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)

Long-term administration of prostacyclin (PGI2) improves the hemodynamic state, symptoms, and survival in patients with primary pulmonary hypertension, but it increases mortality in patients with heart failure despite obvious hemodynamic benefits when it is given acutely. We evaluated the mechanisms of action of PGI2 in patients with heart failure and secondary pulmonary hypertension. Nineteen patients with end-stage heart failure and pulmonary hypertension, all candidates for heart transplantation, underwent right- and left sided cardiac catheterization with micromanometer-tipped catheters and were tested for PGI2 at incremental doses. PGI2 infusion significantly improved pulmonary hemodynamics with a 47% reduction in pulmonary vascular resistance (p=0.0003) and a doubling of pulmonary artery compliance (p <0.0001), reflecting improvement in pulmonary vascular tone. The dose of PGI2 necessary to reach this hemodynamic effect correlated significantly to the baseline severity of pulmonary artery compliance (r=0.54, p=0.01). Furthermore, PGI2 produced a significant positive inotropic effect (contractile element maximum velocity increased from 1.10+/-0.09 to 1.33+/-0.13 circ/s, p <0.009). The hemodynamic effects of PGI2 infusion were independent of the plasma and urinary levels of endogen prostaglandins. Thus, PGI2 at therapeutic doses exerts a positive inotropic effect in patients with heart failure, which may explain the increased mortality rate observed with the long-term use of PGI2 in this type of patient. The spectacular acute benefits on right ventricular afterload, however, may be useful in unstable patients with heart failure and secondary pulmonary hypertension or in transplanted patients with acute right ventricular failure of the donor heart.
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PMID:Effects of prostacyclin on the pulmonary vascular tone and cardiac contractility of patients with pulmonary hypertension secondary to end-stage heart failure. 976 Oct 85

Endothelins (ETs) are 21-amino-acid peptides produced in many cells and tissues. The vascular ET system is represented mainly by ET-1 produced in endothelial cells. PreproET-1 gene expression is regulated by transactivating signals dependent on cooperative interaction of GATA-2 and AP-1 sites. ProET-1 is acted on by a furin-like enzyme to generate big ET-1, a 38-39-amino-acid peptide, which is converted to the mature 21-amino-acid peptide ET-1 by ET-converting enzyme (ECE) in endothelial cells, both intracellularly and on the cell membrane, and on the surface of underlying smooth muscle cells. The mature peptide ET-1 acts in a paracrine manner on smooth muscle cell ET(A) and ET(B) receptors to induce contraction and growth, and in an autocrine or paracrine manner on endothelial cells to induce production of the vasorelaxant and growth-inhibitory agents nitric oxide (NO) and prostacyclin. ET receptors are G-protein-coupled, resulting in activation of phospholipase C and generation of two second messengers, inositol triphosphate and diacylglycerol, which respectively stimulate calcium release and protein kinase C activation. Phospholipase D activation with generation of diacylglycerol, phospholipase A2 stimulation with release of arachidonic acid, activation of the Na+/H+ exchanger, and activation of tyrosine kinases and MAP kinases, are other pathways that contribute to contraction and growth induced by ET receptor stimulation. ET receptors may be downregulated by ET, especially under conditions in which large amounts of ET are being produced in the vasculature. This has been demonstrated in some models of experimental hypertension and in some forms of human hypertension. Some of the effects of angiotensin II, particularly growth of the smooth muscle media of blood vessels, have been shown under some conditions to be mediated by ET-1 via ET(A) receptors. Many ET-induced effects on smooth muscle cells can be blocked by ET(A)-selective ET antagonists, which makes possible an identification of the physiologic and pathophysiologic roles of the ET system in cardiovascular diseases such as hypertension, heart failure, atherosclerosis, coronary heart disease, restenosis after angioplasty, primary pulmonary hypertension, and other pathologic conditions.
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PMID:Vascular biology of endothelin. 988 41

