Responses to converting enzyme and renin inhibition. Role of angiotensin II in humans.

Fisher, Naomi D.L.; Allan, Donald R.; Kifor, Imre; Gaboury, Cynthia L.; Williams, Gordon H.; Moore, Thomas J.; Hollenberg, Norman K.

doi:10.1161/01.hyp.23.1.44

Cited by 73 publications

(50 citation statements)

References 19 publications

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“…The placebo did nothing. Captopril and enalkiren both led to striking renal vasodilation (43). The response to enalkiren again was significantly larger than the response to captopril.…”

Section: Efficacy: Renal Responsesmentioning

confidence: 81%

Renin Inhibition

Fisher¹,

Hollenberg²

2005

Journal of the American Society of Nephrology

158

127

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“…The placebo did nothing. Captopril and enalkiren both led to striking renal vasodilation (43). The response to enalkiren again was significantly larger than the response to captopril.…”

Section: Efficacy: Renal Responsesmentioning

confidence: 81%

Renin Inhibition

Fisher¹,

Hollenberg²

2005

Journal of the American Society of Nephrology

158

127

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“…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. 36 -41 …”

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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“…Renal plasma flow (RPF) was measured by the clearance of paraaminohippurate (PAH; Clinalfa, Laufelfingen, Switzerland) and glomerular filtration rate by the clearance of inulin (Inutest Polyfructosan, Fresenius Pharma, Linz, Austria) by autoanalyzer methods described previously. 11 After a 60-minute control period to establish basal RPF, the drug was dosed by mouth. Each subject received at least 2 separate escalating doses of aliskiren, ranging from 75 to 600 mg (Novartis Pharmaceuticals, Basel, Switzerland).…”

Section: Methodsmentioning

confidence: 99%

Renal and Hormonal Responses to Direct Renin Inhibition With Aliskiren in Healthy Humans

et al. 2008

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Background-Pharmacological interruption of the renin-angiotensin system focuses on optimization of blockade. As a measure of intrarenal renin activity, we have examined renal plasma flow (RPF) responses in a standardized protocol. Compared with responses with angiotensin-converting enzyme inhibition (rise in RPF Ϸ95 mL · min Ϫ1 · 1.73 m Ϫ2 ), greater renal vasodilation with angiotensin receptor blockers (Ϸ145 mL · min Ϫ1 · 1.73 m Ϫ2 ) suggested more effective blockade. We predicted that blockade with the direct oral renin inhibitor aliskiren would produce renal vascular responses exceeding those induced by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Methods and Results-Twenty healthy normotensive subjects were studied on a low-sodium (10 mmol/d) diet, receiving separate escalating doses of aliskiren. Six additional subjects received captopril 25 mg as a low-sodium comparison and also received aliskiren on a high-sodium (200 mmol/d) diet. RPF was measured by clearance of para-aminohippurate. Aliskiren induced a remarkable dose-related renal vasodilation in low-sodium balance. The RPF response was maximal at the 600-mg dose (197Ϯ27 mL · min Ϫ1 · 1.73 m Ϫ2 ) and exceeded responses to captopril (92Ϯ20 mL · min Ϫ1 · 1.73 m

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Responses to converting enzyme and renin inhibition. Role of angiotensin II in humans.

Cited by 73 publications

References 19 publications

Renin Inhibition

Renin Inhibition

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

Renal and Hormonal Responses to Direct Renin Inhibition With Aliskiren in Healthy Humans

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