Slowing the Progression of Diabetic Kidney Disease.

Diabetes is the most frequent cause of kidney disease that progresses to end-stage renal disease worldwide, and diabetic kidney disease is significantly related to unfavorable cardiovascular outcomes. Since the 1990s, specific therapies have emerged and been approved to slow the progression of diabetic kidney disease, namely, renin-angiotensin-aldosterone system blockers (including angiotensin-converting enzyme inhibitors (ACEi) angiotensin receptor blockers (ARBs), the non-steroidal mineralocorticoid receptor antagonist (NS-MRA), finerenone, and sodium-glucose cotransporter-2 (SGLT2) inhibitors). Mechanistically, these different classes of agents bring different anti-inflammatory, anti-fibrotic, and complementary hemodynamic effects to patients with diabetic kidney disease such that they have additive benefits on slowing disease progression. Within the coming year, there will be data on renal outcomes using the glucagon-like peptide-1 receptor agonist, semaglutide. All the aforementioned medications have also been shown to improve cardiovascular outcomes. Thus, all three classes (maximally dosed ACEi or ARB, low-dose SGLT-2 inhibitors, and the NS-MRA, finerenone) form the "pillars of therapy" such that, when used together, they maximally slow diabetic kidney disease progression. Ongoing studies aim to expand these pillars with additional medications to potentially normalize the decline in kidney function and reduce associated cardiovascular mortality.

Effects of sacubitril/valsartan on exercise capacity: a prognostic improvement that starts during uptitration.

PURPOSE: Sacubitril/valsartan is a mainstay of the treatment of heart failure with reduced ejection fraction (HFrEF); however, its effects on exercise performance yielded conflicting results. Aim of our study was to evaluate the impact of sacubitril/valsartan on exercise parameters and echocardiographic and biomarker changes at different drug doses. METHODS: We prospectively enrolled consecutive HFrEF outpatients eligible to start sacubitril/valsartan. Patients underwent clinical assessment, cardiopulmonary exercise test (CPET), blood sampling, echocardiography, and completed the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Sacubitril/valsartan was introduced at 24/26 mg b.i.d. dose and progressively uptitrated in a standard monthly-based fashion to 97/103 mg b.i.d. or maximum tolerated dose. Study procedures were repeated at each titration visit and 6 months after reaching the maximum tolerated dose. RESULTS: Ninety-six patients completed the study, 73 (75%) reached maximum sacubitril/valsartan dose. We observed a significant improvement in functional capacity across all study steps: oxygen intake increased, at peak exercise (from 15.6 ± 4.5 to 16.5 ± 4.9 mL/min/kg; p trend = 0.001), while minute ventilation/carbon dioxide production relationship reduced in patients with an abnormal value at baseline. Sacubitril/valsartan induced positive left ventricle reverse remodeling (EF from 31 ± 5 to 37 ± 8%; p trend < 0.001), while NT-proBNP reduced from 1179 [610-2757] to 780 [372-1344] pg/ml (p trend < 0.0001). NYHA functional class and the subjective perception of limitation in daily life at KCCQ-12 significantly improved. The Metabolic Exercise Cardiac Kidney Index (MECKI) score progressively improved from 4.35 [2.42-7.71] to 2.35% [1.24-4.96], p = 0.003. CONCLUSIONS: A holistic and progressive HF improvement was observed with sacubitril/valsartan in parallel with quality of life. Likewise, a prognostic enhancement was observed.

Latest Knowledge on the Role of Vitamin D in Hypertension.

