Glucocorticoids Promote Na+ Excretion in the Renal Epithelia of Heart Failure Rats by Suppressing Transporter Proteins Involved in Acute Sodium Loading.

ABSTRACT: Glucocorticoid receptors are essential for normal development and stress responses. Their role in H 2 O and Na + metabolism, especially in chronic heart failure (CHF), is not well defined. In a previous study, we found that glucocorticoids potentiate urination in CHF and promote H 2 O excretion by inhibiting the vasopressin receptor 2 pathway. The present study examines the effect of glucocorticoids on renal Na + excretion and the underlying mechanisms in CHF rats with acute sodium loading. CHF was induced by left coronary artery ligation for 8 weeks. Rats were randomly assigned to 5 groups: control, CHF, dexamethasone (DEX)-administered CHF, DEX-administered CHF treated with RU486 (mifepristone, a glucocorticoid receptor antagonist), and RU486-treated CHF. An acute sodium loading test was performed 6 hours after DEX administration. Blood and urine samples were collected, and hemodynamics were measured. The expression and localization of Na + transporter proteins were determined by immunoblotting and immunohistochemistry. DEX increased the urine volume and urinary sodium and improved cardiac function and the estimated glomerular filtration rate in CHF rats. The upregulation of the epithelial sodium channel ß and γ subunits, Na-K-2Cl cotransporter, serum glucocorticoid-regulated kinase 1 (SGK1), and Na + /K + -ATPase in the renal epithelium of CHF rats was downregulated by DEX. These beneficial effects were abolished by RU486. The expression of natriuretic peptide receptor A was opposite that of the above proteins. Glucocorticoids might induce profound natriuresis in CHF rats during acute sodium loading, which is associated with downregulating some Na + transporter proteins in the renal epithelium and improving intrarenal hemodynamics.

Endothelin receptor antagonists for pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension is a devastating disease that leads to right heart failure and premature death. Endothelin receptor antagonists have shown efficacy in the treatment of pulmonary arterial hypertension. OBJECTIVES: To evaluate the efficacy of endothelin receptor antagonists (ERAs) in pulmonary arterial hypertension. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and the reference sections of retrieved articles. The searches are current as of 4 November 2020. SELECTION CRITERIA: We included randomised trials and quasi-randomised trials involving participants with pulmonary arterial hypertension. DATA COLLECTION AND ANALYSIS: Two of five review authors selected studies, extracted data and assessed study quality according to established criteria. We used standard methods expected by Cochrane. The primary outcomes were exercise capacity (six-minute walk distance, 6MWD), World Health Organization (WHO) or New York Heart Association (NYHA) functional class, Borg dyspnoea scores and dyspnoea-fatigue ratings, and mortality. MAIN RESULTS: We included 17 randomised controlled trials involving a total of 3322 participants. Most trials were of relatively short duration (12 weeks to six months). Sixteen trials were placebo-controlled, and of these nine investigated a non-selective ERA and seven a selective ERA.   We evaluated two comparisons in the review: ERA versus placebo and ERA versus phosphodiesterase type 5 (PDE5) inhibitor. The abstract focuses on the placebo-controlled trials only and presents the pooled results of selective and non-selective ERAs. After treatment, participants receiving ERAs could probably walk on average 25.06 m (95% confidence interval (CI) 17.13 to 32.99 m; 2739 participants; 14 studies; I2 = 34%, moderate-certainty evidence) further than those receiving placebo in a 6MWD. Endothelin receptor antagonists probably improved more participants' WHO functional class (odds ratio (OR) 1.41, 95% CI 1.16 to 1.70; participants = 3060; studies = 15; I2 = 5%, moderate-certainty evidence) and probably lowered the odds of functional class deterioration (OR 0.43, 95% CI 0.26 to 0.72; participants = 2347; studies = 13; I2 = 40%, moderate-certainty evidence) compared with placebo. There may be a reduction in mortality with ERAs (OR 0.78, 95% CI 0.58, 1.07; 2889 participants; 12 studies; I2 = 0%, low-certainty evidence), and pooled data suggest that ERAs probably improve cardiopulmonary haemodynamics and may reduce Borg dyspnoea score in symptomatic patients. Hepatic toxicity was not common, but may be increased by ERA treatment from 37 to 67 (95% CI 34 to 130) per 1000 over 25 weeks of treatment (OR 1.88, 95% CI 0.91 to 3.90; moderate-certainty evidence). Although ERAs were well tolerated in this population, several cases of irreversible liver failure caused by sitaxsentan have been reported, which led the licence holder for sitaxsentan to withdraw the product from all markets worldwide.  As planned, we performed subgroup analyses comparing selective and non-selective ERAs, and with the exception of mean pulmonary artery pressure, did not detect any clear subgroup differences for any outcome. AUTHORS' CONCLUSIONS: For people with pulmonary arterial hypertension with WHO functional class II and III, endothelin receptor antagonists probably increase exercise capacity, improve WHO functional class, prevent WHO functional class deterioration, result in favourable changes in cardiopulmonary haemodynamic variables compared with placebo. However, they are less effective in reducing dyspnoea and mortality. The efficacy data were strongest in those with idiopathic pulmonary hypertension. The irreversible liver failure caused by sitaxsentan and its withdrawal from global markets emphasise the importance of hepatic monitoring in people treated with ERAs. The question of the effects of ERAs on pulmonary arterial hypertension has now likely been answered.. The combined use of ERAs and phosphodiesterase inhibitors may provide more benefit in pulmonary arterial hypertension; however, this needs to be confirmed in future studies.