The endothelins (ET) are potent 21-amino-acid vasoconstrictor peptides produced in many different tissues, particularly in the endothelium of blood vessels. ET-1 is the main endothelin secreted by the endothelium, and acts in a paracrine or autocrine fashion on blood vessels by interacting with ETA or ETB receptors on smooth muscle to stimulate contraction or on ETB receptors on endothelial cells to induce the release of vasorelaxants (nitric oxide and prostacyclin). Production of ET-1 is enhanced in several experimental models of hypertension in the rat, such as sodium-sensitive forms, e.g. deoxycorticosterone acetate (DOCA)-salt hypertensive, DOCA-salt-treated spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats, as well as other models such as stroke-prone SHR, angiotensin II-infused rats and fructose-fed rats, and possibly 1-K 1C Goldblatt hypertensive rats. In contrast, SHR, 2-K 1C Goldblatt hypertensive rats and nitric oxide-deficient (L-NAME-treated) hypertensive rats do not exhibit an ET-1 component. Endothelin dependency is manifested by excessive vascular growth, particularly in small arteries, and blood pressure lowering and regression of vascular growth after treatment with endothelin antagonists. The latter may be combined ETA/ETB or selective ETA antagonists, of which several are orally active and already in clinical development. In humans, endothelin-dependent vascular tone has been shown in studies of forearm blood flow. Enhanced expression of ET-1 mRNA has been demonstrated in the endothelium of small arteries of patients with moderate to severe hypertension. In a 4-week trial the combined ETA/ETB antagonist bosentan reduced the blood pressure of essential hypertensive patients equally to enalapril. Bosentan improved hemodynamics in patients with heart failure in acute and 2-week-long studies. Endothelin antagonists also offer promise in a rapidly fatal condition, primary pulmonary hypertension. Thus, the endothelin system appears to be involved in different forms of cardiovascular disease in experimental animals and humans, and its interruption offers great promise as a new therapeutic intervention in hypertension, heart failure and other diseases.
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PMID:Endothelin and endothelin antagonists in hypertension. 988 74

Amrinone-a phosphodiesterase III inhibitor-is used in the treatment of acute heart failure. In addition to its hemodynamic effects, amrinone has been shown to inhibit thromboxane synthesis in vitro. We investigated the effects of amrinone on thromboxane, prostaglandin, and leukotriene synthesis in humans. Eight healthy male volunteers took part in this single-blind study in which either amrinone (a 1.5-mg/kg bolus in 30 min and after that 10 microg/kg/min for 1 h 30 min) or placebo (0.9% NaCl) were infused. Amrinone infusion increased systolic blood pressure but had no significant effect on diastolic blood pressure or heart rate. Amrinone did not modulate thromboxane B2 synthesis stimulated by either spontaneous clotting or calcium-ionophore A23187 in whole blood. Amrinone had no effects on prostaglandin E2 or leukotriene E4 production in A23187-stimulated whole blood, nor did it affect urinary excretion of 11-dehydrothromboxane B2 or 2,3-dinor-6-keto-prostaglandin F1alpha, the index metabolites of thromboxane A2 and prostacyclin productions, respectively. We conclude that amrinone has no effects on eicosanoid production in humans at the dose level used in this study, and that the hemodynamic effects noticed are not mediated via cyclooxygenase or lipoxygenase products of arachidonic acid metabolism.
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PMID:Amrinone, a phosphodiesterase III inhibitor, and arachidonic acid metabolism in humans. 989 Apr 9

The vascular endothelium plays a key role in the local regulation of vascular tone by the release of vasodilator substances (i.e. endothelium-derived relaxing factor (EDRF = nitric oxide, NO) and prostacyclin) and vasoconstrictor substances (i.e. thromboxane A2, free radicals, or endothelin). Using either agents like acetylcholine or changes in flow to stimulate the release of EDRF (NO), clinical studies have revealed the importance of EDRF in both basal and stimulated control of vascular tone in large epicardial coronary arteries and in the coronary microcirculation. The regulatory function of the endothelium is altered by cardiovascular risk factors or disorders such as hypercholesterolemia, chronic smoking, hypertension or chronic heart failure. Endothelial dysfunction appears to have detrimental functional consequences as well as adverse longterm effects, including vascular remodelling. Endothelial dysfunction is associated with impaired tissue perfusion particularly during stress and paradoxical vasoconstriction of large conduit vessels including the coronary arteries. These effects may cause or contribute to myocardial ischemia. Several mechanisms may be involved in the development of endothelial dysfunction, such as reduced synthesis and release of EDRF or enhanced inactivation of EDRF after its release from endothelial cells by radicals or oxidized low-density lipoprotein (LDL). Increased plasma levels of oxidized LDL have been noted in chronic smokers and are related to the extent endothelial dysfunction, raising the possibility that chronic smoking potentiates endothelial dysfunction by increasing circulating and tissue levels of oxidized LDL. In heart failure, cytokines and/or reduced flow (reflecting reduced shear stress) may be involved in the development of endothelial dysfunction and can be reversed by physical training. Other mechanisms include an activated renin-angiotensin system (i.e. postmyocardial infarction) with increased breakdown of bradykinin by enhanced angiotensin converting enzyme (ACE) activity. There is evidence that endogenous bradykinin is involved in coronary vasomotor control both in coronary conduit and resistance vessels. ACE inhibitors enhance endothelial function by a bradykinin-dependent mechanism and probably also by blunting the generation of superoxide anion. Endothelial dysfunction appears to be reversible by administering L-arginine, the precursor of nitric oxide, lowering cholesterol levels, physical training, antioxidants such as vitamin C, or ACE inhibition.
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PMID:Endothelial dysfunction in human disease. 1007 15