Hypertension is the third leading cause of the global disease burden, and while populations live longer, adopt more sedentary lifestyles, and become less economically concerned, the prevalence of hypertension is expected to increase. Pathologically elevated blood pressure (BP) is the strongest risk factor for cardiovascular disease (CVD) and related disability, thus making it imperative to treat this disease. Effective standard pharmacological treatments, i.e., diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blocker (ARBs), beta-adrenergic receptor blockers (BARBs), and calcium channel blockers (CCBs), are available. Vitamin D (vitD) is known best for its role in bone and mineral homeostasis. Studies with vitamin D receptor (VDR) knockout mice show an increased renin-angiotensin-aldosterone system (RAAS) activity and increased hypertension, suggesting a key role for vitD as a potential antihypertensive agent. Similar studies in humans displayed ambiguous and mixed results. No direct antihypertensive effect was shown, nor a significant impact on the human RAAS. Interestingly, human studies supplementing vitD with other antihypertensive agents reported more promising results. VitD is considered a safe supplement, proposing its great potential as antihypertensive supplement. The aim of this review is to examine the current knowledge about vitD and its role in the treatment of hypertension.

Holistic approach to drug therapy in a patient with heart failure.

Heart failure (HF) is a growing global public health problem affecting at least 26 million people worldwide. The evidence-based landscape for HF treatment has changed at a rapid rate over the last 30 years. International guidelines for the management of HF now recommend the use of four pillars in all patients with reduced ejection fraction: angiotensin receptor neprilysin inhibitors or ACE inhibitors, beta blockers, mineralocorticoid receptor antagonists and sodium-glucose co-transporter-2 inhibitors. Beyond the main four pillar therapies, numerous further pharmacological treatments are also available in specific patient subtypes. These armouries of drug therapy are impressive, but where does this leave us with individualised and patient-centred care? This paper reviews the common considerations needed to provide a holistic, tailored and individual approach to drug therapy in a patient with HF with reduced ejection fraction, including shared decision making, initiating and sequencing of HF pharmacotherapy, drug-related considerations, polypharmacy and adherence.

Nonsteroidal anti-inflammatory drug diclofenac accelerates the emergence of antibiotic resistance via mutagenesis.

Overuse of antimicrobial agents are generally considered to be a key factor in the occurrence of antibiotic resistance bacteria (ARB). Nevertheless, it is unclear whether ARB can be induced by non-antibiotic chemicals such as nonsteroidal anti-inflammatory drug (NSAID). Thus, the objective of this study is to investigate whether NSAID diclofenac (DCF) promote the emergence of antibiotic resistance in Escherichia coli K12 MG1655. Our results suggested that DCF induced the occurrence of ARB which showed hereditary stability of resistance. Meanwhile, gene variation was identified on chromosome of the ARB, and DCF can cause bacterial oxidative stress and SOS response. Subsequently, transcriptional levels of antioxidant (soxS, sodA, sodC, gor, katG, ahpF) and SOS (recA, lexA, uvrA, uvrB, ruvA, ruvB, dinB, umuC, polB) system-related genes were enhanced. However, the expression of related genes cannot be increased in high-dosage treatment compared with low-dosage samples because of cytotoxicity and cellular damage. Simultaneously, high-dosage DCF decreased the mutation frequency but enhanced the resistance of mutants. Our findings expand our knowledge of the promoting effect on the emergence of ARB caused by DCF. More attention and regulations should be given to these potential ecological and health risks for widespread DCF.

Effects of Melaleuca alternifolia Chell (Tea Tree) and Eucalyptus globulus Labill. Essential Oils on Antibiotic-Resistant Bacterial Biofilms.

In the present investigation, the anti-biofilm potential of two essential oils (EOs), Melaleuca alternifolia Chell (Tea-Tree) (TTO) and Eucalyptus globulus Labill. (EEO) was characterized and tested "in vitro" against both mature biofilms and biofilms in the process of formation, produced by strains belonging to three main categories of antibiotic resistant bacteria (ARB): Vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA) and broad-spectrum ß-lactamase-producing Escherichia coli (ESBL). The study was carried out in 96-well microtiter-plates using EOs alone, in association with each other and in combination with antibiotics against both single and multi-species biofilm. The study demonstrated the ability of TTO and EEO to counteract the ARB strains in sessile form, with promising results in particular against the biofilm in formation. Mature biofilm by ESBL E. coli was the most sensitive in the results from the quantification study of viable cells performed in multi-species biofilms. Lastly, in all tests, carried out using TTO/EEO associations and EOs/antibiotic combinations, the synergistic effect which emerged from the FIC-index has been confirmed, and both the reduction of biofilm in formation, and the removal of mature structure was obtained at very low concentrations, with values from 4 to >512-fold lower than the minimum inhibitory concentration (MIC) of the single compounds.

