Journal of the Renin-Angiotensin-Aldosterone System最新文献

Amiloride is a potassium retaining diuretic and natriuretic which acts by reversibly blocking luminal epithelial sodium channels (ENaCs) in the late distal tubule and collecting duct. Amiloride is indicated in oedematous states, and for potassium conservation adjunctive to thiazide or loop diuretics for hypertension, congestive heart failure and hepatic cirrhosis with ascites. Historical studies on its use in hypertension were poorly controlled and there is insufficient data on dose-response. It is clearly highly effective in combination with thiazide diuretics where it counteracts the adverse metabolic effects of the thiazides and its use in the Medical Research Council Trial of Older Hypertensive Patients, demonstrated convincing outcome benefits on stroke and coronary events. Recently it has been shown to be as effective as spironolactone in resistant hypertension but there is a real need to establish its potential role in the much larger number of patients with mild to moderate hypertension in whom there is a paucity of information with amiloride particularly across an extended dose range.

Objectives: The aims of this secondary analysis were to: (a) characterize medication use following hospital discharge for patients with chronic kidney disease (CKD), and (b) investigate relationships of medication use with the primary composite outcome of acute care utilization 90 days after hospitalization.

Methods: The CKD-Medication Intervention Trial (CKD-MIT) enrolled acutely ill hospitalized patients with CKD stages 3-5 not dialyzed (CKD 3-5 ND). In this post hoc analysis, data for medication use were characterized, and the relationship of medication use with the primary outcome was evaluated using Cox proportional hazards models.

Results: Participants were taking a mean of 12.6 (standard deviation=5.1) medications, including medications from a wide variety of medication classes. Nearly half of study participants were taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB). ACE inhibitor/ARB use was associated with decreased risk of the primary outcome (hazard ratio=0.51; 95% confidence interval 0.28-0.95; p=0.03) after adjustment for baseline estimated glomerular filtration rate, age, sex, race, blood pressure, albuminuria, and potential nephrotoxin use.

Conclusions: A large number, variety, and complexity of medications were used by hospitalized patients with CKD 3-5 ND. ACE inhibitor or ARB use at hospital discharge was associated with a decreased risk of 90-day acute care utilization.

Objective: Intrarenal interferon-γ significantly contributes to the development of glomerular injury in which angiotensinogen and monocyte chemoattractant protein 1 levels are elevated. However, the exact nature of the role that interferon-γ plays in regulating angiotensinogen and monocyte chemoattractant protein 1 expression has not been fully delineated. Therefore, the aim of this study was to investigate the role that interferon-γ plays in angiotensinogen and monocyte chemoattractant protein 1 expression.

Methods: Primary cultured rat mesangial cells were treated with 0-20 ng/mL interferon-γ for 2, 8 or 24 hours. Expression levels of angiotensinogen, monocyte chemoattractant protein 1, suppressors of cytokine signaling 1, an intracellular suppressor of Janus kinase-signal transducers and activators of transcription signaling and activity of the Janus kinase-signal transducers and activators of transcription pathway were evaluated by reverse transcriptase polymerase chain reaction and western blot analysis.

Results: Interferon-γ increased angiotensinogen expression in mesangial cells with maximal augmentation observed following 5 ng/mL interferon-γ at 8 hours of treatment (1.87 ± 0.05, mRNA, relative ratio). Further increases were reduced or absent using higher concentrations of interferon-γ. Following treatments, monocyte chemoattractant protein 1 expression was induced in a linear dose-dependent manner (6.85 ± 0.62-fold by 20 ng/mL interferon-γ at 24 hours). In addition, interferon-γ induced STAT1 phosphorylation and suppressors of cytokine signaling 1 expression in a linear dose-dependent manner. The suppression of STAT1 and suppressors of cytokine signaling 1 expression by small interference RNAs facilitated an increase in interferon-γ-induced angiotensinogen expression, indicating that these two factors negatively regulate angiotensinogen expression. In contrast, the increase in interferon-γ-induced monocyte chemoattractant protein 1 expression was attenuated in STAT1-deficient mesangial cells, suggesting that STAT1 positively regulates monocyte chemoattractant protein 1 expression in mesangial cells.

Conclusion: These results demonstrate that while interferon-γ increases both angiotensinogen and monocyte chemoattractant protein 1 expression, STAT1 plays an opposing role in the regulation of each factor in mesangial cells.

Introduction: The effect of renal sympathetic denervation (RDN) on neurohormonal responses is largely unknown. We aimed to assess the effect of RDN on the renin-angiotensin-aldosterone system (RAAS) and endogenous catecholamines.

Methods: A total of 60 patients with hypertension underwent RDN and remained on a stable antihypertensive drug regimen. Samples for plasma aldosterone, plasma renin and urine (nor)metanephrine were collected at baseline and at 6 months post procedure. Ambulatory blood pressure (BP) recordings were obtained at baseline and at 6 months post procedure.