Prednisone lowers serum uric acid levels in patients with decompensated heart failure by increasing renal uric acid clearance.

Clinical studies have shown that large doses of prednisone could lower serum uric acid (SUA) in patients with decompensated heart failure (HF); however, the optimal dose of prednisone and underlying mechanisms are unknown. Thirty-eight patients with decompensated HF were randomized to receive standard HF care alone (n = 10) or with low-dose (15 mg/day, n = 8), medium-dose (30 mg/day, n = 10), or high-dose prednisone (60 mg/day, n = 10), for 10 days. At the end of the study, only high-dose prednisone significantly reduced SUA, whereas low- and medium-dose prednisone and standard HF care had no effect on SUA. The reduction in SUA in high-dose prednisone groups was associated with a significant increase in renal uric acid clearance. In conclusion, prednisone can reduce SUA levels by increasing renal uric acid clearance in patients with decompensated HF.

Effect of Corticosteroid on Renal Water and Sodium Excretion in Symptomatic Heart Failure: Prednisone for Renal Function Improvement Evaluation Study.

BACKGROUND: Recent evidence indicates that prednisone can potentiate renal responsiveness to diuretics in heart failure (HF). However, the optimal dose of prednisone is not known. METHOD: Thirty-eight patients with symptomatic HF were randomized to receive standard HF care alone (n = 10) or with low-dose (15 mg/d, n = 8), medium-dose (30 mg/d, n = 10), or high-dose prednisone (60 mg/d, n = 10), for 10 days. During this time, we recorded the 24-hour urinary output and the 24-hour urinary sodium excretion, at baseline, on day 5 and day 10. We also monitored the change in the concentration of serum creatinine, angiotensin II, aldosterone, high-sensitive C-reactive protein, tumor necrosis factor-α, interleukin 1ß, and interleukin 6. RESULTS: Low-dose prednisone significantly enhanced urine output. However, the effects of medium- and high-dose prednisone on urine output were less obvious. As for renal sodium excretion, high-dose prednisone induced a more potent natriuresis than low-dose prednisone. Despite the potent diuresis and natriuresis induced by prednisone, serum creatinine, angiotensin II, and aldosterone levels were not elevated. These favorable effects were not associated with an inflammatory suppression by glucocorticoids. CONCLUSIONS: Only low-dose prednisone significantly enhanced urine output. However, high-dose prednisone induced a more potent renal sodium excretion than low-dose prednisone.

[The clinical analysis of plakophilin-2 gene mutation in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia].