Treatment of Hypertension: A Review.

Importance: Hypertension, defined as persistent systolic blood pressure (SBP) at least 130 mm Hg or diastolic BP (DBP) at least 80 mm Hg, affects approximately 116 million adults in the US and more than 1 billion adults worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (coronary heart disease, heart failure, and stroke) and death. Observations: First-line therapy for hypertension is lifestyle modification, including weight loss, healthy dietary pattern that includes low sodium and high potassium intake, physical activity, and moderation or elimination of alcohol consumption. The BP-lowering effects of individual lifestyle components are partially additive and enhance the efficacy of pharmacologic therapy. The decision to initiate antihypertensive medication should be based on the level of BP and the presence of high atherosclerotic CVD risk. First-line drug therapy for hypertension consists of a thiazide or thiazidelike diuretic such as hydrochlorothiazide or chlorthalidone, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker such as enalapril or candesartan, and a calcium channel blocker such as amlodipine and should be titrated according to office and home SBP/DBP levels to achieve in most people an SBP/DBP target (<130/80 mm Hg for adults <65 years and SBP <130 mm Hg in adults ≥65 years). Randomized clinical trials have established the efficacy of BP lowering to reduce the risk of CVD morbidity and mortality. An SBP reduction of 10 mm Hg decreases risk of CVD events by approximately 20% to 30%. Despite the benefits of BP control, only 44% of US adults with hypertension have their SBP/DBP controlled to less than 140/90 mm Hg. Conclusions and Relevance: Hypertension affects approximately 116 million adults in the US and more than 1 billion adults worldwide and is a leading cause of CVD morbidity and mortality. First-line therapy for hypertension is lifestyle modification, consisting of weight loss, dietary sodium reduction and potassium supplementation, healthy dietary pattern, physical activity, and limited alcohol consumption. When drug therapy is required, first-line therapies are thiazide or thiazidelike diuretics, angiotensin-converting enzyme inhibitor or angiotensin receptor blockers, and calcium channel blockers.

Actions of Novel Angiotensin Receptor Blocking Drugs, Bisartans, Relevant for COVID-19 Therapy: Biased Agonism at Angiotensin Receptors and the Beneficial Effects of Neprilysin in the Renin Angiotensin System.

Angiotensin receptor blockers (ARBs) used in the treatment of hypertension and potentially in SARS-CoV-2 infection exhibit inverse agonist effects at angiotensin AR1 receptors, suggesting the receptor may have evolved to accommodate naturally occurring angiotensin 'antipeptides'. Screening of the human genome has identified a peptide (EGVYVHPV) encoded by mRNA, complementary to that encoding ANG II itself, which is an inverse agonist. Thus, opposite strands of DNA encode peptides with opposite effects at AR1 receptors. Agonism and inverse agonism at AR1 receptors can be explained by a receptor 'switching' between an activated state invoking receptor dimerization/G protein coupling and an inverse agonist state mediated by an alternative/second messenger that is slow to reverse. Both receptor states appear to be driven by the formation of the ANG II charge-relay system involving TyrOH-His/imidazole-Carboxylate (analogous to serine proteases). In this system, tyrosinate species formed are essential for activating AT1 and AT2 receptors. ANGII is also known to bind to the zinc-coordinated metalloprotease angiotensin converting enzyme 2 (ACE2) used by the COVID-19 virus to enter cells. Here we report in silico results demonstrating the binding of a new class of anionic biphenyl-tetrazole sartans ('Bisartans') to the active site zinc atom of the endopeptidase Neprilysin (NEP) involved in regulating hypertension, by modulating humoral levels of beneficial vasoactive peptides in the RAS such as vasodilator angiotensin (1-7). In vivo and modeling evidence further suggest Bisartans can inhibit ANG II-induced pulmonary edema and may be useful in combatting SARS-CoV-2 infection by inhibiting ACE2-mediated viral entry to cells.

