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

The pathogenesis of preeclampsia stems from aberrant changes at the placental interface. The trophoblastic endovascular invasion of tonic spiral arteries that converts them to passive conduits falters. Uteroplacental insufficiency and fetoplacental hypoxemia result. Secondary maternal oxidative stress and an excessive inflammatory response to pregnancy generate the clinical syndrome of preeclampsia. Current treatment focuses on preventing seizures, controlling hypertension, preserving renal function and delivering the baby. We propose that the pathophysiological changes induced by preeclampsia in the placenta parallel those caused by persistent hypoxemia in the lungs at high altitude or with chronic obstructive pulmonary disease. Unrelenting pulmonary hypoxic vasoconstriction induces pulmonary hypertension and cor pulmonale. Inhalation of nitric oxide and phosphodiesterase-5 inhibitors opposes pulmonary hypoxic vasoconstriction, alleviates pulmonary hypertension and improves systemic oxygenation. Notably nitric oxide donor therapy also counters hypoxemic fetoplacental vasoconstriction, a biological response analogous to pulmonary hypoxic vasoconstriction. Fetal oxygenation and nutrition improve. Placental upstream resistance to umbilical arterial blood flow decreases. Fetal right ventricular impedance falls. Heart failure (cor placentale) is avoided. Emergency preterm delivery can be postponed. Other than low dose aspirin and antioxidants vitamins C and E no available therapy specifically targets the underlying disease profile. We hypothesize that, like nitric oxide donation, pharmacological inhibition of placental phosphodiesterase-5 will also protect the fetus but for a longer time. Biological availability of guanosine 3'5'-cyclic monophosphate is boosted due to slowed hydrolysis. Adenosine 3'5'-cyclic monphosphate levels increase in parallel. Cyclic nucleotide accumulation dilates intact tonic spiral arteries and counters hypoxemic fetoplacental vasoconstriction. Intervillous and intravillous perfusion pick up. Maternal to fetal placental circulatory matching improves. Enhanced placental oxygen uptake alleviates hypoxemic fetal stress. Appropriate fetal nutrition resumes. Cor placentale and severe intrauterine growth restriction are averted. Increased maternal cyclic nucleotide concentrations promote systemic vasodilatation so that blood pressures fall. Preemption of oxidative stress initiated by "consumptive" oxidation of nitric oxide stabilizes the vascular endothelium and corrects coagulopathy. Anti-inflammatory and immunosuppressant adenosine 3'5'-cyclic monphosphate offsets the extreme gestational inflammatory response. Cellular injury and multi-organ damage are prevented. One tablet a day of the new long acting phosphodiesterase-5 inhibitor, tadalafil (half life of 17.5 h) theoretically should allow a preterm pregnancy affected by preeclampsia to continue safely. Selective monitoring of vital organ functions guards against life-threatening maternal complications. Regular biophysical profiling warns the obstetrician of impending fetal compromise. Fetal growth and vital organ maturation can continue. As a result workloads imposed upon neonatal intensivists will lighten. Parental anxiety and concern will be allayed. The cost of treating preeclamptic mothers and their extremely low birth weight infants will decrease. Money saved by midwifery services in poorer states can be used to pay for better prenatal care. Severe preeclampsia/eclampsia will be less common. Maternal and perinatal morbidity and mortality will be reduced. Because the human immunodeficiency virus often infects individuals at a workforce eligible age, the global acquired immunodeficiency syndrome pandemic has already brought many nations to the brink of economic ruin. Potentially productive lives saved for the future will help restore them fiscally.
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PMID:Hypothesis: selective phosphodiesterase-5 inhibition improves outcome in preeclampsia. 1550 76

We review the diuretics regarding the mechanism of action, way of clinical use and their adverse effects. Recent progress of molecular biology revealed the molecular target of diuretics and thereby, the molecular mechanism of diuretic action became clear to understand. Loop diuretics and thiazides are the most widely used diuretics and the physiologic adaptation to their prolonged use are mentioned. Carbonic anhydrase inhibitors are not used as diuretics but for correction of metabolic alkalosis and treatment of glaucoma. Potassium-sparing diuretics have modest natriuresis but the combination with loop diuretics or thiazides results in strong natriuresis. Adenosine type 1 receptor antagonist has been developed for treatment of edema in chronic heart failure. Vasopressin type 2 receptor antagonists are developed for a new type of diuretics to increase the free water clearance in cases of chronic heart failure and SIADH. The recombinant atrial natriuretic polypeptide is recently used as diuretics in acute heart failure. Knowledge of pharmacological action of diuretics could help the appropriately clinical use of diuretics, in particular the diuretics-resistant edema.
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PMID:[Diuretics; their characteristics and future development]. 1567 32

Adenosine (Ado) triggers several protective mechanisms that may attenuate development of heart failure, both locally and systemically. We developed a procedure allowing sustained increase in endogenous Ado production by the combined application of Ado metabolism inhibitors and nucleotide precursors. We found that our procedure attenuate the development of heart failure induced by adriamycin.
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PMID:Prevention of adriamycin induced heart failure by an increase in endogenous adenosine production. 1602 13