OBJECTIVE: The purpose of this study was to screen genetic variations in plakophilin-2 (PKP2) gene in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) and investigate the differences in clinical features between mutation and no-mutation groups. METHODS: Thirty unrelated Chinese patients clinically diagnosed with ARVC/D and 50 healthy controls were included. Genomic DNA was isolated from peripheral blood samples. PCR and direct sequencing were used to detect variations in PKP2 gene. RESULTS: Eight PKP2 mutant variants were identified in 10 ARVC/D patients (8 men, 2 women). Among the eight mutation, three (c.2194C>T, c. 1170+ 1G>A and c. 810_813delGGTC) were novel mutation. Clinical features of the PKP2 mutation group were similar to those of the non-mutation group. CONCLUSIONS: The rate of PKP2 mutation is 33.3% (10/30) in ARVC/D patients. The penetrance of PKP2 mutation for ARVC/D tends to be higher in man patients. No significant differences could be detected in phenotype characteristics between patients with and without PKP2 mutation.

Effects of glucocorticoids in potentiating diuresis in heart failure patients with diuretic resistance.

Diuretic resistance in heart failure is defined as a state in which diuretic response is diminished or lost before the therapeutic goal of relief from congestion has been reached. Diuretic resistance is very common and is associated with poor outcomes. Over the past decade, several new drugs and devices targeting decongestion and improvement in renal function in patients with heart failure have failed to show benefit in randomized clinical trials. Glucocorticoids had been used to manage diuretic resistance before the advent of loop diuretics. More recent evidence appears to confirm that glucocorticoids may also help to overcome resistance to loop diuretics. This review tries to summarize the available evidence and potential mechanisms related to glucocorticoid therapy in patients with heart failure and its effect on diuretic resistance.

Cardiac outcome prevention effectiveness of glucocorticoids in acute decompensated heart failure: COPE-ADHF study.

INTRODUCTION: Newly emerging evidence showed that glucocorticoids could potentiate natriuretic peptides' action by increasing the density of natriuretic peptide receptor A, leading to a potent diuresis and a renal function improvement in patients with acute decompensated heart failure (ADHF). Therefore, glucocorticoid therapy may be used in patients with ADHF. METHODS: One hundred two patients with ADHF were randomized to receive glucocorticoids or standard treatment. Change from baseline in serum creatinine (SCr) at day 7 and cardiovascular death within 30 days were recorded. The study was terminated early because of slow site initiation and patient enrolment. RESULTS: Glucocorticoid therapy seemed to be well tolerated. There was a remarkable SCr reduction after 7 days treatment. The change from baseline in SCr is -0.14 mg/dL in glucocorticoid group versus -0.02 mg/dL in standard treatment group (P < 0.05). Although sample size is limited, a cardiovascular death reduction at 30 days was observed in glucocorticoid group with odds ratio of 0.26 (3 deaths in glucocorticoid vs. 10 deaths in standard treatment group, P < 0.05). The survival benefit associated with glucocorticoid therapy persisted during the follow-up. Patient-assessed dyspnea and physician-assessed global clinical status were also improved in glucocorticoid group. CONCLUSIONS: Limited data indicate that glucocorticoid therapy may be used safely in patients with ADHF in short term. Glucocorticoid therapy did not cause heart failure deterioration. Further investigations are warranted.