Effect of different treatments for obstructive sleep apnoea on blood pressure.

OBJECTIVE: Obstructive sleep apnoea (OSA) is a common cause of secondary hypertension. This network meta-analysis (NMA) assessed the effect of different OSA treatments on lowering blood pressure. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched for relevant randomized controlled trials. The search strategies included the concepts of OSA, blood pressure, hypertension, and blood pressure-reducing treatments without language or data restriction (from inception to 1 June 2021). The outcomes included office SBP, office DBP, daytime SBP (dSBP) and DBP (dDBP), and night-time SBP (nSBP) and DBP (nDBP). A Bayesian network meta-analysis was performed, and mean differences with 95% credibility intervals were calculated. RESULTS: We reviewed 49 randomized controlled trials involving 4893 patients and the following interventions: continuous positive-airway pressure (CPAP), mandibular advancement devices, nocturnal supplemental oxygen, surgery, ß-blocker, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), renal sympathetic denervation (RDN), mineralocorticoid receptor antagonists (MRAs), calcium channel blockers. MRAs were significantly associated with blood pressure reduction followed by ACEI/ARB. RDN could reduce office SBP, office DBP, 24-h SBP, 24-h DBP, dSBP, and dDBP. CPAP also demonstrated modest blood pressure lowering. CONCLUSION: MRAs and ACEIs/ARBs can reduce blood pressure effectively in patients with OSA. RDN is a novel hypertension treatment that lowered blood pressure in such patients. CPAP was associated with mild but stable blood pressure reduction, and it might be helpful as an adjunctive therapy in OSA patients with hypertension. REVIEW REGISTRATION: This systematic review and meta-analysis was registered in PROSPERO: CRD42021240891.

Degradation and inactivation of chromosomal and plasmid encoded resistance genes/ARBs and the impact of different matrices on UV and UV/H2O2 based advanced oxidation process.

This study reports a structured investigation on the degradation kinetics of different types (gyrAR,tetAR, qnrSR) and conformational forms (chromosomal, plasmids) of ARGs and mobile genetic elements (intl-1, plasmids) as a function of water matrix (DI water, phosphate buffer, wastewater) with UV and UV/H2O2 treatments. Extracellular, intracellular and the free-ARGs fate were tracked to infer the impact of various parameters on the degradation efficacy of the treatment process. The degradation profile of e-ARGs (118-454 bp) showed 1-4 log reductions but did not correlate strongly to amplicon size indicating the importance of active sites distribution and/or types of ARGs for UV induced gene damage. The i-ARGs showed similar degradation rates compared to e-ARGs for UV in phosphate buffer (PBS) but showed (1.3-2 times) slower rates for i-ARGs with UV/H2O2 due to scavenging of OH radicals by the cellular components. While the ARB inactivation was effective, but ARG damage was not supplemental as i-ARGs and f-ARGs persisted. In the wastewater matrix, generation of radical species was contributing to improved degradation rates from UV/H2O2 treatment, specifically for f-ARGs resulting in significantly improved degradation (p<0.05) compared to PBS. These indicates a non-selective nature of attack from radical species generated from UV irradiation on the effluent organic matter (EfOM) than sequenced based damage to the genes from UV. For the plasmid degradation, conformational differences pertaining to the supercoiled structures and intracellular forms influenced slower (1.2-2.8 times) UV mediated gene damage rate as opposed to chromosomal ARGs. These results can be useful for better assessing UV based treatment processes for effective ARG removal.

Effects of losartan on bladder dysfunction due to aging-related severe hypertension in rats.

