Functional and Biochemical Analysis of Angiotensin II–Forming Pathways in the Human Heart

Wolny, Arlene C.; Clozel, Jean‐Paul; Rein, Josiane; Mory, Paul; Vogt, Paul; Turino, Marko; Kiowski, Wolfgang; Fischli, Walter

doi:10.1161/01.res.80.2.219

Cited by 229 publications

(141 citation statements)

References 39 publications

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“…Alternative pathways to renin cleavage of angiotensinogen are not thought to be of any great physiological importance, 32 whereas a substantial proportion of tissue Ang II is generated by non-ACE pathways. 33,34 Hence, it has been proposed that more effective blockade of tissue Ang II formation may occur with renin inhibition than with ACE inhibition. 35 Further differences between renin inhibition, ACE inhibition, and angiotensin receptor blockade could arise from disparate effects on circulating and tissue levels of bioactive Ang peptides and different patterns of stimulation of the various receptor subtypes.…”

Section: Discussionmentioning

confidence: 99%

Blood Pressure Lowering in Essential Hypertension With an Oral Renin Inhibitor, Aliskiren

et al. 2003

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Abstract-Inhibition of the first and rate-limiting step of the renin-angiotensin system has long been an elusive therapeutic goal. Aliskiren, the first known representative of a new class of completely nonpeptide, orally active, renin inhibitors, has been shown to inhibit the production of angiotensin I and II in healthy volunteers and to reduce blood pressure (BP) in sodium-depleted marmosets. The aim of this randomized, double-blind, active comparator trial study was to assess the BP-lowering efficacy and safety of aliskiren. Key Words: renin Ⅲ blood pressure Ⅲ hypertension, essential Ⅲ blood pressure monitoring, ambulatory Ⅲ receptors, angiotensin Ⅲ losartan T he renin-angiotensin system (RAS) has well-established roles in both blood pressure (BP) regulation and atherogenesis. 1,2 Recent clinical trial evidence suggests that blockade of the RAS by angiotensin-converting enzyme inhibition or by angiotensin receptor blockade may influence largevessel atherosclerosis and cardiovascular morbidity and mortality independent of BP lowering. 3,4 As renin catalyzes the first and rate-limiting step of the system and has high specificity for angiotensinogen, blockade of the production of angiotensin (Ang) II by direct inhibition of renin has long been a therapeutic goal. Indeed, intravenous administration of the early renin inhibitors, such as enalkiren and remikiren, did reduce angiotensin levels and lower BP without any important adverse effects. 5-8 However, to date, due to relatively low potency, poor oral bioavailability (Ͻ1%), short durations of action, and high costs of synthesis, none of these peptide and peptidomimetic inhibitors has made it to the end of clinical trials. 9 Aliskiren, an octanamide, is the first known representative of a new class of completely nonpeptide, low-molecularweight, orally active transition-state renin inhibitors. 10 Designed through the use of molecular modeling techniques, it is a potent and specific in vitro inhibitor of human renin (IC50 in the low nanomolar range), with a plasma half-life of Ϸ24 hours. 10 Aliskiren has good water solubility and low lipophilicity and is resistant to biodegradation by peptidases in the intestine, blood circulation, and the liver. 10 When administered orally to sodium-depleted marmosets, it caused significant and sustained reductions in arterial blood pressure (unpublished data). In single-dose and multiple-dose tolerability studies in healthy normotensive male volunteers, oral doses up to 640 mg daily for 8 days were well tolerated and did not result in any significant toxicity. 11 Micromolar plasma concentrations were achieved, and aliskiren was shown to cause a dose-dependent decrease in plasma renin activity (PRA), to effectively block the formation of both Ang I and Ang II, and to decrease plasma and urine aldosterone levels. 11 In this study, we studied for the first time the efficacy, safety, and tolerability of 4 weeks of treatment with 37.5, 75, 150 and 300 mg aliskiren in healthy individuals with mild to moderate hypertension. We compared...

