Case Report: Brief Report: Acute Renal Failure after Losartan Treatment in a Patient with Bilateral Renal Artery Stenosis

Holm, Ellen; Randløv, Annette; Strandgaard, Svend

doi:10.3109/08037059609078075

Cited by 25 publications

(19 citation statements)

References 18 publications

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“…1 However, they may cause secondary effects, such as coughing, deterioration of renal function in cases of underlying renal artery stenosis, and, more rarely, angioedema. [2][3][4][5][6][7] In addition, these agents are not very effective in some patients, particularly African Americans, in whom high blood pressure (BP) is associated with low renin levels and a response to salt depletion. 8,9 The development of new classes of antihypertensive agents with different mechanisms of action, therefore, remains an important goal.…”

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confidence: 99%

Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure

et al. 2008

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Abstract-Overactivity of the brain renin-angiotensin system has been implicated in the development and maintenance of hypertension. We reported previously that angiotensin II is converted to angiotensin III by aminopeptidase A in the mouse brain. We then used specific and selective aminopeptidase A inhibitors to show that angiotensin III is one of the main effector peptides of the brain renin-angiotensin system, exerting tonic stimulatory control over blood pressure in hypertensive rats. Aminopeptidase A, the enzyme generating brain angiotensin III, thus represents a potential candidate central nervous system target for the treatment of hypertension. Given this possible clinical use of aminopeptidase A inhibitors, it was, therefore, important to investigate their pharmacological activity after oral administration. We investigated RB150, a dimer of the selective aminopeptidase A inhibitor, EC33, generated by creating a disulfide bond. This chemical modification allows prodrug to cross the blood-brain barrier when administered by systemic route. Oral administration of RB150 in conscious DOCA-salt rats inhibited brain aminopeptidase A activity, resulting in values similar to those obtained with the brains of normotensive rats, demonstrating the central bioavailability of RB150. Oral RB150 treatment resulted in a marked dose-dependent reduction in blood pressure in DOCA-salt but not in normotensive rats, with an ED 50 in the 1-mg/kg range, achieved in Ͻ2 hours and lasting for several hours. This treatment also significantly decreased plasma arginine-vasopressin levels and increased diuresis, which may participate to the blood pressure decrease by reducing the size of fluid compartment. Thus, RB150 may be the prototype of a new class of centrally active antihypertensive agents. Key Words: aminopeptidase A inhibitors Ⅲ blood pressure Ⅲ brain renin-angiotensin system Ⅲ DOCA-salt rats Ⅲ hypertension H ypertension is a major cardiovascular risk factor, affecting Ϸ20% of the adult population, of which 95% have essential hypertension. Blockers of the systemic renin-angiotensin system (RAS), angiotensin (Ang) I-converting enzyme (ACE; EC 3.4.15.11) inhibitors or Ang II receptor type 1 (AT 1 ) antagonists, have since been shown to be efficient and safe for treating hypertension. 1 However, they may cause secondary effects, such as coughing, deterioration of renal function in cases of underlying renal artery stenosis, and, more rarely, angioedema. [2][3][4][5][6][7] In addition, these agents are not very effective in some patients, particularly African Americans, in whom high blood pressure (BP) is associated with low renin levels and a response to salt depletion. 8,9 The development of new classes of antihypertensive agents with different mechanisms of action, therefore, remains an important goal. In this way, because a brain RAS hyperactivity has been implicated in the development and maintenance of hypertension, 10 -13 its components could constitute interesting targets. Among the bioactive peptides of the brain RAS, Ang I...

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Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure

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“…Blockers of the renin-angiotensin system (RAS), either angiotensin I-converting enzyme (ACE) inhibitors or angiotensin II (AngII) receptor type 1 (AT 1 ) antagonists, have proved to be efficient and safe (3). ACE inhibitors cause cough and more rarely angioedema (4)(5)(6), and renal function may deteriorate with both ACE inhibitors and AT 1 receptor antagonists in cases of underlying renal artery stenosis (7)(8)(9). In addition, blockers of the RAS are poorly effective in some patients, especially in African Americans in whom high blood pressure (BP) is accompanied by a low-renin state and is usually responsive to salt-depletion (10,11).…”

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Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: A potential treatment of salt-dependent hypertension