Aging is a major risk factor for bladder dysfunction. Anti-hypertensive drugs, angiotensin II type 1 receptor blockers (ARBs), are reported to ameliorate lower urinary tract dysfunction in rodent models and humans. We aimed to examine the preventive effect of an ARB, losartan, against bladder dysfunction due to aging-related severe hypertension. Male spontaneously hypertensive rats (SHRs) (36-week-old) were administered losartan (0, 3, or 10 mg/kg, p.o.) for 18 weeks. Age-matched, vehicle-treated Wistar Kyoto rats (WKYs) were used as controls. After the treatments, bladder and renal weight, mean blood pressure, and voiding parameters were measured. Additionally, detrusor thickness and bladder arterial wall thickness were evaluated using hematoxylin and eosin staining. Renal morphology was also assessed using periodic acid-Schiff staining. Compared to WKYs, SHRs demonstrated significantly higher bladder weight/body weight ratio (BBR), renal weight/body weight ratio, mean blood pressure, detrusor thickness, bladder arterial wall thickness, urine output, water intake, post-voiding residual urine volume, bladder capacity, intercontraction interval, and rate of glomerular and tubular injury and a lower urine osmolality. A low dose of losartan decreased the urine output, post-voiding residual urine volume, and bladder capacity in SHRs but not mean blood pressure in SHRs. A high dose of losartan decreased the BBR, mean blood pressure, detrusor thickness, bladder arterial wall thickness, post-voiding residual urine volume, bladder capacity, intercontraction interval, and glomerular and tubular injury in SHRs. Losartan inhibits bladder dysfunction in aged SHRs. The ARB losartan might be a preventive drug for bladder dysfunction due to aging-related severe hypertension.

Sacubitril/Valsartan: A New Dawn has Begun! A Revisited Review.

Heart Failure (HF) is among the major causes of global morbidity as well as mortality. Increased prevalence, frequent and prolonged hospitalization, rehospitalization, long-term consumption of healthcare resources, absenteeism, and death upsurge the economic burden linked to HF. For decades, Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin II Receptor Blockers (ARBs), Beta-Blockers (BBs), and mineralocorticoid receptor antagonists (MRA), have remained the mainstay of the standard of care for HF management. Despite their proven efficacy and cost-effectiveness, HF remains a global pandemic and is still increasing in prevalence. Sacubitril/ Valsartan (SAC/VAL) is an Angiotensin Receptor/Neprilysin Inhibitor (ARNI) that proved out to be a game-changer drug in HF treatment. Recent data indicated that SAC/VAL is more efficient and can improve the overall quality of life of HF patients with reduced ejection fraction (HFrEF) with fewer side effects. It is now incorporated in the guidelines as an alternative to ACEIs or ARBs to lower morbidity in addition to mortality in HFrEF patients. This review article will discuss the current guidelines-approved indications and highlight the potential emerging indications, in addition to the currently ongoing clinical trials that will expand the use of SAC/VAL.

Calcium channel blockers, angiotensin II receptor antagonists and alpha-blockers accentuate blood pressure reducing caused by dental local anesthesia.

OBJECTIVE: The primary aim of this study was to investigate the effect associated with patients' factor such as systemic disease on the blood pressure of patients in dental procedure. The secondary aim of this study was to investigate the effect associated with systemic disease and antihypertensive on the blood pressure changes with local anesthesia. METHODS: The blood pressure was measured before and after local anesthesia injection for dental treatment. The effect associated with patients' factor such as systemic disease on the blood pressure and the effect on blood pressure changes of the type of antihypertensive drugs and the systemic disease were analyzed using a multivariate analysis of variance test. RESULTS: We analyzed 1306 patients scheduled for the dental procedure. Age and some systemic diseases such as hypertension and angina pectoris affected blood pressure before local anesthesia. On the other hand, age and systemic diseases did not affect blood pressure changes. And, some antihypertensive affected systolic blood pressure changes. CONCLUSIONS: The blood pressure change with local anesthesia was not associated with systemic diseases and age but was associated with antihypertensive agents. In particular, calcium channel blockers, angiotensin II receptor antagonists and alpha-blockers accentuate blood pressure reducing caused by local anesthesia. CLINICAL RELEVANCE: The blood pressure change with local anesthesia was associated with antihypertensive agents. This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (number UMIN000030695).

