Aliskiren inhibits experimental venous thrombosis in two-kidney one-clip hypertensive rats (original) (raw)
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Journal of Human Hypertension, 2008
Aliskiren, an octanamide, is nonpeptide, low molecular weight, orally active renin inhibitor effectively preventing angiotensin and aldosterone release. This drug has been recently approved for the treatment of hypertension. Considering potential links between hypertension, platelets, the coagulation cascade and fibrinolysis we sought to evaluate the effect of aliskiren on human biomarkers of hemostasis. In vitro effects of whole blood preincubation with escalating concentrations of aliskiren (500, 1000 and 2000 ng ml À1) were assessed in 20 aspirin-naive volunteers with multiple risk factors for vascular disease. A total of 33 biomarkers were measured, of which 18 are related to platelet function, 12 to coagulation and 3 to fibrinolysis. Pretreatment of blood samples with aliskiren 500 ng ml À1 resulted in a significant increase of antithrombin-III (AT-III) activity (P ¼ 0.003). All other tested biomarkers were not significantly affected. Spiking whole blood with the higher aliskiren doses was associated with various trends in biomarker activity, where 1000 ng ml À1 concentration mostly decreased (7/33), and 2000 ng ml À1 mostly increased (6/33) some biomarkers. In the therapeutic concentration of 500 ng ml À1 aliskiren does not affect hemostatic biomarkers, except for a moderate but highly significant (P ¼ 0.003) increase of AT-III activity. Higher aliskiren doses were associated with more profound biomarker changes, but they are likely not to be clinically relevant since they show diverging (that is, both mild antiplatelet and platelet-activating) trends, and considering the 2-to 4-fold safety margin. It is suggested that antithrombotic properties of aliskiren be explored further in an ex vivo clinical setting.
The Journal of Clinical Hypertension, 2014
Arterial stiffness and endothelial dysfunction are important determinants of cardiovascular events in patients with arterial hypertension. There are few data regarding the role of aliskiren on the central hemodynamics and endothelial function in patients with uncontrolled arterial hypertension. The aim of this study was to assess the addition of aliskiren to other antihypertensive drug treatment for arterial stiffness and endothelial function. Thirty uncontrolled hypertensive patients (mean age, 60.4AE12.2 years), without any other cardiovascular risk factors, were enrolled. Augmentation index (AIx) and carotid-femoral pulse wave velocity (cfPWV) by applanation tonometry and reactive hyperemia peripheral arterial tonometry (RH PAT) index using peripheral arterious tonometry at baseline and after 6 months of aliskiren titrated to 300 mg once a day was evaluated. The addition of aliskiren had no effect on values of central AIx (33.26AE10.74% vs 28.86AE10.74%; P=.36) but did significantly improve values of cfPWV (9.36AE2.65 m/s vs 8.72AE2.48 m/s; P=.04) and RH PAT index (1.64AE0.57 vs 1.75AE0.45; P=.05). In addition to improving systolic and diastolic blood pressure, the addition of aliskiren to concomitant antihypertensive drugs in uncontrolled hypertensive patients may be effective in improving aortic stiffness and endothelial function. These results encourage further studies to evaluate the use of aliskiren for cardiovascular prevention.
