 vs. 5.12 +/- 0.65 fg/ng; n = 25; p = 0.044). In assessing the drug treatment, decreased ECE-1 expression could be observed in patients who received a beta-blocker (ECE-1/GAPDH: 3.90 +/- 58 fg/ng; n = 31 vs. 5.81 +/- 0.76 fg/ng; n = 12; p = 0.077). These data suggest an involvement of the ET system is cardiovascular disease that may be clinically important.
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PMID:Endothelin-converting enzyme-1 mRNA expression in human cardiovascular disease. 959 98

We have previously reported that production of endothelin (ET)-1 is markedly increased in failing hearts of rats with chronic heart failure (CHF). It was also reported that the production of angiotensin II (Ang II) is increased in the failing heart. In this study we investigated both converting enzymes of the ET-1 system and the angiotensin system. We used left coronary artery-ligated rats as a model of CHF. The peptide level of ET-1 in the left ventricle (LV) was markedly higher in CHF rats than in control rats. In the LV, expression of preproET-1 mRNA was also markedly higher in CHF rats than in controls. The expression of endothelin-converting enzyme (ECE)-1 mRNA in the rats with CHF was similar to that in controls. Therefore, we believed that the increase in ET-1 production in the failing heart originated from an increase in preproET-1 production rather than increase in ECE. The expression of angiotensin-converting enzyme (ACE) mRNA in failing hearts of CHF rats was significantly higher than that of the sham-operated rats. The expression of angiotensinogen mRNA in failing hearts of these CHF rats was slightly higher than that of the sham-operated rats. This study suggests that there is a difference in the role of peptide synthesis between the ECE system and the ACE system in rats with CHF.
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PMID:Endothelin-converting enzyme and angiotensin-converting enzyme in failing hearts of rats with myocardial infarction. 959

Cardiotoxicity is an uncommon side-effect of 5-FU-based chemotherapy. Coronary artery vasospasms have been postulated to be involved in the pathogenesis of this rare but serious problem. We found high plasma levels of ET-1, a potent natural vasoconstrictor, in two patients who experienced two of the commonest clinical manifestations of 5-FU-induced cardiac toxicity--i.e., angina pectoris and chronic heart failure. We, therefore, propose ET-1 as the ultimate mediator of this toxicity, even though the mechanism of ET-1 increase in peripheral venous blood is still unknown. Finally, another important question still remains unresolved: is the release of ET-1 from normal coronary endothelial cells the prime cause or simply the consequence of 5-FU-related cardiotoxicity?
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PMID:Endothelin-1 and 5-fluorouracil-induced cardiotoxicity. 968 87

The endothelin family consists of three structurally similar isopeptides: ET-1, ET-2, and ET-3. The two receptor subtypes, ETA and ETB, have different receptor affinities for the isopeptides. Stimulation of ETA and ETB receptors results in vasoconstriction, and ETB stimulation also causes vasodilation. These receptors may have profound impact on the etiologies of various diseases, including heart failure and hypertension. Studies with endothelin-receptor antagonists in animals and humans with heart failure show promising short- and long-term results. The place of the agents in the treatment of essential hypertension remains controversial, but they may have a greater role in hypertensive blacks and transplant recipients.
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PMID:The role of endothelin in heart failure and hypertension. 969 45


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