While pharmaceutical innovation has been highly successful in reducing mortality in chronic heart failure, this has not been matched by similar success in decompensated heart failure syndromes. Despite outstanding issues over definitions and end points, we argue in this paper that an unprecedented wealth of pharmacologic innovation may soon transform the management of these challenging patients. Agents that target contractility, such as cardiac myosin activators and novel adenosine triphosphate-dependent transmembrane sodium-potassium pump inhibitors, provide inotropic support without arrhythmogenic increases in cytosolic calcium or side effects of more traditional agents. Adenosine receptor blockade may improve glomerular filtration and diuresis by exerting a direct beneficial effect on glomerular blood flow while vasopressin antagonists promote free water excretion without compromising renal function and may simultaneously inhibit myocardial remodeling. Urodilatin, the renally synthesized isoform of atrial natriuretic peptide, may improve pulmonary congestion via vasodilation and enhanced diuresis. Finally, metabolic modulators such as perhexiline may optimize myocardial energy utilization by shifting adenosine triphosphate production from free fatty acids to glucose, a unique and conceptually appealing approach to the management of heart failure. These advances allow optimism not only for the advancement of our understanding and management of decompensated heart failure syndromes but for the translational research effort in heart failure biology in general.
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PMID:Emerging therapies for the management of decompensated heart failure: from bench to bedside. 1717 76

The adversarial relationship between the heart and the kidney in heart failure results from normal homeostatic mechanisms which become inappropriate in the setting of heart failure. The cardio-renal syndrome represents the sum total of this adversarial relation and is clinically manifest as worsening renal function limiting diuresis in spite of volume overload. Tubuloglomerular feedback is a major pathophysiologic component of this syndrome. Adenosine, acting via A1 receptors, plays a major role in tubuloglomerular feedback in the normal state and in cardio-renal syndrome. Preclinical studies and initial human studies suggest that adenosine antagonism increases diuresis and preserves glomerular filtration in the setting of decompensated heart failure. Considering the ubiquitous distribution of adenosine receptors in the body, it is crucial to tailor this therapeutic agent to avoid side effects, especially neurotoxicity. Larger studies are presently underway to understand the therapeutic potential of this novel class of agents.
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PMID:Role of adenosine antagonism in the cardio-renal syndrome: pathophysiology and therapeutic potential. 1788 91

Adenosine is well known to be a cardioprotective substance in ischemic heart disease. However, the modulation of adenosine receptors and the production and degradation of endogenous adenosine in chronic heart failure (CHF) are not fully understood. We analyzed the gene expression patterns of adenosine-related genes in human failing and nonfailing myocardium using DNA microarray analysis and quantitative real time-polymerase chain reaction (RT-PCR). DNA microarray analysis revealed that the gene expression of adenosine A2a, A2b, and A3 receptors (A2aR, A2bR, and A3R) as well as that of adenosine deaminase (ADA) decreased in failing myocardium. The down-regulation of these genes was verified by quantitative RT-PCR. We also measured the activities of these adenosine metabolism-related enzymes in failing myocardium and cardiac adenosine levels in patients with CHF. In CHF patients, we observed the decreased enzyme activity of ADA and the elevation of cardiac adenosine levels in CHF patients. To enhance the signaling of adenosine receptors, we increased plasma adenosine levels using dipyridamole, which decreased the severity of CHF. The gene expression of A2aR, A2bR, A3R, and ADA was decreased in the failing hearts, and this decrease may impair adenosine-related signal transduction. The activities of adenosine-related enzymes were altered, thus increasing the myocardial adenosine levels; this increase may compensate for the impairment of adenosine-related signal transduction in patients with CHF. The impairment of adenosine-related signal transmission contributes to the pathophysiology of CHF.
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PMID:Impact of adenosine receptor signaling and metabolism on pathophysiology in patients with chronic heart failure. 1803 66

Adenosine is known as an endogenous cardioprotectant. We previously reported that plasma adenosine levels increase in patients with chronic heart failure (CHF), and that a treatment that further elevates plasma adenosine levels may improve the pathophysiology of CHF. Therefore, we performed a prospective, open-randomized clinical trial to determine whether or not exposure to dipyridamole for 1 year improves CHF pathophysiology compared with conventional treatments. The study enrolled 28 patients (mean+/-SEM: 66+/-4 years of age) attending specialized CHF outpatient clinics with New York Heart Association (NYHA) class II or III, no major complications, and stable CHF status during the most recent 6 months under fixed medications. They were randomized into three groups with or without dipyridamole (Control: n=9; 75 mg/day: n=9; 300 mg/day: n=10) in addition to their original medications and were followed up for 1 year. The other drugs were not altered. Among the enrolled patients, 100%, 4%, 100%, and 79% received angiotensin-converting enzyme inhibitors, aldosterone analogue, loop diuretics, and beta-adrenoceptor blocker, respectively. Fifteen patients suffered from dilated cardiomyopathy, and 7/3/3 patients suffered from ischemic/valvular/hypertensive heart diseases, respectively. Mean blood pressure was comparable among the groups. While the baseline conditions were comparable, we found that echocardiographic ejection fraction (p<0.01 vs. baseline, p<0.01 vs. Control), left ventricular systolic diameter (p<0.05, p<0.05), Specific Activity Scale (SAS) score (p<0.05, p<0.01), maximal oxygen consumption (p<0.05, p<0.05) and plasma B-type natriuretic peptide level (p<0.01, p<0.01) were significantly improved in patients with dipyridamole after 1 year, generally in a dose-dependent manner. Therefore, we suggest that an additional administration of dipyridamole further improves CHF pathophysiology.
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PMID:Long-term oral administration of dipyridamole improves both cardiac and physical status in patients with mild to moderate chronic heart failure: a prospective open-randomized study. 1804 22

