aliskiren and candesartan

Fibrosis is characterized by excessive deposition of extracellular matrix components such as collagen in tissues or organs. Fibrosis can develop in the heart, kidneys, liver, skin or any other body organ in response to injury or maladaptive reparative processes, reducing overall function and leading eventually to organ failure. A variety of cellular and molecular signaling mechanisms are involved in the pathogenesis of fibrosis. The renin-angiotensin-aldosterone system (RAAS) interacts with the potent Transforming Growth Factor β (TGFβ) pro-fibrotic pathway to mediate fibrosis in many cell and tissue types. RAAS consists of both classical and alternative pathways, which act to potentiate or antagonize fibrotic signaling mechanisms, respectively. This review provides an overview of recent literature describing the roles of RAAS in the pathogenesis of fibrosis, particularly in the liver, heart, kidney and skin, and with a focus on RAAS interactions with TGFβ signaling. Targeting RAAS to combat fibrosis represents a promising therapeutic approach, particularly given the lack of strategies for treating fibrosis as its own entity, thus animal and clinical studies to examine the impact of natural and synthetic substances to alter RAAS signaling as a means to treat fibrosis are reviewed as well.

Topics: Amides; Angiotensins; Animals; Benzimidazoles; Biphenyl Compounds; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Fumarates; Gene Expression Regulation; Humans; Kidney; Liver; Molecular Targeted Therapy; Myocardium; Pyridones; Renin-Angiotensin System; Signal Transduction; Skin; Tetrazoles; Transforming Growth Factor beta

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Chronic Disease; Clinical Trials as Topic; Drug Therapy, Combination; Evidence-Based Medicine; Fumarates; Kidney Diseases; Losartan; Tetrazoles; Valine; Valsartan

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Antihypertensive Agents; Aspartic Acid Endopeptidases; Benzimidazoles; Biphenyl Compounds; Drug Combinations; Drug Design; Endothelin Receptor Antagonists; Endothelin-Converting Enzymes; Fumarates; Humans; Hypertension; Immunotherapy, Active; Metalloendopeptidases; Mineralocorticoid Receptor Antagonists; Phenylpropionates; Pyrimidines; Randomized Controlled Trials as Topic; Renin; Tetrazoles

The majority of patients with essential hypertension of moderate severity (WHO grade 2) require combination therapy. We aimed to investigate whether the single-pill combination of aliskiren 300  mg and hydrochlorothiazide (HCT) 25  mg (ALIS 300/HCT 25) improves the BP reduction in hypertensive patients not adequately controlled by the free combination of candesartan 32  mg and HCT 25  mg (CAN 32 + HCT 25).. In an open-label, single-arm study, patients with mean sitting diastolic blood pressure (DBP) between 100-109  mmHg at baseline received 4-week treatment with CAN 32 + HCT 25 (Phase 1), followed - in patients whose BP was not controlled - by 4-week treatment with ALIS 300/HCT 25 (Phase 2). The DBP change between weeks 4 and 8 was the primary endpoint. The ClinicalTrials.gov Identifier is NCT00867490.. In the 186 patients treated, CAN 32 + HCT 25 reduced systolic BP (SBP)/DBP by 18.9/12.2 mmHg. Those 123 patients with uncontrolled hypertension switched to ALIS 300/HCT 25 experienced a further SBP/DBP reduction of 2.8/3.1  mmHg between week 4 and week 8 (p = 0.0064 and p < 0.0001), and 33.3% achieved DBP normalisation. In 61 patients not controlled after week 8 (SBP ≥ 140  mmHg or DBP  ≥  90  mmHg), who participated in an optional study extension, amlodipine 5  mg was added. Triple therapy over 4 weeks decreased SBP/DBP by further 9.2/5.9  mmHg (p < 0.0001 each). Adverse events with suspected drug relationship were noted in 4.3% (Phase 1), 3.3% (Phase 2), and 1.6% (extension) of the patients. Limitations of the study include the open-label, non-randomised approach and short treatment duration across the individual phases.. In this open-label, single-arm switch study reflecting clinical practice, patients with moderate hypertension not controlled by the free combination of CAN 32 + HCT 25 achieved a clinically and statistically significant reduction of blood pressure from the single pill combination of ALIS 300/HCT 25, and the optional addition of amlodipine.

Topics: Adult; Aged; Algorithms; Amides; Amlodipine; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Dose-Response Relationship, Drug; Drug Combinations; Drug Resistance; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Tetrazoles; Treatment Failure; Treatment Outcome

Blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor blockers (ARBs) slow the progression of various chronic kidney diseases and chronic allograft dysfunction. RAS inhibition can be achieved also by directly blocking renin upstream from ACE. However, direct renin inhibition can have additional effects since formation of renoprotective Ang II breakdown products such as angiotensin (Ang) (1-7) that are produced by ACE2 are also inhibited.. Using a Fischer-to-Lewis renal transplantation model, the effect of the renin inhibitor aliskiren (10 mg/kg/day) was assessed on the development of chronic allograft dysfunction compared with vehicle treatment and Ang II receptor blockers candesartan.. Aliskiren had no effect on renal function (proteinuria, creatinine clearance) or on renal morphological changes (glomerulosclerosis collagen deposition, myofibroblast accumulation and macrophage infiltration) compared with the vehicle- and candesartan-treated animals determined 24 weeks after transplantation. On the other hand, atrophy of tubular cells was significantly attenuated. Candesartan reduced both proteinuria and structural injury of the kidney. In aliskiren-treated animals reduced serum Ang II and Ang (1-7) levels were detected, whereas the level of urine angiotensinogen was unchanged.. The renin inhibitor aliskiren does not slow the progression of chronic allograft dysfunction. We suggest that the lack of protection might be due to reduced formation of the protective Ang II breakdown products such as Ang (1-7) or due to unchanged intrarenal RAS activity demonstrated by urinary angiotensinogen levels.

Topics: Amides; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Fumarates; Kidney; Kidney Transplantation; Male; Models, Animal; Peptide Fragments; Rats; Rats, Inbred F344; Rats, Inbred Lew; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Tetrazoles; Transplantation, Homologous

A direct renin inhibitor (DRI) had a benefit in decreasing albuminuria in type 2 diabetic patients having already been treated with angiotensin (Ang) II type 1 receptor blocker (ARB), suggesting that aliskiren may have another effect other than blockade of the traditional renin-angiotensin system (RAS). Recently, prorenin bound to (pro)renin receptor ((P)RR) was found and shown to evoke two pathways; the generation of Ang peptides and the receptor-dependent activation of extracellular signal-related protein kinase (ERK). Because (P)RR is present in the podocytes, a central component of the glomerular filtration barrier, we hypothesized that aliskiren influences the (P)RR-induced two pathways in human podocytes.. Human podocytes were treated with 2 nmol/l prorenin in the presence and absence of an angiotensin-converting enzyme inhibitor (ACEi) imidaprilat, an ARB candesartan, a DRI aliskiren, or the siRNA knocking down the (P)RR mRNA and the intracellular AngII levels and the phosphorylation of ERK were determined.. The expression of (P)RR mRNA of human podocytes was unaffected by the treatment with RAS inhibitors, but decreased by 69% with the siRNA treatment. The basal levels of intracellular AngII and the prorenin-induced increase in intracellular AngII were significantly reduced by aliskiren and siRNA treatment, compared with imidaprilat and candesartan. The prorenin-induced ERK activation was reduced to control level by the siRNA treatment, but it was unaffected by imidaprilat, candesartan, or aliskiren.. Aliskiren is the most potent inhibitor of intracellular AngII levels of human podocytes among RAS inhibitors, although it is incapable of inhibiting the (P)RR-dependent ERK phosphorylation.

Topics: Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Cells, Cultured; Extracellular Signal-Regulated MAP Kinases; Fumarates; Humans; Imidazolidines; Phosphorylation; Podocytes; Prorenin Receptor; Receptors, Cell Surface; Renin; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Tetrazoles

Pre-treatment with angiotensin receptor blockers is known to improve neurological outcome after stroke. This study investigated for the first time, whether the renin inhibitor aliskiren has similar neuroprotective effects.. Since aliskiren specifically blocks human renin, double transgenic rats expressing human renin and angiotensinogen genes were used. To achieve a systolic blood pressure of 150 or 130 mmHg animals were treated with aliskiren (7.5 or 12.5 mg/kg*d) or candesartan (1.5 or 10 mg/kg*d) via osmotic minipump starting five days before middle cerebral artery occlusion with reperfusion. Infarct size was determined by magnetic resonance imaging. mRNA of inflammatory marker genes was studied in different brain regions.. The mortality of 33.3% (7 of 21 animals) in the vehicle group was reduced to below 10% by treatment with candesartan or aliskiren (p<0.05). Aliskiren-treated animals had a better neurological outcome 7 days post-ischemia, compared to candesartan (Garcia scale: 9.9±0.7 vs. 7.3±0.7; p<0.05). The reduction of infarct size in the aliskiren group did not reach statistical significance compared to candesartan and vehicle (24 h post-ischemia: 314±81 vs. 377±70 and 403±70 mm(3) respectively). Only aliskiren was able to significantly reduce stroke-induced gene expression of CXC chemokine ligand 1, interleukin-6 and tumor necrosis factor-alpha in the ischemic core.. Head-to-head comparison suggests that treatment with aliskiren before and during cerebral ischemia is at least as effective as candesartan in double transgenic rats. The improved neurological outcome in the aliskiren group was blood pressure independent. Whether this effect is due to primary anti-inflammatory mechanisms has to be investigated further.

