Aliskiren Improves Nitric Oxide Bioavailability and Limits Atherosclerosis

Verma, Subodh; Gupta, Milan

doi:10.1161/hypertensionaha.108.114488

Cited by 7 publications

(5 citation statements)

References 15 publications

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“…The severe hypercholesterolemia, enhanced oxidative stress, and inflammation are the possible contributors for the development and progression of atherosclerosis. These finding was in agreement with other researches [12,23,51]. This favourable effect of aliskiren may be mediated through inhibition of angiotensin II which is considered as the main pro-atherosclerotic mediator [47].…”

Section: Discussionsupporting

confidence: 93%

Antiatherosclerotic potential of aliskiren: its antioxidant and anti-inflammatory effects in rabbits: a randomized controlled trial

Al-Aubaidy¹,

Sahib²,

Mohammad³

et al. 2013

J Pharm Technol Drug Res

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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.

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Section: Discussionsupporting

confidence: 93%

Antiatherosclerotic potential of aliskiren: its antioxidant and anti-inflammatory effects in rabbits: a randomized controlled trial

Al-Aubaidy¹,

Sahib²,

Mohammad³

et al. 2013

J Pharm Technol Drug Res

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“…The renin inhibitor aliskiren increases eNOS expression, enhances eNOS phosphorylation at serine 1177 (thereby increasing activity), decreases NADPH oxidase expression, augments vascular BH 4 levels and restores eNOS uncoupling in Watanabe heritable hyperlipidaemic rabbits (Imanishi et al ., 2008b) (Figure 2). The anti‐atherosclerotic effect of aliskiren (Verma and Gupta, 2008) is comparable with the AT 1 receptor blocker (ARB) valsartan (Imanishi et al ., 2008b) or irbesartan (Nussberger et al ., 2008). Combination therapy of aliskiren and valsartan had an additive effect on endothelial function, BH 4 content, NO release and plaque volume reduction (Imanishi et al ., 2008b).…”

Section: Therapeutic Effects Of Enhancing Enos Expression and Preventmentioning

confidence: 99%

Therapeutic effect of enhancing endothelial nitric oxide synthase (eNOS) expression and preventing eNOS uncoupling

Förstermann

2011

British Journal of Pharmacology

260

182

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Nitric oxide (NO) produced by the endothelium is an important protective molecule in the vasculature. It is generated by the enzyme endothelial NO synthase (eNOS). Similar to all NOS isoforms, functional eNOS transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH), via the flavins flavin adenine dinucleotide and flavin mononucleotide in the carboxy-terminal reductase domain, to the heme in the amino-terminal oxygenase domain. Here, the substrate L-arginine is oxidized to L-citrulline and NO. Cardiovascular risk factors such as diabetes mellitus, hypertension, hypercholesterolaemia or cigarette smoking reduce bioactive NO. These risk factors lead to an enhanced production of reactive oxygen species (ROS) in the vessel wall. NADPH oxidases represent major sources of this ROS and have been found upregulated in the presence of cardiovascular risk factors. NADPH-oxidase-derived superoxide avidly reacts with eNOS-derived NO to form peroxynitrite (ONOO -). The essential NOS cofactor (6R-) 5,6,7, is highly sensitive to oxidation by this ONOO -. In BH4 deficiency, oxygen reduction uncouples from NO synthesis, thereby converting NOS to a superoxide-producing enzyme. Among conventional drugs, compounds interfering with the renin-angiotensin-aldosterone system and statins can reduce vascular oxidative stress and increase bioactive NO. In recent years, we have identified a number of small molecules that have the potential to prevent eNOS uncoupling and, at the same time, enhance eNOS expression. These include the protein kinase C inhibitor midostaurin, the pentacyclic triterpenoids ursolic acid and betulinic acid, the eNOS enhancing compounds AVE9488 and AVE3085, and the polyphenolic phytoalexin trans-resveratrol. Such compounds enhance NO production from eNOS also under pathophysiological conditions and may thus have therapeutic potential. AbbreviationsACEI, angiotensin-converting enzyme inhibitor; ARB, AT1 receptor blocker; BH4 (6R-)5,6,7,8-tetrahydrobiopterin; DOCA, deoxycorticosterone acetate; eNOS, endothelial nitric oxide synthase; GCH1, guanosine-5′-triphosphate cyclohydrolase 1; GPx1, glutathione peroxidase 1; NO, nitric oxide; Nox, homolog protein of the nicotinamide adenine dinucleotide phosphate oxidase subunit gp91phox; O2 -·, superoxide anion; ONOO -, peroxynitrite; ROS, reactive oxygen species; SHR, spontaneously hypertensive rats; SOD, superoxide dismutase IntroductionThe signalling molecule nitric oxide (NO) regulates vital functions such as neurotransmission or vascular tone (via activation of soluble guanylyl cyclase), gene transcription and mRNA translation (via iron-responsive elements), and posttranslational modifications of proteins via ADP-ribosylation (Förstermann et al., 1994). However, NO can also react with superoxide anion (O2 -·), forming the potent cytotoxin peroxynitrite (ONOO -). ONOO -causes oxidative damage, nitration and S-nitrosylation of biomolecules including proteins, lipids and DNA (Ridnour et al., 2004). BJPBritish Journal of Pharmacology DOI:10.1111DOI:10. /j.147...

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“…44 Imanishi et al 45 demonstrated that Aliskiren improved heritable hyperlipidemic rabbits and enhanced endothelial-dependent relaxation in thoracic aortic segments. 44 Imanishi et al 45 demonstrated that Aliskiren improved heritable hyperlipidemic rabbits and enhanced endothelial-dependent relaxation in thoracic aortic segments.…”

Section: Other Antihypertensive Agentsmentioning

confidence: 99%

Approach to a Successful Selection of Antihypertensive Drugs for the Patient With Atherosclerosis

Velasco

Rojas²,

Pirela³

2013

American Journal of Therapeutics

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Coronary heart disease has become a medical and public health issue associated with multiple risk factors such as age, diet, and sedentary life style. Associations between hypertension and atherosclerosis have been extensively studied, and several trials have demonstrated antiatherosclerotic properties in some of the most widely used antihypertensive agents. Hence, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers have been the target for a number of controlled randomized trials studying its effect on atherosclerosis progression. Carotid intima-media thickness measurement by ultrasound is used as surrogate of atherosclerosis in most of these controlled trials. This review of the literature aims to summarize the most significant controlled trials involving antihypertensive therapy and atherosclerosis regression based on the carotid intima-media thickness measurement.

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Aliskiren Improves Nitric Oxide Bioavailability and Limits Atherosclerosis

Cited by 7 publications

References 15 publications

Antiatherosclerotic potential of aliskiren: its antioxidant and anti-inflammatory effects in rabbits: a randomized controlled trial

Antiatherosclerotic potential of aliskiren: its antioxidant and anti-inflammatory effects in rabbits: a randomized controlled trial

Therapeutic effect of enhancing endothelial nitric oxide synthase (eNOS) expression and preventing eNOS uncoupling

Approach to a Successful Selection of Antihypertensive Drugs for the Patient With Atherosclerosis

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