Adenosine A1 antagonists are being developed for the treatment of renal dysfunction in patients with congestive heart failure. After early small studies prompted hope that these agents could increase urine output without worsening the glomerular filtration rate, larger studies published and presented in 2007 confirmed their beneficial impact on weight and renal function. However, in many studies the renal benefits disappear with higher doses, suggesting that specificity may be lost with higher doses of these drugs. Investigations in animals indicate that there may also be direct benefits on the myocardium and in the lung. Although studies have not shown adverse effects at optimal dosing, the widespread actions of adenosine mandate that safety be established. Ongoing studies should be able to demonstrate whether adenosine A1 antagonists can be used to improve renal function without adversely affecting patients with heart failure.
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PMID:Adenosine A1 antagonists and the cardiorenal syndrome. 1876 81

Mitochondrial dysfunction is implicated in the pathogenesis of diabetic cardiomyopathy, a common complication of diabetes. Adenosine nucleotide translocase (ANT) translocates ADP/ATP across the inner mitochondrial membrane. Our study aimed to test the hypothesis that overexpression of ANT1 in cardiomyocytes has cardioprotective effects in diabetic cardiomyopathy induced by streptozotocin (STZ). Mice specifically overexpressing murine ANT1 in the heart were generated using alpha-myosin heavy chain promoter. Expression of ANT1 mRNA and protein in hearts was characterized by real-time polymerase chain reaction and Western blot analysis. Five- to 6-month-old male transgenic mice and their age-matched wild-type littermates were subjected to type 1 diabetes induced by STZ. Six weeks later, haemodynamic measurement was performed to assess cardiac function. Ventricular mRNA expression of atrial natriuretic peptide, a molecular marker of heart failure, was characterized by RNase-protection assay. Both ANT1 mRNA and ANT1 protein were specifically overexpressed in the heart of transgenic mice. Heart weight was decreased and cardiac function was dramatically impaired in wild-type mice 6 weeks after induction of diabetes, but ANT1 overexpression prevented these significant changes. The mRNA expression level of atrial natriuretic peptide confirmed the haemodynamic findings, being upregulated in wild-type mice receiving STZ, but showing no statistical differences in ANT1 transgenic mice. Cardiomyocyte-restricted overexpression of ANT1 prevents the development of diabetic cardiomyopathy; therefore, accelerated ADP/ATP exchange could be a new promising target to treat diabetic cardiomyopathy.
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PMID:Myocardial overexpression of adenine nucleotide translocase 1 ameliorates diabetic cardiomyopathy in mice. 1894 56

Adenosine has been shown to exert direct antihypertrophic effects on the heart, and plasma adenosine levels have been shown to be elevated in patients with heart failure. It has therefore been proposed that endogenously synthesized adenosine may function as a cardiac antihypertrophic factor. The present study was aimed to determine whether the adenosine system is altered in a potential adaptive manner following phenylephrine-induced hypertrophy in cultured neonatal rat ventricular myocytes. Phenylephrine produced significant hypertrophy as determined by cell size and atrial natriuretic peptide gene expression, which was accompanied by significantly increased gene and protein expression of adenosine A(1), A(2a), and A(3) receptors. These effects and the hypertrophic response were prevented by the alpha(1)-adrenoceptor antagonist prazosin as well as pharmacological agonists for all adenosine receptor subtypes. The upregulation of adenosine receptors by phenylephrine was also abrogated by adenosine 5'-(alpha,beta-methylene)diphosphate, an inhibitor of ectosolic 5'-nucleotidase. Moreover, phenylephrine significantly increased production of adenosine from myocytes in the presence of a nucleoside transport and adenosine deaminase inhibitor, the combination of which abrogated the hypertrophic effect of phenylephrine. The latter effect was reversed by adenosine receptor antagonists. Phenylephrine also produced a significant upregulation in expression levels of equilibrative nucleoside transporter 1 although expression levels of equilibrative nucleoside transporter 2 were unaffected. Taken together, our results suggest an adaptive upregulation of the adenosine system to phenylephrine-induced cardiomyocyte hypertrophy that serves to limit the hypertrophic effect of alpha(1-)adrenoceptor activation.
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PMID:Compensatory upregulation of the adenosine system following phenylephrine-induced hypertrophy in cultured rat ventricular myocytes. 1996 59


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