Fallacies in medical practice: Renin-angiotensin-aldosterone system inhibition and COVID-19 as a Paradigm.

In emergency situations, such as during the coronavirus disease 2019 (COVID-19) pandemic, medical community looks for quick answers and guidance. Under these circumstances, experts instead of admitting ignorance, feel obliged to give an answer, often pressurized by political or other authorities, even when such an answer is unavailable. Under these circumstances, publications based on fallacious reasoning are virtually unavoidable. In the present review, we summarize examples underlying fallacious reasoning recommendations regarding treatment with Renin-Angiotensin-Aldosterone inhibitors (RAASi) in the COVID-19 context. Most scientific societies emphasize that RAASi use is safe and that these agents should not be discontinued, based mainly on the results of observational studies (OSs) and occasionally preprints, as relevant randomized controlled trials (RCTs) are currently lacking. However, over the past 4 decades, results from successful RCTs have repeatedly proved that practices based on OSs were wrong. Lack of RCTs results in uncertainty. In this setting, the physician's wisdom and knowledge related to pathophysiologic mechanisms and effect of pharmacologic agents become even more important as they may limit fallacies. Based on these principles, in diseases (e.g., mild, or moderate arterial hypertension, etc.) where equally effective alternative therapies to RAASi are available, these therapies should be applied, whereas in diseases (e.g., heart failure, diabetic kidney disease, etc.), where equally effective alternative therapy compared to RAASi is not available, RAASi should be used. Admittedly this strategy, like all the other recommendations, is not based on solid evidence but is intended to be individualized and follows the Hippocratic "Primum non nocere".

Transforming Growth Factor-ß and the Renin-Angiotensin System in Syndromic Thoracic Aortic Aneurysms: Implications for Treatment.

Thoracic aortic aneurysms (TAAs) are permanent pathological dilatations of the thoracic aorta, which can lead to life-threatening complications, such as aortic dissection and rupture. TAAs frequently occur in a syndromic form in individuals with an underlying genetic predisposition, such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). Increasing evidence supports an important role for transforming growth factor-ß (TGF-ß) and the renin-angiotensin system (RAS) in TAA pathology. Eventually, most patients with syndromic TAAs require surgical intervention, as the ability of present medical treatment to attenuate aneurysm growth is limited. Therefore, more effective medical treatment options are urgently needed. Numerous clinical trials investigated the therapeutic potential of angiotensin receptor blockers (ARBs) and ß-blockers in patients suffering from syndromic TAAs. This review highlights the contribution of TGF-ß signaling, RAS, and impaired mechanosensing abilities of aortic VSMCs in TAA formation. Furthermore, it critically discusses the most recent clinical evidence regarding the possible therapeutic benefit of ARBs and ß-blockers in syndromic TAA patients and provides future research perspectives and therapeutic implications.

In vitro and in vivo identification of clinically approved drugs that modify ACE2 expression.

The COVID-19 pandemic caused by SARS-CoV-2 has is a global health challenge. Angiotensin-converting enzyme 2 (ACE2) is the host receptor for SARS-CoV-2 entry. Recent studies have suggested that patients with hypertension and diabetes treated with ACE inhibitors (ACEIs) or angiotensin receptor blockers have a higher risk of COVID-19 infection as these drugs could upregulate ACE2, motivating the study of ACE2 modulation by drugs in current clinical use. Here, we mined published datasets to determine the effects of hundreds of clinically approved drugs on ACE2 expression. We find that ACEIs are enriched for ACE2-upregulating drugs, while antineoplastic agents are enriched for ACE2-downregulating drugs. Vorinostat and isotretinoin are the top ACE2 up/downregulators, respectively, in cell lines. Dexamethasone, a corticosteroid used in treating severe acute respiratory syndrome and COVID-19, significantly upregulates ACE2 both in vitro and in vivo. Further top ACE2 regulators in vivo or in primary cells include erlotinib and bleomycin in the lung and vancomycin, cisplatin, and probenecid in the kidney. Our study provides leads for future work studying ACE2 expression modulators.