Endothelin receptor antagonists for pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension is a devastating disease, which leads to right heart failure and premature death. Recent evidence suggests that endothelin receptor antagonists may be promising drugs in the treatment of pulmonary arterial hypertension. OBJECTIVES: To evaluate the efficacy of endothelin receptor antagonists in pulmonary arterial hypertension. SEARCH METHODS: We searched CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE, and the reference section of retrieved articles. Searches are current as of January 2012. SELECTION CRITERIA: We included randomised trials (RCTs) and quasi-randomised trials involving patients with pulmonary arterial hypertension. DATA COLLECTION AND ANALYSIS: Five review authors independently selected studies, assessed study quality and extracted data. MAIN RESULTS: We included 12 randomised controlled trials involving 1471 patients. All the trials were of relatively short duration (12 weeks to six months). After treatment, patients treated with endothelin receptor antagonists could walk on average 33.71 metres (95% confidence interval (CI) 24.90 to 42.52 metres) further than those treated with placebo in a six-minute walk test. Endothelin receptor antagonists improved more patients' World Health Organization/New York Heart Association (WHO/NYHA) functional class status than placebo (odds ratio (OR) 1.60; 95% CI 1.20 to 2.14), and reduced the odds of functional class deterioration compared with placebo (OR 0.26; 95% CI 0.16 to 0.42). There was a reduction in mortality that did not reach statistical significance on endothelin receptor antagonists (OR 0.57; 95% CI 0.26 to 1.24), and limited data suggest that endothelin receptor antagonists improve the Borg dyspnoea score and cardiopulmonary haemodynamics in symptomatic patients. Hepatic toxicity was not common, and endothelin receptor antagonists were well tolerated in this population. However, several cases of irreversible liver failure caused by sitaxsentan have been reported that led to license holder for sitaxsentan to withdraw the product from all markets worldwide. AUTHORS' CONCLUSIONS: Endothelin receptor antagonists can increase exercise capacity, improve WHO/NYHA functional class, prevent WHO/NYHA functional class deterioration, reduce dyspnoea and improve cardiopulmonary haemodynamic variables in patients with pulmonary arterial hypertension with WHO/NYHA functional class II and III. However, there was only a trend towards endothelin receptor antagonists reducing mortality in patients with pulmonary arterial hypertension. Efficacy data are strongest in those with idiopathic pulmonary hypertension. The irreversible liver failure caused by sitaxsentan and its withdrawal from global markets emphasise the importance of hepatic monitoring in patients treated with endothelin receptor antagonists.

Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy.

Background: Dilated cardiomyopathy (DCM), a specific form of cardiomyopathy, frequently presents clinically with either left ventricular or biventricular enlargement, often leading to progressive heart failure. In recent years, the application of bioinformatics technology to scrutinize the onset, progression, and prognosis of DCM has emerged as a fervent area of interest among scholars globally. Methods: In this study, core genes closely related to DCM were identified through bioinformatics analysis, including weighted gene co expression network analysis (WGCNA) and single sample gene set enrichment analysis (ssGSEA) and so on. The correlation was verified through experiments on DCM patients, DCM rat models, and core gene knockout mice. Subsequently, the effects of glucocorticoids on DCM and the regulation of core genes were observed. Result: In the present study, natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through WGCNA and ssGSEA. Significant impairment of cardiac and renal function was observed in both DCM patients and rats, concomitant with a notable reduction in NPR1 expression. NPR1 KO mice displayed symptomatic manifestations of DCM, underscoring the pivotal role of NPR1 in its pathogenesis. Notably, glucocorticoid treatment led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression. Discussion: These findings highlight the critical involvement of NPR1 in the pathophysiology of DCM and its potential as a key target for glucocorticoid-based DCM therapy. The study provides a robust theoretical and experimental foundation for further investigations into DCM etiology and therapeutic strategies.

Glucocorticoids ameliorate cardiorenal syndrome through the NPR1/SGK1 pathway in natriuretic peptide receptor A­heterozygous mice.

Natriuretic peptides, which are produced by the heart, bind to natriuretic peptide receptor A (NPR1 encoded by natriuretic peptide receptor 1 gene) and cause vasodilation and natriuresis. Thus, they serve an important role in regulating blood pressure. In the present study, microinjection of CRISPR associated protein 9/single guide RNA into fertilized C57BL/6N mouse eggs was performed to generate filial generation zero (F0) Npr1 knockout homozygous mice (Npr1-/-). F0 mice mated with wild-type (WT) mice to obtain F1 Npr1 knockout heterozygous mice with stable heredity (Npr1+/-). F1 self-hybridization was used to expand the population of heterozygous mice (Npr1+/-). The present study performed echocardiography to investigate the impact of NPR1 gene knockdown on cardiac function. Compared with those in the WT group (C57BL/6N male mice), the left ventricular ejection fraction, myocardial contractility and renal sodium and potassium excretion and creatinine-clearance rates were decreased, indicating that Npr1 knockdown induced cardiac and renal dysfunction. In addition, expression of serum glucocorticoid-regulated kinase 1 (SGK1) increased significantly compared with that in WT mice. However, glucocorticoids (dexamethasone) upregulated NPR1 and inhibited SGK1 and alleviated cardiac and renal dysfunction caused by Npr1 gene heterozygosity. SGK1 inhibitor GSK650394 ameliorate cardiorenal syndrome by suppressing SGK1. Briefly, glucocorticoids inhibited SGK1 by upregulating NPR1, thereby ameliorating cardiorenal impairment caused by Npr1 gene heterozygosity. The present findings provided novel insight into the understanding of cardiorenal syndrome and suggested that glucocorticoids targeting the NPR1/SGK1 pathway may be a potential therapeutic target to treat cardiorenal syndrome.

