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Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.
© 2016 American Heart Association, Inc.
OBJECTIVE - Chronic kidney disease (CKD) amplifies atherosclerosis, which involves renin-angiotensin system (RAS) regulation of macrophages. RAS influences peroxisome proliferator-activated receptor-γ (PPARγ), a modulator of atherogenic functions of macrophages, however, little is known about its effects in CKD. We examined the impact of combined therapy with a PPARγ agonist and angiotensin receptor blocker on atherogenesis in a murine uninephrectomy model.
METHODS - Apolipoprotein E knockout mice underwent uninephrectomy (UNx) and treatment with pioglitazone (UNx + Pio), losartan (UNx + Los), or both (UNx + Pio/Los) for 10 weeks. Extent and characteristics of atherosclerotic lesions and macrophage phenotypes were assessed; RAW264.7 and primary peritoneal mouse cells were used to examine pioglitazone and losartan effects on macrophage phenotype and inflammatory response.
RESULTS - UNx significantly increased atherosclerosis. Pioglitazone and losartan each significantly reduced the atherosclerotic burden by 29.6% and 33.5%, respectively; although the benefit was dramatically augmented by combination treatment which lessened atherosclerosis by 55.7%. Assessment of plaques revealed significantly greater macrophage area in UNx + Pio/Los (80.7 ± 11.4% vs. 50.3 ± 4.2% in UNx + Pio and 57.2 ± 6.5% in UNx + Los) with more apoptotic cells. The expanded macrophage-rich lesions of UNx + Pio/Los had more alternatively activated, Ym-1 and arginine 1-positive M2 phenotypes (Ym-1: 33.6 ± 8.2%, p < 0.05 vs. 12.0 ± 1.1% in UNx; arginase 1: 27.8 ± 0.9%, p < 0.05 vs. 11.8 ± 1.3% in UNx). In vitro, pioglitazone alone and together with losartan was more effective than losartan alone in dampening lipopolysaccharide-induced cytokine production, suppressing M1 phenotypic change while enhancing M2 phenotypic change.
CONCLUSION - Combination of pioglitazone and losartan is more effective in reducing renal injury-induced atherosclerosis than either treatment alone. This benefit reflects mitigation in macrophage cytokine production, enhanced apoptosis, and a shift toward an anti-inflammatory phenotype.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Biomarkers of oxidative stress and inflammation predict cardiovascular events in maintenance hemodialysis patients. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) reduce cardiovascular mortality in the general population, but their benefit in maintenance hemodialysis patients is not fully explored. To test whether ACE inhibitors and ARBs differentially affect markers of oxidative stress, inflammation, and fibrinolysis during hemodialysis, we conducted a randomized, double-blind, placebo-controlled 3×3 crossover study. We randomly assigned 15 participants undergoing hemodialysis to placebo, ramipril (5 mg/d), and valsartan (160 mg/d) for 7 days, with a washout period of 3 weeks in between the treatments. On the morning of the seventh day of drug treatment, participants underwent serial blood sampling during hemodialysis. Neither ramipril nor valsartan affected BP during hemodialysis. Ramipril increased IL-1β concentrations (P=0.02) and decreased IL-10 concentrations (P=0.04) compared with placebo. Valsartan and ramipril both lowered IL-6 levels during dialysis (P<0.01 for each compared with placebo). Valsartan increased F(2)-isoprostane levels, and ramipril suggested a similar trend (P=0.09). Valsartan and ramipril both lowered D-dimer levels (P<0.01 for both), whereas only ramipril seemed to prevent a rise in vWf levels (P=0.04). In summary, during hemodialysis, valsartan induces a greater anti-inflammatory effect compared with ramipril, although ramipril seems to prevent dialysis-induced endothelial dysfunction as measured by levels of vWf. A prospective clinical trial is necessary to determine whether ACE inhibitors and ARBs also differ with respect to their effects on cardiovascular mortality in this population.