Topics: Amides; Angiotensinogen; Animals; Animals, Genetically Modified; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Brain; Brain Ischemia; Cerebral Arterial Diseases; Cerebrovascular Disorders; Chemokine CXCL1; Fumarates; Gene Expression; Humans; Interleukin-6; Rats; Renin; Reverse Transcriptase Polymerase Chain Reaction; Stroke; Tetrazoles; Tumor Necrosis Factor-alpha

Recurrent focal segmental glomerulosclerosis (FSGS) after renal transplantation with nephrotic syndrome is a serious problem with a high risk of graft loss. The therapeutic role of renin-angiotensin-system (RAS) blockers in recurrent FSGS is not clear. We present the safety and efficacy of an intensified triple RAS blockade with an ACE-inhibitor, an AT 1 receptor blocker and the direct renin inhibitor aliskiren in a 29-year-old renal transplant recipient with biopsy proven recurrence of FSGS and relapsing severe nephrotic syndrome. We subsequently used full dose ramipril, candesartan and aliskiren under a close monitoring of kidney function and electrolytes and examined the effect on proteinuria, clinical course and tolerability over 12 months. We found a significant and sustained antiproteinuric effect under triple RAS blockade. RAS blockade was generally well tolerated. This can offer a new therapeutic approach in selected hypertensive patients with recurrent FSGS.

Topics: Adult; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Benzimidazoles; Biphenyl Compounds; Drug Therapy, Combination; Female; Fumarates; Glomerulosclerosis, Focal Segmental; Humans; Hypertension, Renal; Kidney Transplantation; Nephrotic Syndrome; Plasma Exchange; Proteinuria; Ramipril; Recurrence; Renin; Renin-Angiotensin System; Rituximab; Tetrazoles

Many of the effects of angiotensin (Ang) II are mediated through specific plasma membrane receptors. However, Ang II also elicits biological effects from the interior of the cell (intracrine), some of which are not inhibited by Ang receptor blockers (ARBs). Recent in vitro studies have identified high glucose as a potent stimulus for the intracellular synthesis of Ang II, the production of which is mainly chymase dependent. In the present study, we determined whether hyperglycemia activates the cardiac intracellular renin-Ang system (RAS) in vivo and whether ARBs, ACE, or renin inhibitors block synthesis and effects of intracellular Ang II (iAng II).. Diabetes was induced in adult male rats by streptozotocin. Diabetic rats were treated with insulin, candesartan (ARB), benazepril (ACE inhibitor), or aliskiren (renin inhibitor).. One week of diabetes significantly increased iAng II levels in cardiac myocytes, which were not normalized by candesartan, suggesting that Ang II was synthesized intracellularly, not internalized through AT(1) receptor. Increased intracellular levels of Ang II, angiotensinogen, and renin were observed by confocal microscopy. iAng II synthesis was blocked by aliskiren but not by benazepril. Diabetes-induced superoxide production and cardiac fibrosis were partially inhibited by candesartan and benazepril, whereas aliskiren produced complete inhibition. Myocyte apoptosis was partially inhibited by all three agents.. Diabetes activates the cardiac intracellular RAS, which increases oxidative stress and cardiac fibrosis. Renin inhibition has a more pronounced effect than ARBs and ACE inhibitors on these diabetes complications and may be clinically more efficacious.

Topics: Amides; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Benzazepines; Benzimidazoles; Biphenyl Compounds; Diabetes Mellitus, Experimental; Endomyocardial Fibrosis; Fumarates; Insulin; Myocytes, Cardiac; Oxidative Stress; Rats; Renin; Tetrazoles

The occurrence of a functional intracellular renin-angiotensin system (RAS) has emerged as a new paradigm. Recently, we and others demonstrated intracellular synthesis of ANG II in cardiac myocytes and vascular smooth muscle cells that was dramatically stimulated in high glucose conditions. Cardiac fibroblasts significantly contribute to diabetes-induced diastolic dysfunction. The objective of the present study was to determine the existence of the intracellular RAS in cardiac fibroblasts and its role in extracellular matrix deposition. Neonatal rat ventricular fibroblasts were serum starved and exposed to isoproterenol or high glucose in the absence or presence of candesartan, which was used to prevent receptor-mediated uptake of ANG II. Under these conditions, an increase in ANG II levels in the cell lysate represented intracellular synthesis. Both isoproterenol and high glucose significantly increased intracellular ANG II levels. Confocal microscopy revealed perinuclear and nuclear distribution of intracellular ANG II. Consistent with intracellular synthesis, Western analysis showed increased intracellular levels of renin following stimulation with isoproterenol and high glucose. ANG II synthesis was catalyzed by renin and angiotensin-converting enzyme (ACE), but not chymase, as determined using specific inhibitors. High glucose resulted in increased transforming growth factor-beta and collagen-1 synthesis by cardiac fibroblasts that was partially inhibited by candesartan but completely prevented by renin and ACE inhibitors. In conclusion, cardiac fibroblasts contain a functional intracellular RAS that participates in extracellular matrix formation in high glucose conditions, an observation that may be helpful in developing an appropriate therapeutic strategy in diabetic conditions.

Topics: Adrenergic beta-Agonists; Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Benzazepines; Benzimidazoles; Biphenyl Compounds; Blotting, Western; Cells, Cultured; Collagen Type I; Dose-Response Relationship, Drug; Extracellular Matrix; Fibroblasts; Fumarates; Glucose; Heart Ventricles; Isoproterenol; Microscopy, Confocal; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; Tetrazoles; Time Factors; Transforming Growth Factor beta; Up-Regulation