Background: Aliskiren is a direct renin inhibitor. It counteracts renin-angiotensin system and is used to treat hypertension. This study aims to evaluate the effect of aliskiren on the progression of atherosclerosis in domestic rabbits. Methods: Twenty-one local domestic rabbits were divided into three groups each group had special dietary regimen for 8 weeks: Group I (normal control), Group II (atherogenic control) and Group III (2% Cholesterol + aliskiren 40mg/kg/day orally). Blood samples were collected at the end of experiment (8 weeks) for measurement of serum lipid profile, plasma high sensitive C-reactive protein (hs-CRP), plasma malondialdehyde (MDA) and plasma reduced glutathione (GSH). Immunohistochemical analysis including vascular cell adhesion molecule-1 (VCAM-1); monocyte chemoattractant protein-1 (MCP-1); tumor necrotic factor - α (TNF-α); and interleukin – 17 (IL-17). Histopathologic assessment of aortic atherosclerotic changes were also performed. Results: Compared to normal control group, there is a significant increase in the level of lipid profile, hs-CRP (134.1±1.2ug/L), and malondialdehyde (0.561±0.136umol/L) in the atherogenic diet group, while GSH was significantly reduced (0.58±0.024mmol/L) at (p ≤ 0.05). Immunohistochemical analysis showed that expression of aortic VCAM-1; MCP-1; TNF-α; and interleukin–17 were significantly increased in atherogenic control group compared to normal control group (p<0.001). In addition, animals on atherogenic diet have significant atherosclerotic lesion compared to normal control group. Aliskiren group appears to have no significant effect on lipid profile compared to atherogenic control group, but it has statistically significant reduction in hs-CRP (73.1±3.88ug/L) and MDA (0.261±0.15umol/L) at (p ≤ 0.05). Aliskiren treatment failed to significantly increase the level of plasma reduced glutathione. In addition, aliskiren treatment significantly reduced the expression of VCAM-1; MCP-1; TNF-α; and IL–17 (p≤0.05). Histopathological examination of aortic arch showed that aliskiren significantly reduced atherosclerotic lesion (p≤0.005). Conclusion: We can conclude that aliskiren is helpful in reducing lipid peroxidation, systemic inflammation and aortic expression of inflammatory markers used in this study and hence reduces the progression of atherosclerotic plague.
Aliskiren: review of efficacy and safety data with focus on past and recent clinical trials
Therapeutic Advances in Chronic Disease, 2013
Aliskiren is the newest antihypertensive drug and the first orally active direct renin inhibitor to become available for clinical use. Clinical data have substantiated that the antihypertensive effectiveness of aliskiren is similar to that of the other major antihypertensive agents. Furthermore, aliskiren has a similar safety profile to placebo. Combination treatment with aliskiren showed significant blood pressure and proteinuria reductions compared with monotherapy. Aliskiren decreases plasma renin activity in contrast to other renin–angiotensin–aldosterone related drugs. The efficacy of aliskiren in treating major cardiovascular events and the prevention of end-organ damage are being investigated in the ASPIRE HIGHER program. Although the first studies of the ASPIRE HIGHER program such as ALOFT, AVOID, AGELESS showed favorable findings, ASPIRE and AVANT-GARDE studies provided contradictory results. Subsequently, the ALTITUDE study was terminated early because of safety issues and...
T he renin-angiotensin system is widely accepted as a central mediator of chronic kidney disease (CKD) and is the main target of therapies aiming to slow down or ameliorate the progression of the disease. 1 Aliskiren is a novel, direct inhibitor of renin activation that has been added to angiotensin-converting enzyme blockers and angiotensin II receptor 1 inhibitors and, at least theoretically, may avoid angiotensin II escape that is observed after treatment with drugs from the other 2 classes. Although the beneficial effect of aliskiren in normalizing blood pressure and proteinuria has been shown in both humans 4,5 and animal models, 6,7 data regarding its anti-inflammatory and, most importantly, its antifibrotic capacity in models of CKD are still missing. To evaluate the effect of aliskiren on regression of renal fibrosis, we used a heterozygous transgenic mouse model that expresses an artificial mouse renin gene (RenTg) in the liver at constantly high levels 8 against which alis...
American journal of hypertension, 2011
The direct renin inhibitor aliskiren is known to exhibit a strong antihypertensive effect. However, the organoprotective potential of aliskiren beyond its antihypertensive properties is less clear. This study investigates the antifibrotic nephroprotective effects of aliskiren in a nonhypertensive mouse model for progressive renal fibrosis. COL4A3(-/-) mice received aliskiren via osmotic minipumps. Placebo-treated animals served as controls. Therapy was initiated in 6-week-old animals already showing renal damage (proteinuria ~1 g/l, starting renal fibrosis) and lasted for 4 weeks. Six animals were sacrificed after 9.5 weeks; serum urea and proteinuria were measured. Kidneys were further investigated using histological, immunohistological, and western blot techniques. Survival until end-stage renal failure was monitored in the remaining animals. COL4A3(-/-) mice did not develop hypertension. Aliskiren serum levels were in the therapeutic range (288 ± 44 ng/ml). Therapy significantly ...