AIMS - The long-term cardioprotective effect of angiotensin receptor blockers (ARBs) is associated with the short-term lowering of its primary target blood pressure, but also with the lowering of albuminuria. Since the individual blood pressure and albuminuria response to an ARB varies between and within an individual, we tested whether the variability and discordance in systolic blood pressure (SBP) and albuminuria response to ARB therapy are associated with its long-term effect on cardiovascular outcomes.
METHODS AND RESULTS - The combined data of the RENAAL and IDNT trials were used. We first investigated the extent of variability and discordance in SBP and albuminuria response (baseline to 6 months). Subsequently, we assessed the combined impact of residual Month 6 SBP and albuminuria level with cardiovascular outcome. In ARB-treated patients, 421 patients (34.5%) either had a reduction in SBP but no reduction in albuminuria, or vice versa, indicating substantial discordance in response in these parameters. The initial reduction in SBP and albuminuria independently correlated with cardiovascular protection: HR per 5 mmHg SBP reduction 0.97 (95% CI 0.94-0.99) and HR per decrement log albuminuria 0.87 (95% CI 0.76-0.99). Across all SBP categories at Month 6, a progressively lower cardiovascular risk was observed with a lower albuminuria level. This was particularly evident in patients who reached the guideline recommended SBP target of ≤130 mmHg.
CONCLUSION - The SBP and albuminuria response to ARB therapy is variable and discordant. Therapies intervening in the renin-angiotensin-aldosterone system with the aim of improving cardiovascular outcomes may therefore require a dual approach targeting both blood pressure and albuminuria.
Angiotensin (Ang) II plays important roles in the development of hypertension and cardiovascular and renal injury. Pharmaceutical approaches to block its activity led to the development of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Numerous trials have documented their efficacy in controlling blood pressure, minimising left ventricular remodelling, preventing progression to heart failure, ameliorating proteinuria and retarding renal disease progression. Although they are considered safe in general, there remain concerns about the potential for adverse events in certain target populations. Recently, several novel, low molecular weight renin inhibitors without the extended peptide-like backbone of previous renin inhibitors were developed with favourable pharmacokinetic properties. They have been shown to successfully reduce Ang II levels in normal volunteers and to lower blood pressure in patients with mild-to-moderate hypertension. In this review, the authors summarise current knowledge about these renin inhibitors.
In the present study, we examined signal transduction mechanism of reactive oxygen species (ROS) production and the role of ROS in angiotensin II-induced activation of mitogen-activated protein kinases (MAPKs) in rat neonatal cardiomyocytes. Among three MAPKs, c-Jun NH(2)-terminal kinase (JNK) and p38 MAPK required ROS production for activation, as an NADPH oxidase inhibitor, diphenyleneiodonium, inhibited the activation. The angiotensin II-induced activation of JNK and p38 MAPK was also inhibited by the expression of the Galpha(12/13)-specific regulator of G protein signaling (RGS) domain, a specific inhibitor of Galpha(12/13), but not by an RGS domain specific for Galpha(q). Constitutively active Galpha(12)- or Galpha(13)-induced activation of JNK and p38 MAPK, but not extracellular signal-regulated kinase (ERK), was inhibited by diphenyleneiodonium. Angiotensin II receptor stimulation rapidly activated Galpha(13), which was completely inhibited by the Galpha(12/13)-specific RGS domain. Furthermore, the Galpha(12/13)-specific but not the Galpha(q)-specific RGS domain inhibited angiotensin II-induced ROS production. Dominant negative Rac inhibited angiotensin II-stimulated ROS production, JNK activation, and p38 MAPK activation but did not affect ERK activation. Rac activation was mediated by Rho and Rho kinase, because Rac activation was inhibited by C3 toxin and a Rho kinase inhibitor, Y27632. Furthermore, angiotensin II-induced Rho activation was inhibited by Galpha(12/13)-specific RGS domain but not dominant negative Rac. An inhibitor of epidermal growth factor receptor kinase AG1478 did not affect angiotensin II-induced JNK activation cascade. These results suggest that Galpha(12/13)-mediated ROS production through Rho and Rac is essential for JNK and p38 MAPK activation.