Fournié‐Zaluski

Fassot

Valentin

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

122

131

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The hyperactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several types of experimental and genetic hypertension animal models. We previously reported that in the murine brain, aminopeptidase A (APA) is involved in the conversion of angiotensin II (AngII) to AngIII and that AngIII is one of the main effector peptides of the brain RAS in the control of vasopressin release. Here we report that brain AngIII exerts a tonic stimulatory effect on blood pressure in a model of salt-dependent hypertension, the DOCA-salt rat, characterized by a depressed systemic but a hyperactive brain RAS. Similar high blood pressure accompanied by a low systemic renin state was described in some patients, especially in hypertensive African Americans who are resistant to treatment by blockers of the systemic RAS. We developed RB150, a prodrug of the specific and selective APA inhibitor, EC33. RB150 given i.v. is able to cross the blood-brain barrier, to inhibit brain APA, and to block the formation of central AngIII. A single dose of systemic RB150 (15 mg͞kg, i.v.) in conscious DOCA-salt rats inhibited brain APA activity and markedly reduced blood pressure for up to 24 h. These results demonstrate the crucial role of brain APA as a candidate target for the treatment of hypertension and suggest that RB150, a potent systemically active APA inhibitor, could be the prototype of a new class of antihypertensive agents for the treatment of certain forms of hypertension.

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“…Patient-months of exposure are based on patients for whom either the date of stopping aliskiren was known or who continued to take aliskiren until the end of the study period. In order to detect any early-onset events, the differences between ID in month 1 (ID 1 ) and months 2 to 6 (ID [2][3][4][5][6] ) of treatment were calculated with 95% confidence intervals (CIs).…”

Section: Discussionmentioning

confidence: 99%

“…This classification resulted in only four cases of acute renal failure, which were all possibly related to the use of aliskiren. A large proportion of the individuals with renal events were 70 years or older ( Abbreviations: ADR, adverse drug reaction; CI, 95% confidence interval for ID 1 -ID 2-6 ; ID 1 , incidence density for each event during the first month of treatment; ID 2-6 , incidence density for each event during treatment months 2 to 6; ID 1 ˗ID 2-6 , arithmetic difference between ID 1 and ID [2][3][4][5][6] ; N 1 , total number of reports of each event during the first month of treatment; N 2-6 , total number of reports of each event during treatment in months 2 to 6; NA, not applicable; RFS, reason for stopping.…”

Section: Renal Eventsmentioning

confidence: 99%

“…3 These agents, however, have been associated with adverse renal events especially in elderly individuals and those with arterial stenosis. 4,5 Furthermore, ACE inhibitors and ARBs have also been associated with angioneurotic edema caused by the reduction in bradykinin breakdown and consequent vasodilatation. [6][7][8] Since aliskiren also acts on the renin-angiotensin system, renal and angioneurotic edema events were a potential concern for aliskiren.…”

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confidence: 99%

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Utilisation and Tolerability of Aliskiren in the Primary Care Setting in England

Coughtrie

Doe

Layton

et al. 2016

J of Clinical Hypertension

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2Aliskiren (Rasilez), a direct renin inhibitor, is indicated for the treatment of essential hypertension. A postmarketing prescription-event monitoring (PEM) study was conducted in England to monitor the safety and utilization of aliskiren. Summary statistics and event incidence densities were calculated. The cohort consisted of 6385 individuals with a median age of 68 years (interquartile range, 59-76). Aliskiren was largely prescribed for its licensed indication of hypertension (93.3%) and was reported as "effective" by the prescriber in 77.4% of individuals. Frequently reported clinical events during treatment were diarrhea (3.1% of on-treatment events), malaise/lassitude (3.0%), and nausea/ vomiting (1.2%), which were also common reasons for treatment cessation. Renal events were rare, with 24 cases probably or possibly related to aliskiren use, and four of which were classified as acute renal failure using RIFLE (Risk Injury Failure Loss End-Stage Kidney Disease) criteria. These results should be used in conjunction with other clinical and pharmacoepidemiologic studies to optimize the safe prescribing of aliskiren. J Clin Hypertens (Greenwich).

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Case Report: Brief Report: Acute Renal Failure after Losartan Treatment in a Patient with Bilateral Renal Artery Stenosis

Cited by 25 publications

References 18 publications

Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure

Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure

Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: A potential treatment of salt-dependent hypertension

Utilisation and Tolerability of Aliskiren in the Primary Care Setting in England

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