Sustained-Release Ivabradine Hemisulfate in Patients With Systolic Heart Failure.

BACKGROUND: Ivabradine has potent actions in reducing heart rate and improving clinical outcomes of chronic heart failure with reduced ejection fraction (HFrEF). At present, only the short-acting formulation of ivabradine is available that needs to be administered twice daily. OBJECTIVES: This study sought to evaluate the role of ivabradine hemisulfate sustained release (SR), a novel long-acting formulation of ivabradine dosed once daily, in stable patients with HFrEF. METHODS: Patients with stabilized HFrEF in New York Heart Association functional class II-IV were enrolled and randomized to receive placebo or ivabradine SR in addition to standard medications. The primary endpoint was the change of left ventricular (LV) end-systolic volume index from baseline to week 32. RESULTS: We randomly assigned 181 patients to placebo and 179 patients to ivabradine SR. After 32 weeks, a significant improvement of LV end-systolic volume index from baseline was observed in both arms with a greater effect in the ivabradine SR arm. Ivabradine SR therapy also exhibited superiority in improving LV end-diastolic volume index, LV ejection fraction, resting heart rate, the Kansas City Cardiomyopathy Questionnaire score, and hospital admission for heart failure worsening and cardiovascular disease in comparison to placebo. Overall adverse events showed no difference between the treatment arms. There were fewer occurrences of worsening heart failure in the ivabradine SR arm. CONCLUSIONS: The present study demonstrates that ivabradine SR once daily in addition to optimum standard therapy improved heart function in patients with HFrEF. (Clinical Trial of Systolic Heart Failure Treatment of IvabRadine Hemisulfate Sustained-release Tablets [FIRST]; NCT02188082).

Glucocorticoids improve renal responsiveness to atrial natriuretic peptide by up-regulating natriuretic peptide receptor-A expression in the renal inner medullary collecting duct in decompensated heart failure.

In heart failure, the renal responsiveness to exogenous and endogenous atrial natriuretic peptide (ANP) is blunted. The mechanisms of renal hyporesponsiveness to ANP are complex, but one potential mechanism is decreased expression of natriuretic peptide receptor-A (NPR-A) in inner medullary collecting duct (IMCD) cells. Newly emerging evidence shows that glucocorticoids could produce potent diuresis and natriuresis in patients with heart failure, but the precise mechanism is unclear. In the present study, we found dexamethasone (Dex) dramatically increased the expression of NPR-A in IMCD cells in vitro. The NPR-A overexpression induced by Dex presented in a time- and dose-dependent manner, which emerged after 12 h and peaked after 48 h. The cultured IMCD cells were then stimulated with exogenous rat ANP. Consistent with the findings with NPR-A expression, Dex greatly increased cGMP (the second messenger for the ANP) generation in IMCD cells, which presented in a time- and dose-dependent manner as well. In rats with decompensated heart failure, Dex dramatically increased NPR-A expression in inner renal medulla, which was accompanied by a remarkable increase in renal cGMP generation, urine flow rate, and renal sodium excretion. It is noteworthy that Dex dramatically lowered plasma ANP, cGMP levels, and left ventricular end diastolic pressure. These favorable effects induced by Dex were glucocorticoid receptor (GR)-mediated and abolished by the GR antagonist 17ß-hydroxy-11ß-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one (RU486). Collectively, glucocorticoids could improve renal responsiveness to ANP by up-regulating NPR-A expression in the IMCD and induce a potent diuretic action in rats with decompensated heart failure.