Aldosterone enhances angiotensin II (Ang II)-induced plasminogen activator inhibitor (PAI)-1 expression in vitro. This study tested the hypothesis that angiotensin II type 1 (AT(1)) and aldosterone receptor antagonism interact to decrease PAI-1 in humans. Effects of candesartan (16 mg/d), spironolactone (25 mg/d), or combined candesartan/spironolactone on mean arterial pressure (MAP), endocrine, and fibrinolytic variables were measured in 18 normotensive subjects [age 33.7 yr (95% confidence interval 29.3, 38.0), body mass index 26.6 (24.7, 28.4) kg/m(2)] in whom the renin-angiotensin-aldosterone system was activated by furosemide (20 mg/d). Candesartan [83.3 mm Hg (78.9, 87.7)], but not spironolactone [89.4 mm Hg (85.4, 93.5)], decreased MAP, compared with baseline [92.2 mm Hg (88.9, 95.5), P < 0.001] and furosemide alone [89.1 mm Hg (85.7, 92.4), P = 0.002]. Coadministration of spironolactone with candesartan did not further decrease MAP. Candesartan dramatically increased Ang II [177.9 pg/ml (113.3, 242.6)], compared with baseline [34.8 pg/ml (29.3, 40.4), P = 0.002] and furosemide alone [40.6 pg/ml (29.7, 51.5), P = 0.003]. Spironolactone increased Ang II [51.5 pg/ml (41.3, 61.7), P = 0.014 vs. baseline, P = 0.004 vs. candesartan]. There was no additive effect of candesartan and spironolactone on Ang II [197.6 pg/ml (134.2, 261.0)]. Aldosterone was lower during candesartan [8.9 ng/dl (7.3, 10.6), P = 0.007] than during furosemide alone [14.1 ng/dl (10.9, 17.3), P = 0.007], spironolactone [18.7 ng/dl (14.5, 22.9), P = 0.002], or combined candesartan/spironolactone [13.9 ng/dl (11.8, 15.9), P = 0.006]. Furosemide increased PAI-1 antigen [27.8 ng/ml (20.6, 35.0), P = 0.002 vs. 19.3 ng/ml (13.4, 25.2) baseline], even in the presence of candesartan [27.2 ng/ml (16.5, 37.8), P = 0.042 vs. baseline] or spironolactone [27.3 ng/ml (17.9, 36.8), P = 0.015 vs. baseline]. However, coadministration of AT(1) and aldosterone receptor antagonists prevented the furosemide-induced increase in PAI-1 [19.2 ng/ml (9.8, 28.6), P = 0.974 vs. baseline, P < 0.05 vs. candesartan, spironolactone or furosemide alone]. This study evidences an interactive effect of endogenous Ang II and aldosterone on PAI-1 production in humans.
ACE inhibition reduces plasminogen activator inhibitor-1 (PAI-1), a risk factor for myocardial infarction, whereas the effect of angiotensin receptor antagonism on PAI-1 is uncertain. The present study compares the time course of effects of ACE inhibition and angiotensin type 1 (AT1) receptor antagonism on morning plasma PAI-1 antigen. Blood pressure and endocrine, metabolic, and fibrinolytic variables were measured in 20 insulin-resistant (defined by fasting glucose >8.3 mmol/L, body mass index >28 kg/m2, or fasting serum triglyceride > or =2.8 mmol/L) hypertensive subjects (mean age, 47.9+/-2.1 years) (1) before and after 1 week of hydrochlorothiazide 12.5 mg/d, and (2) before and 1, 3, 4, and 6 weeks after addition of ramipril (escalated to 10 mg/d) or losartan (escalated to 100 mg/d). Hydrochlorothiazide decreased systolic (P=0.011) and diastolic (P=0.019) pressure. Ramipril (from 133.6+/-5.1/94.5+/-2.4 to 127.0+/-3.1/91.4+/-3.3 mm Hg) or losartan (from 137.0+/-3.9/93.1+/-2.9 to 123.7+/-2.6/86.4+/-2.1 mm Hg) further reduced systolic (P=0.009) and diastolic (P=0.037) pressure. The pressure effects of the 2 drugs were similar. Hydrochlorothiazide increased plasma PAI-1 (P=0.013) but not tissue-type plasminogen activator (tPA) (P=0.431) antigen. Addition of either ramipril or losartan significantly decreased plasma PAI-1 antigen (P=0.046). However, the effect of losartan on PAI-1 antigen was not sustained throughout the 6-week treatment period, such that there was a significant drugxtime interaction (P=0.043). tPA antigen decreased during either ramipril or losartan (P=0.032), but tPA activity decreased only during losartan (P=0.018). Short-term interruption of the renin-angiotensin-aldosterone system by either ACE inhibition or AT1 receptor antagonism decreases PAI-1 antigen, but the duration of this effect is greater for ACE inhibition than for AT1 receptor antagonism.