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Section: Discussionmentioning

confidence: 99%

Blood Pressure Lowering in Essential Hypertension With an Oral Renin Inhibitor, Aliskiren

et al. 2003

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“…Studies have suggested that non-ACE pathways are, by inference, responsible for about 40% of Ang II generation in the intact human kidney [86] and that chymase is the dominant Ang II-generating pathway in the human heart, coronary arteries, and atherosclerotic aorta in vitro [85,87,88]. It has thus been proposed that abnormal activation of the tissue RAAS may contribute to the pathogenesis of cardiovascular disease even in the absence of derangements in the circulating system [89].…”

Section: Raas Overviewmentioning

confidence: 99%

Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation

Raimondo¹,

Tuttolomondo²,

Buttà³

et al. 2012

CPD

112

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Abstract:The role of inflammation in cardiovascular disease and in hypertensive disease above all, is complex. Several studies confirm that activation of renin-angiotensin-aldosteron system (RAAS), through increase in the production of angiotensin II (Ang II), is closely related to local vascular inflammation. Over the BP lowering effects of anti-hypertensive treatments, several ancillary effects for every class may be found, distinguishing the various drugs from one another. Given the pro-inflammatory effects of Ang II and aldosterone, agents that interfere with the components of RAAS, such as ACE inhibitors, Angiotensin Recpetor Blockers (ARBs), and mineralocorticoid receptor antagonists (spironolactone or the more selective eplerenone), represent logical therapeutic tools to reduce vascular inflammation and cardiovascular risk, as suggested in large clinical trials in patients with hypertension and diabetes. Regarding ACE inhibitors, actually there is no convincing evidence indicating that ACEi's reduce plasma levels of major inflammatory markers in hypertension models. Lack of evidence concerns especially these inflammation markers, such as fibrinogen of CRP, which are less closely related to atherosclerotic disease and vascular damage and conversely are affected by several more aspecific factors. Results obtained by trials accomplished using ARBs seem to be more univocal to confirm, although to great extent, these is an anti-inflmmatory effect of drugs bocking AT1 receptor. In order to strictly study the effects of blockage of RAAS on inflammation, future studies may explore different strategies by, for example, simultaneously acting on the ACE and the AT1 angiotensin receptors.

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“…Until now, there have been many reports of peptides with respect to analysis of drugs in plasma using column switching techniques [13][14][15]. Analysis of ANG peptides has been performed using HPLC combined with radioimmunoassay [16][17][18][19]. Liquid chromatography-mass spectrometry (LC-MS) features high selectively and high sensitivity.…”

Section: Introductionmentioning

confidence: 99%

Method Development and Validation of Liquid Chromatography-Tandem Mass Spectrometry for Angiotensin-II in Human Plasma: Application to Study Interaction Between Atorvastatin & Olmesartan Drug Combination

Pal

2014

Ind J Clin Biochem

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Simple and sensitive Liquid ChromatographyTandem Mass Spectrometry (LCMS/MS) method was developed and validated, then was implicated on hypertensive human subjects to study drug interaction of atorvastatin (ATVS) and Olmesartan (OLM) on status of Angiotensin-II (ANG-II). The ANG-II in plasma was extracted with 5 mL methanol containing 5 % formic acid through C 18 (cartridges) liquid-liquid extraction, dried and reconstituted with 1 mL of 16 % acetonitrile in 0.1 % formic acid in water. The chromatographic separation of ANG-II with a Agilent technology 6410 Triple quadrupole was carried multiple reaction monitoring scan mode with a Agilent 1290 Infinity LC system for UHPLC. The sample were separated on a (Thermo Scientific) Hy-Purity advance (50 9 4.6 mm, 5 lm) using Mobile Phase A: 16 % acetonitrile in 0.1 % formic acid in water and Mobile Phase B: 0.1 % formic acid in methanol at a flow rate of 0.3 mL/min, performed at ambient temperature. The mobile phase gradient of 16 % acetonitrile in water was linearly increased to 38 % acetonitrile over 10 min and subsequently the mobile-phase was increased to 100 % acetonitrile over 15 min. The developed method was validated for specificity, accuracy, precision, stability, linearity, sensitivity and recovery. The method was linear between peak area ratio of standard and internal standard over the range of 50-800 ng/mL. The method was successfully applied for the drug interaction study revealed levels of ANG-II were significantly higher in ATV-S ? OLM treatment condition as compared to individual treatment of OLM. This reflects the reason of low effectiveness of ATVS ? OLM in combination instead of synergistic activity.

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Functional and Biochemical Analysis of Angiotensin II–Forming Pathways in the Human Heart

Cited by 229 publications

References 39 publications

Blood Pressure Lowering in Essential Hypertension With an Oral Renin Inhibitor, Aliskiren

Blood Pressure Lowering in Essential Hypertension With an Oral Renin Inhibitor, Aliskiren

Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation

Method Development and Validation of Liquid Chromatography-Tandem Mass Spectrometry for Angiotensin-II in Human Plasma: Application to Study Interaction Between Atorvastatin & Olmesartan Drug Combination

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