Systematic review: Renin-angiotensin system inhibitors in chemoprevention of hepatocellular carcinoma.

BACKGROUND: Neoangiogenesis is one of the key pathogenetic mechanisms in hepatocellular carcinoma (HCC). Modulation of the renin-angiotensin system (RAS) by angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) seems to be a possible adjuvant therapy for HCC, due to the anti-angiogenic and anti-fibrogenic activity of these drugs. AIM: To elucidate the role of ARBs and ACE-Is in HCC. METHODS: We performed an electronic search of the literature using the most accessed online databases (PubMed, Cochrane library, Scopus and Web of Science), entering the query terms "angiotensin-converting enzyme inhibitors" OR "ACE inhibitors" OR "ACE-I" AND "hepatocarcinoma*" OR "hepatocellular carcinoma; moreover "angiotensin II type 1 receptor blockers" OR "ARBs" AND "hepatocarcinoma*" OR "hepatocellular carcinoma". Eligibility criteria were: (1) prospective or retrospective clinical studies; (2) epidemiological studies; and (3) experimental studies conducted in vivo or in vitro. Abstracts, conference papers, and reviews were excluded a priori. We limited our literature search to articles published in English, in peer-reviewed journals. RESULTS: Thirty-one studies were selected. Three interventional studies showed that ACE-Is had a significant protective effect on HCC recurrence only when used in combination with vitamin K or branched chain aminoacids, without a significant increase in overall survival. Of six retrospective observational studies, mainly focused on overall survival, only one demonstrated a prolonged survival in the ACE-Is group, whereas the two that also evaluated tumor recurrence showed conflicting results. All experimental studies displayed beneficial effects of RAS inhibitors on hepatocarcinogenesis. Numerous experimental studies, conducted either on animals and cell cultures, demonstrated the anti-angiogenetic and antifibrotic effect of ACE-Is and ARBs, thanks to the suppression of some cytokines such as vascular endothelial growth factor, hypoxia-inducible factor-1a, transforming growth factor-beta and tumor necrosis factor alpha. All or parts of these mechanisms were demonstrated in rodents developing fewer HCC and preneoplastic lesions after receiving such drugs. CONCLUSION: In humans, RAS inhibitors - alone or in combination - significantly suppressed the cumulative HCC recurrence, without prolonging patient survival, but some limitations intrinsic to these studies prompt further investigations.

Magnolol ameliorates pneumonectomy and monocrotaline-induced pulmonary arterial hypertension in rats through inhibition of angiotensin II and endothelin-1 expression.

BACKGROUND: Magnolol, a major bioactive component extracted from Magnolia officinalis, exerts several beneficial effects, such as anti-inflammatory and anti-hypertensive activities. PURPOSE: In this study, we investigated whether magnolol has a protective effect on pneumonectomy and monocrotaline-induced pulmonary arterial hypertension (PAH) in rats. DESIGN/METHODS: The alterations of right ventricular (RV) hypertrophy, pulmonary vascular remodeling, histopathological parameters, and related gene expression and signaling pathways in lungs by magnolol treatment were studied in the PAH rats. RESULTS: Administration of magnolol greatly ameliorated the characteristic features of PAH, including increased pulmonary arterial pressure, RV hypertrophy, and pulmonary vascular remodeling. Moreover, magnolol inhibited angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/Ang II type 1 receptor (AT-1R) cascade, whereas upregulates ACE2 in the lungs of PAH rats. The overexpression of endothelin-1 (ET-1) and ETA receptor occurred in the PAH rats was significantly attenuated by magnolol through inhibition of Akt/ERK1/2/GSK3ß/ß-catenin pathway. Compared with that of untreated PAH rats, higher expression of endothelial nitric oxide synthase, and lower expression of inducible nitric oxide synthase and O2- production in lungs were observed in magnolol-treated PAH rats. CONCLUSION: We demonstrated that treatment with magnolol reduces the development of PAH induced by pneumonectomy and monocrotaline in rats, and suppressing Ang II and ET-1-mediated processes may contribute to its protective effects. These findings suggest that magnolol may be a potential agent for PAH therapy.