An increased pulmonary vascular resistance (PVR) or an increased transpulmonary gradient (TPG) is a risk factor for increased 3-day and 3-month mortality after heart transplantation (HTx). The reversibility of increased PVR or TPG under pharmacologic testing is supposed to indicate a decreased probability of right ventricular failure/death after transplantation. We tested the response of an increased PVR (> 2.5 Wood units, WU) and/or of an increased TPG (> 15 mm Hg) in 29 right heart catheterizations (thermodilution catheter) of 23 patients (54 +/- 8 years, mean NYHA-class 3.1 +/- 0.6, ischemic n = 8, dilated cardiomyopathy n = 15). Increasing doses of prostaglandin I2 (PGI2, mean maximum dose 13.5 +/- 6.4 ng/kg/min) were applied stepwise over at least 10 min at the maximum dose level. We analyzed any dependence of the reversibility of PVR and TPG under prostaglandin I2 on hemodynamic values, echocardiographic parameters, demographic data, and laboratory findings. A decrease of PVR to a range usually accepted as no contraindication for HTx (< or = 4 WU) was found in each patient without symptomatic systemic hypotension during application of PGI2 (baseline value: 4.7 +/- 1.3 WU, during PGI2: 2.3 +/- 0.6 WU). An unresponsive, fixed increased PVR or TPG was not observed using PGI2. In 62% of investigations, both PVR and TPG decreased below 2.5 WU and 15 mmHg, respectively. The extent of reversibility of PVR and TPG was individually different and did not depend on the mean pulmonary artery pressure, mean capillary wedge pressure, cardiac output, mean systemic artery pressure or echocardiographic parameters (EDD, FS, ES-distance), sodium, urea or bilirubin levels, medication, age of the patients or the duration of the disease. The baseline PVR correlated inversely with its percentile value during PGI2 (r = -0.76, p < 0.05). In advanced heart failure, PGI2 decreases PVR in ranges of lower risk concerning orthotopic HTx, without causing an intolerable systemic hypotension. The individual extent of reversibility of PVR and TPG under PGI2 is not influenced by basic hemodynamic parameters or the patient's demographic profile.
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PMID:[Pharmacological testing of the reversibility of increased pulmonary vascular resistance before heart transplantation with prostaglandin I2 (prostacyclin)]. 1020 34

Primary pulmonary hypertension (PPH) is a pulmonary vascular disease characterized by an elevation in mean pulmonary artery pressure and pulmonary vascular resistance. Recently, PPH gained national attention because of its association with appetite suppressants. PPH may also be associated with pregnancy, hypothyroidism, autoimmune disorders, human immunodeficiency virus infection, and the use of drugs such as oral contraceptives and cocaine. Patients with PPH may report dyspnea on exertion and fatigue. Early diagnosis is crucial. New therapeutic regimens have dramatically reduced mortality rates and improved quality of life by halting the progression of pulmonary vascular remodeling and averting right-sided heart failure. These therapies include high-dose calcium channel antagonists, anticoagulants, and continuous intravenous prostacyclin. Lung or heart-lung transplantation remains a viable therapeutic option for patients who are treated late in the disease process, who are not responsive to medical management, or who remain symptomatic and continue to deteriorate.
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PMID:Diagnosing and treating primary pulmonary hypertension. 1050 69