The Impact of Glucocorticoid Therapy on Guideline-Directed Medical Treatment Titration in Patients Hospitalized for Heart Failure with Low Blood Pressure: A Retrospective Study.

BACKGROUND: Positive inotropic and renal protective actions of glucocorticoids have been observed clinically. Therefore, glucocorticoids may be used in patients with heart failure and low blood pressure (HF-LBP). METHODS: The medical records of 144 consecutive patients with HF-LBP who received glucocorticoids as an adjunctive treatment to facilitate the up-titration of ß-blocker and angiotensin-converting enzyme inhibitor were reviewed. RESULTS: After four weeks of treatment, the metoprolol and captopril (or equivalent) dosages were progressively and consistently increased from 25 (interquartile range [IQR] = 12.5-75 mg/day) to 100 mg/day (IQR = 50-178.8 mg/day) and from 0 (IQR = 0-25 mg/day) to 12.5 mg/day (IQR = 0-50 mg/day), respectively. There was a remarkable beneficial hemodynamic response to the glucocorticoid treatment signified by an increase in blood pressure and decrease in heart rate. The average heart rate decreased by 6 beat per minute (bpm) (0.5-16 bpm), and the mean arterial blood pressure increased from 74.06 ± 7.81 to 78.85 ± 7.91 mmHg. We also observed an improvement in renal function and an increased diuretic response following glucocorticoid treatment. As a result, the left ventricular ejection fraction increased from 28.92 ± 8.06% to 33.86 ± 8.76%, and the diuretic response increased from 776.7 mL/40 mg furosemide (IQR = 133.8-2000 mL) to 4000 mL/40 mg furosemide on day 28 (IQR = 2200-5925 mL). CONCLUSION: The use of glucocorticoid treatment to maintain hemodynamic and renal functional targets when titrating guideline-directed medical treatment in patients with HF-LBP may be safe, effective, and feasible.

Semi-quantification of renal perfusion using 99mTc-DTPA in systolic heart failure: a feasibility study.

BACKGROUND: Renal scintigraphy with 99mTc-diethylenetriaminepentaacetic acid (DTPA) may be used to study renal perfusion (RP) in heart failure (HF) patients. The goal of this study was to establish a new method to assess RP in patients with systolic HF. METHODS: In this retrospective, single-center, observational study, 86 subjects with left ventricular ejection fraction ≤ 45% and 31 age-matched subjects without HF underwent renal scintigraphy with 99mTc-DTPA. Patients with HF were classified into two categories according to the New York Heart Association (NYHA) functional class, i.e., moderate HF with NYHA functional class I or II and severe HF with NYHA functional class III or IV. The first-pass time-activity curve of the renal scintigraph was recorded. The GFR was determined by Gates' method. The time to peak perfusion activity (Tp), the slope of the perfusion phase (Sp), the slope of the washout phase (Sw), and glomerular filtration rate (GFR) in the study were obtained. Differences between groups were assessed by one-way analysis of variance with the Bonferroni post hoc test and rank-sum test. RESULTS: RP in HF was impaired despite comparable GFRs between the control and HF groups. RP in HF was characterized by a longer Tp and a shallower Sp and Sw. The primary parameter (Tp) was significantly prolonged in patients with HF (41.63 ± 12.22 s in severe HF vs. 26.95 ± 6.26 s in moderate HF vs. 17.84 ± 3.17 s in control, P < 0.001). At a cutoff point of 22 s, there was a high sensitivity (0.895) and specificity (0.935) in identifying patients with HF. CONCLUSIONS: Renal scintigraphy with 99mTc-DTPA may represent a new and useful method to noninvasively monitor RP abnormalities in HF.

Glucocorticoids Reverse Diluted Hyponatremia Through Inhibiting Arginine Vasopressin Pathway in Heart Failure Rats.