Comparative effects of avocado oil and losartan on blood pressure, renal vascular function, and mitochondrial oxidative stress in hypertensive rats.

OBJECTIVE: Angiotensin II (Ang-II) antagonism alleviates hypertensive kidney damage by improving mitochondrial function and decreasing oxidative stress. This condition also is associated with altered renal vascular tone due to enhanced constriction by Ang-II. Thus, approaches ameliorating these events are desirable to alleviate kidney damage. Avocado oil, a source of antioxidants and oleic acid, is known to improve mitochondrial function, while oleic acid has antihypertensive effects. Therefore, the aim of this study was to test whether avocado oil counteracts, to a similar degree as the Ang-II blocker losartan, the deleterious effects of hypertension on blood pressure, renal vascular performance, kidney mitochondrial function, and oxidative stress. METHODS: Hypertensive rats induced with Nω-nitro-l-arginine methyl ester (L-NAME) were supplemented during 45 d with avocado oil or losartan. Vascular responses were analyzed in perfused kidney. Membrane potential, reactive oxygen species levels, and glutathione were analyzed in isolated kidney mitochondria. RESULTS: In hypertensive rats, avocado oil decreased 21.2% and 15.5% diastolic and systolic blood pressures, respectively, and alleviated impaired renal vasodilation. Hypertension decreased membrane potential by 83.7% and augmented reactive oxygen species levels by 51% in mitochondria fueled with a complex I substrate, whereas it augmented the levels of oxidized glutathione in 48%. These alterations were normalized by avocado oil at a comparable degree to losartan. CONCLUSIONS: Because avocado oil mimicked the effects of losartan, we propose that the effects of avocado oil might be mediated by decreasing the actions of Ang-II on mitochondria. These results suggest that avocado oil intake might be a nutritional approach to attenuate the deleterious effects of hypertension on kidney.

Intensity of hydration changes the role of renin-angiotensin-aldosterone system blockers in contrast-induced nephropathy risk after coronary catheterisation in patients with chronic kidney disease.

OBJECTIVE: This study evaluated the potential effect of hydration intensity on the role of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) on contrast-induced nephropathy in patients with renal insufficiency. METHODS: All eligible patients were included and stratified according to hydration intensity defined as saline hydration volume to body weight tertiles: <10.21 mL/kg, 10.21 to <17.86 mL/kg, and ⩾17.86 mL/kg. RESULTS: In total, 84 (6.7%) of 1254 patients developed contrast-induced nephropathy: 6.2% in the ACEI/ARB group versus 10.8% in the non-ACEI/ARB group ( P=0.029), with an adjusted odds ratio (OR) of 0.89 (95% confidence interval (CI) 0.46-1.73, P=0.735). The incidence of contrast-induced nephropathy was lower in the ACEI/ARB group than in the non-ACEI/ARB group in the second tertile ( P=0.031), while not significantly different in the first ( P=0.701) and third ( P=0.254) tertiles. ACEIs/ARBs were independently associated with a lower contrast-induced nephropathy risk (OR 0.26, 95% CI 0.09-0.74, P=0.012) and long-term all-cause death (hazard ratio 0.461, 95% CI 0.282-0.755, P=0.002) only in the second hydration volume to body weight tertile. CONCLUSION: The effects of ACEIs/ARBs on contrast-induced nephropathy risk vary according to saline hydration intensity in chronic kidney disease patients, and may further reduce contrast-induced nephropathy risk in patients administered moderate saline hydration.