Although it has been shown that long-term exercise training preserves endothelium-mediated nitric oxide vasodilator function in chronic heart failure (CHF), whether exercise training exerts similar beneficial effects on endothelial/prostaglandin-mediated vasodilator capacity in coronary circulation during the development of CHF has not been determined. Fifteen mongrel dogs were surgically instrumented for measurement of left ventricular pressure, aortic pressure, coronary blood flow and left circumflex coronary artery diameter. Dogs (n = 5) who underwent 4 weeks of cardiac pacing (210 b/min for 3 weeks and 240 b/min for the 4th week) developed CHF as characterized by significant reduction in left ventricular systolic pressure, mean arterial pressure and left ventricular dP/dt, increases in left ventricular end-diastolic pressure and heart rate, as well as clinical signs of CHF. Endothelial prostaglandin-mediated vasodilation of the epicardial coronary artery was impaired, as manifested by an attenuated arachidonic acid (AA)-induced dilation of the artery (epicardial artery diameter increased by: 0.78 +/- 0. 84% in CHF versus 4.6 +/- 0.89% in normal, P < 0.05); however, prostacyclin (PGI(2))-induced and nitroglycerin-induced vasodilation of the coronary circulation were not altered. In contrast, dogs (n = 6) with cardiac pacing plus daily exercise training (4.4 +/- 0.3 km/h, 2 h/day) only developed mild cardiac dysfunction, and the response of the epicardial coronary artery diameter to AA was preserved (epicardial artery diameter increased by 4.2 +/- 0.98% from baseline, P 0.05 compared to its respective control). Thus, long-term exercise training preserves endothelial/prostaglandin-mediated dilation of epicardial coronary artery during development of CHF.
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PMID:Chronic exercise training preserves prostaglandin-induced dilation of epicardial coronary artery during development of heart failure in awake dogs. 1075 44

The 21-amino acid peptide endothelin-1 (ET-1) is the predominant isoform of the endothelin peptide family, which includes ET-2, ET-3, and ET-4. It exerts various biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET-1 is synthesized by endothelin-converting enzymes (ECE), chymases, and non-ECE metalloproteases; it is regulated in an autocrine fashion in vascular and nonvascular cells. ET-1 acts through the activation of G(i)-protein-coupled receptors. ET(A) receptors mediate vasoconstriction and cell proliferation, whereas ET(B) receptors are important for the clearance of ET-1, endothelial cell survival, the release of nitric oxide and prostacyclin, and the inhibition of ECE-1. ET is activated in hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because increased vascular ET-1 levels occur in the absence of changes in plasma. Experimental studies using molecular and pharmacological inhibition of the ET system and the first clinical trials have demonstrated that ET-1 takes part in normal cardiovascular homeostasis. Thus, ET-1 plays a major role in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure, mainly through pressure-independent mechanisms. ET antagonists are promising new agents in the treatment of cardiovascular diseases.
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PMID:Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. 1106

Meta-analysis of previous relatively small clinical trials, comparing intravenous magnesium with placebo in acute myocardial infarction (AMI) patients, mainly without thrombolytic therapy, demonstrated that magnesium reduced in-hospital mortality by 19%, mainly by reducing the incidence of serious arrhythmias and left ventricular heart failure by one quarter. These findings have led us to hypothesize that magnesium treatment inhibits platelet-dependent thrombosis in patients with coronary artery disease (CAD). In a prospective, double blind, and crossover study, we have recently demonstrated that oral magnesium treatment inhibits thrombus formation measured by platelet-dependent thrombosis in stable CAD patients by 35%. This effect appears to be independent of platelet aggregation and activation, and is additive to that of aspirin. High dose of intravenous magnesium can inhibit thrombus formation and is associated with suppression of platelet aggregation. Magnesium treatment can dose-dependently inhibit a wide variety of agonists of platelet aggregation, such as thromboxane A2 and stimulate prostacyclin synthesis. The molecular basis for these effects is likely modulated via reduction of intracellular calcium mobilization. Hypomagnesemia also selectively impaired the release of nitric oxide from the coronary endothelium. We have recently demonstrated that oral magnesium treatment can improve endothelium-dependent vasodilation in CAD patients with optimal lipid values. Because nitric oxide is a potent endogenous vasodilator and inhibitor of platelet aggregation and adhesion, hypomagnesemia could promote vasoconstriction and coronary thrombosis in hypomagnesemic states. These findings suggest a potential mechanism whereby magnesium may beneficially alter outcomes in CAD patients.
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PMID:The role of magnesium as antithrombotic therapy. 1110 30


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