BACKGROUND - Glomerular and vascular sclerosis increase with aging, and angiotensin inhibitors ameliorate progression of this injury. We investigated the potential for achieving regression of existing age-related sclerosis, and the mechanisms by which angiotensin type 1 receptor antagonist (AIIRA) may affect remodeling of this sclerosis. We focused on plasminogen activator inhibitor-1 (PAI-1) because it is directly induced by angiotensin, inhibits matrix degradation, and may thus be pivotal in remodeling.
METHODS - Eighteen-month-old male Sprague-Dawley rats were treated with the AIIRA losartan (N = 8, 80 mg/L, dry weight), sacrificed at age 21 and 24 months, and compared with age-matched untreated controls (N = 15). Blood pressure and renal function were monitored, and morphological, biochemical, and molecular analyses were done on aorta and kidney.
RESULTS - Body weight increased in both groups. Mean arterial pressure (MAP) and serum creatinine remained normal (24-month MAP 115 +/- 8 vs. 113 +/- 6 mm Hg, controls vs. AIIRA, P = NS). Aorta wall thickness ratio was reduced by AIIRA at 21 and 24 months vs. age-matched controls (21 months 0. 12 +/- 0.01 vs. 0.15 +/- 0.01, P = 0.006; 24 months 0.10 +/- 0.005 vs. 0.14 +/- 0.003, AIIRA vs. controls, respectively, P = 0.0027). The aorta wall thickness ratio after treatment with AIIRA for six months was even lower than that of 18-month control rats (P = 0.018). AIIRA reduced proteinuria versus age-matched control at 24 months (253 +/- 62 vs. 390 +/- 51 mg/24 h, P = 0.0017). AIIRA at 24 months decreased glomerulosclerosis versus age-matched control (sclerosis index, 0 to 4+ scale: 0.06 +/- 0.02 vs. 0.49 +/- 0.12, P = 0.0082) to levels even lower than the 18-month baseline (0.37 +/- 0.14, P = 0.014). Renal collagen content increased with aging and was decreased by AIIRA at 24 months (5.0 +/- 0.7 vs. 3.1 +/- 0.5% collagen, P < 0.05). Apoptosis, assessed by TUNEL, was increased in tubular and interstitial cells in aging and was reduced by AIIRA versus control and baseline, respectively (TUNEL scoring, AIIRA 24 months 0.33 +/- 0.16 vs. 1.06 +/- 0.23 and 0.80 +/- 0.05, P < 0.05). PAI-1 mRNA in kidney was decreased at 24 months in AIIRA versus age-matched controls (PAI-1/GAPDH density ratio: AIIRA 24 months 0. 34 +/- 0.05 vs. 24-month controls 0.99 +/- 0.05, P < 0.05). Increased glomerular PAI-1 immunostaining with aging was decreased by AIIRA at 24 months versus age-matched controls, even below baseline (staining score 0 to 4+, 0.57 +/- 0.15 vs. control 0.90 +/- 0.07, P < 0.05; baseline 1.05 +/- 0.02, P < 0.01).
CONCLUSION - We conclude that AIIRA not only slows the progression of glomerular and vascular sclerosis in aging, but can also induce regression of these processes. The mechanisms appear to involve modulation of cortical cell turnover and inhibition of PAI-1 expression.