Results: Mean age was 64±9 years, and 30/60 patients were male. At 6 months, average daytime systolic and diastolic ambulatory BP decreased by 10 and 6 mmHg, respectively (p<0.001). No significant change was observed in plasma aldosterone (median=248.0 pmol/L (interquartile range (IQR) 113.3-369.5 pmol/L) vs. median=233.0 pmol/L (IQR 110.3-360.8 pmol/L); p=0.66); renin (median=19.5 µIU/mL (IQR 6.8-119.5 µIU/mL) vs. median=14.3 µIU/mL (IQR 7.2-58.0 µIU/mL); p=0.32), urine metanephrine (median=0.46 µmol/L (IQR 0.24-0.77 µmol/L) vs. median=0.46 µmol/L (IQR 0.22-0.88 µmol/L); p=0.75) and normetanephrine (median=1.41 µmol/L (IQR 0.93-2.00 µmol/L vs. median =1.56 (IQR 0.74-2.50 µmol/L); p=0.58) between baseline and 6 months, respectively. No correlation was found between the decrease in mean systolic daytime BP and changes in RAAS hormones or endogenous catecholamines.

Conclusion: Despite significant reductions in ambulatory BP, RDN did not result in a significant change in endogenous catecholamines or in RAAS hormones at 6 months.

Objective: This study was undertaken to determine whether use of the renin-angiotensin system (RAS) inhibitors would increase colorectal cancer morbidity and mortality.

Methods: Databases were electronically searched to collect data of RAS use and colorectal cancer morbidity and mortality from inception to October 2018. Stata 12.0 software was used to perform a meta-analysis.

Results: A total of 16 publications involving 2,847,597 participants were included. RAS inhibitor use was related to colorectal cancer risk (relative risk (RR): 0.86; 95% confidence interval (CI): 0.78-0.93) and mortality (RR: 0.80; 95% CI: 0.66-0.98) decrement. Subgroup analysis showed angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) (RR: 0.82; 95% CI: 0.69-0.96) or ARB (RR: 0.86; 95% CI: 0.73-0.98) or ACEI (RR: 0.81; 95% CI: 0.70-0.92) were related to colorectal cancer risk decrement. Furthermore, RAS inhibitor use was related to colorectal cancer risk decrement in Caucasians (RR: 0.88; 95% CI: 0.80-0.96) and Asians (RR: 0.72; 95% CI: 0.61-0.85). Additionally, dose-response showed that per one year duration of RAS inhibitor use incremental increase was related to 6% colorectal cancer risk decrement (RR: 0.94; 95% CI: 0.90-0.97).

Conclusion: According to the evidence, RAS inhibitor use was associated with colorectal cancer risk and mortality decrement.

Introduction: Angiotensin II (Ang II) is multifunctional peptide that plays an important role in blood pressure regulation and maintenance electrolyte homeostasis. It shows biological effects by activating two main receptors: AT₁ and AT₂. The aim of the present work was to investigate the effect of Ang II on NRK-52E cells in in vitro studies. Furthermore, an attempt was made to determine the effectiveness of the AT₁ and AT₂ receptor blocker activity (respectively, losartan and PD123319).

Methods: The study was carried out using adherent NRK-52E cell line. Immunofluorescence and Western Blot method were used to confirm the presence of AT₁ and AT₂ receptors in the cells. The SRB and MTT tests showed decrease in the viability of NRK-52E cells incubated with Ang II in comparison to the control (without Ang II).

Results: The blockade of the AT₁ receptor caused an increase in cell viability in comparison to cells incubated with Ang II only. The blockade of AT₂ receptor also triggered statistically significant increase in cell viability in comparison with cells only exposed to Ang II. Combined administration of blockers for both receptors (losartan and PD123319) decreased Ang II cytotoxicity against NRK-52E cell line. The apoptosis was only observed in cells incubated with Ang II in comparison with control cells. However, simultaneous use of both blockers caused statistically significant decrease in apoptosis.

Conclusions: The result of our study indicates that Ang II causes damaging effect on NRK-52E cells by directing them to programmed cell death. It seems that not only does the AT₂ receptor itself play an important role in the induction of apoptosis, but also its interaction with AT₁ receptor does as well.

Introduction: Prognostic benefits of zofenopril over ramipril in the early phase of acute myocardial infarction have been reported by the SMILE study, but these benefits have not been tested in clinical practice in the Chinese population. The objective of this study was to compare the effectiveness and safety of zofenopril plus aspirin against ramipril plus aspirin in patients with acute myocardial infarction.

Methods: Patients in the early phase of acute myocardial infarction received 30 mg zofenopril (ZF cohort, N=191) or 5 mg ramipril (RP cohort, N=256) b.i.d. plus 100 mg aspirin/day. Data regarding hospitalisation for cardiovascular disease, non-cardiovascular events and mortality were collected and analysed.

Results: During 1 year of treatment, 47 (25%) patients in the ZF cohort and 97 (40%) patients in the RP cohort were hospitalised due to cardiovascular disease (p=0.002), and three (2%) patients in the ZF cohort and 14 (6%) patients in the RP cohort died (p=0.043). Lower incidences of dry cough (p=0.001) and anaemia (p=0.049) were reported in the ZF cohort.

Conclusions: The study recommends zofenopril with 100 mg aspirin for a longer period in patients with acute myocardial infarction with systolic dysfunction.