Background Arginine vasopressin dependent antidiuresis plays a key role in water-sodium retention in heart failure. In recent years, the role of glucocorticoids in the control of body fluid homeostasis has been extensively investigated. Glucocorticoid deficiency can activate V2R (vasopressin receptor 2), increase aquaporins expression, and result in hyponatremia, all of which can be reversed by glucocorticoid supplement. Methods and Results Heart failure was induced by coronary artery ligation for 8 weeks. A total of 32 rats were randomly assigned to 4 groups (n=8/group): sham surgery group, congestive heart failure group, dexamethasone group, and dexamethasone in combination with glucocorticoid receptor antagonist RU486 group. An acute water loading test was administered 6 hours after drug administration. Left ventricular function was measured by a pressure-volume catheter. Protein expressions were determined by immunohistochemistry and immunoblotting. The pressure-volume loop analysis showed that dexamethasone improves cardiac function in rats with heart failure. Western blotting confirmed that dexamethasone remarkably reduces the expressions of V2R, aquaporin 2, and aquaporin 3 in the renal-collecting ducts. As a result of V2R downregulation, the expressions of glucocorticoid regulated kinase 1, apical epithelial sodium channels, and the furosemide-sensitive Na-K-2Cl cotransporter were also downregulated. These favorable effects induced by dexamethasone were mostly abolished by the glucocorticoid receptor inhibitor RU486, indicating that the aforementioned effects are glucocorticoid receptor mediated. Conclusions Glucocorticoids can reverse diluted hyponatremia via inhibiting the vasopressin receptor pathway in rats with heart failure.

Endothelin receptor antagonists for pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension is a devastating disease, which leads to right heart failure and premature death. Recent evidence suggests that endothelin receptor antagonists may be promising drugs in the treatment of pulmonary arterial hypertension. OBJECTIVES: To evaluate the efficacy of endothelin receptor antagonists in pulmonary arterial hypertension. SEARCH STRATEGY: We searched CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE, and the reference section of retrieved articles. Searches are current as of Februray 2008. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-randomised controlled trials involving patients with pulmonary arterial hypertension. DATA COLLECTION AND ANALYSIS: Five review authors independently selected studies, assessed study quality and extracted data. MAIN RESULTS: Five new studies have been added to this updated review, which now includes 11 randomised controlled trials involving 1457 patients. All the trials were of relatively short duration (12 weeks to 6 months). After treatment, patients treated with endothelin receptor antagonists could walk on average 33.7 metres (95% confidence interval [CI] 24.9 to 42.5 metres) further than those treated with placebo in a 6 minute walk test. Endothelin receptor antagonists improved more patients' World Health Organization/New York Heart Association (WHO/NYHA) functional class status than placebo (odds ratio [OR] 1.6; 95% confidence interval [CI] 1.2 to 2.1), and reduced the odds of functional class deterioration compared to placebo (OR 0.26; 95% CI 0.16 to 0.42 ). There was a trend for endothelin receptor antagonists to reduce mortality (OR 0.48; 95% CI 0.21 to 1.09), and limited data suggest that endothelin receptor antagonists improve Borg dyspnoea score and cardiopulmonary haemodynamics in symptomatic patients. Hepatic toxicity was not common, and endothelin receptor antagonists were well tolerated in this population. AUTHORS' CONCLUSIONS: Endothelin receptor antagonists can increase exercise capacity, improve WHO/NYHA functional class, prevent WHO/NYHA functional class deterioration, reduce dyspnoea and improve cardiopulmonary haemodynamic variables in patients with pulmonary arterial hypertension with WHO/NYHA functional class II and III. However, there was only a trend towards endothelin receptor antagonists reducing mortality in patients with pulmonary arterial hypertension. Efficacy data are strongest in those with idiopathic pulmonary hypertension.

Potent diuretic effects of prednisone in heart failure patients with refractory diuretic resistance.

BACKGROUND: Refractory congestive heart failure (CHF) with diuretic resistance is life-threatening and predicts a short life expectancy. Glucocorticoids have been proven to have potent diuretic effects in animal studies; however, their efficacy in CHF patients with diuretic resistance is not known. METHODS: Thirteen CHF patients with significant volume overload and diuretic resistance who failed to respond to a conventional sequential nephron blockade therapeutic strategy; that is, the coadministration of a thiazide (hydrochlorothiazide) and spironolactone, in combination with loop diuretics, were studied. Prednisone (1 mg/kg daily) was then added to standard care, with other medications unchanged, to determine diuretic efficacy in these CHF patients. Variables included body weight, urine volume, serum electrolytes and renal function. RESULTS: Adding prednisone resulted in striking diuresis with a mean (+/- SD) body weight reduction of 9.39+/-3.09 kg. Prednisone significantly decreased serum creatinine by 52.21+/-48.68 mumol/L and increased glomerular filtration rate by 33.63+/-15.87 mL/min/1.73 m(2) compared with baseline. All patients were discharged from hospital with improved clinical status and renal function, and 11 patients remained alive in the long term. The main side effect of prednisone appeared to be hyperglycemia in diabetic patients. CONCLUSIONS: The present study demonstrated that prednisone can rapidly eliminate volume overload and improve clinical status and renal function in CHF patients with diuretic resistance. Further prospective randomized clinical studies are warranted to confirm its clinical efficacy.

Treatments for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a devastating disease that leads to right heart failure and premature death. Historically, we are restricted by limited options for drug treatment. Over the past decade, with advances in our understanding of pathophysiological and molecular mechanisms, many new therapeutic strategies (synthetic prostacyclin and prostacyclin analogues, endothelin receptor antagonists and sildenafil) have been developed for the treatment of PAH, and the clinical efficacy has been tested in many randomized-controlled trials (RCTs). In this overview, we review the evidence for the use of historical and new treatments that arises from the Cochrane Collaboration of Systematic Reviews and from recent RCTs.

[Effect of spironolactone on left ventricular remodeling in patients with acute myocardial infarction].

OBJECTIVE: To investigate the effect of spironolactone on left ventricular remodeling (LVRM) in patients with acute myocardial infarction. METHODS: In this multicentric, randomized, controlled study, spironolactone 40 mg/d was randomly administered in addition to the routine treatment for patients with AMI. During the 6 months the serum PIIINP, BNP and echocardiography were examined in all patients to assess myocardial fibrosis, LV function and volume. RESULTS: A total of 88 AMI patients entered the study came from 4 hospitals in Shijiazhuang. There were 43 patients with anterior MI and 45 with inferior MI. In anterior MI group 23 patients received spironolactone and 20 accepted the routine treatment. In inferior MI group 23 received spironolactone and 22 accepted the routine treatment. In anterior MI group: (1) At 3rd, 6th month PIIINP and BNP serum levels were significantly lower in the spironolactone group compared with those in control group [PIIINP (260.2 +/- 59.9) vs (328.0 +/- 70.3) ng/L, P = 0.001, (197.1 +/- 46.3) vs (266.7 +/- 52.4) ng/L, P < 0.001], [BNP (347.4 +/- 84.0) vs (430.1 +/- 62.9) ng/L, P < 0.001, (243.7 +/- 79.7) vs (334.6 +/- 62.8) ng/L, P < 0.001]; (2) There were smaller LVEDD and LVESD in spironolactone group compared with those in control group after 6 months intervention [(51.0 +/- 5.5) vs (55.6 +/- 4.5) mm, P = 0.005, (35.7 +/- 4.6) vs (39.1 +/- 5.6) mm, P = 0.046]. However, in inferior MI group: (1) There were no significant differences in PIIINP and BNP values between the two groups after 6 months intervention; (2) There were no significant differences in the LVEDD, LVESD, LVEF after 6 months treatment. CONCLUSION: (1) In patients with anterior MI, spironolactone combined with the routine treatment could inhibit myocardial fibrosis and left ventricular dilation and prevent LVRM. (2) In patients with inferior MI, no significant difference in prevention of LVRM was found between the spironolactone combined with the routine treatment and the routine treatment alone.