Atypical reactions associated with use of angiotensin‐converting enzyme inhibitors and apheresis

Owen, H.; Brecher, Mark E.

doi:10.1046/j.1537-2995.1994.341095026976.x

Cited by 132 publications

(78 citation statements)

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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

et al. 2008

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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.

120

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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“…One study of 299 consecutive patients undergoing plasmapheresis showed that all 14 patients (100%) receiving ACE inhibitors at the time of plasmapheresis reported these symptoms. 2 In contrast, only 20 (7%) of 285 patients not receiving ACE inhibitors reported these symptoms. Thus, ACE inhibitors should ideally be withheld in patients undergoing plasmapheresis.…”

Section: While Undergoing This Treatment Modalitymentioning

confidence: 99%

65-Year-Old Woman With Shortness of Breath and Dark Urine

Lim

Greene

2011

Mayo Clinic Proceedings

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A 65-year-old previously healthy woman presented to her primary care physician with a 6-week history of increasing dyspnea, accompanied by a dry cough, fatigue, malaise, and poor appetite. Before her initial presentation and the onset of the aforementioned symptoms, she had attributed her illness to an upper respiratory tract infection. She also reported a 1-week history of passing dark urine and had been treated empirically 2 weeks previously with a 3-day course of oral trimethoprim-sulfamethoxazole for presumptive urinary tract infection. At the time of presentation, she denied any other constitutional symptoms, recent travel, medication changes (except for the trimethoprim-sulfamethoxazole), and animal or occupational exposure. Her medical history was remarkable for hypertension, hypothyroidism, diverticulosis, and peptic stricture in the gastroesophageal junction status after a balloon dilatation. Initial laboratory studies yielded the following results (reference ranges provided parenthetically for abnormal values): hemoglobin, 8.4 g/dL (12.0-15.5 g/dL); leukocytes, 12.3 × 10 9 /L (3.5-10.5 × 10 9 /L); platelet count, 449 × 10 9 /L; prothrombin time, 12.5 s (8.3-10.8 s); serum sodium, 131 mmol/L (135-145 mmol/L); potassium, 3.9 mmol/L; creatinine, 4.8 mg/dL (0.6-1.1 mg/dL); blood urea nitrogen, 56 mg/ dL (6-21 mg/dL); chloride, 95 mmol/L (100-108 mmol/L); bicarbonate, 23 mEq/L; calcium, 9.6 mg/dL; and glucose, 97 mg/dL. Findings on liver function tests were as follows: aspartate aminotransferase, 29 IU/L; alanine aminotransferase, 21 IU/L; total and direct bilirubin, 0.2 mg/dL and 0.1 mg/dL, respectively; albumin, 3.5 g/dL; and total protein, 6.6 g/dL.Because previous serum creatinine values had been in the normal range, the patient was admitted to her local hospital for further work-up for acute renal failure. On admission she was hemodynamically stable and her vital signs were as follows: blood pressure, 134/78 mm Hg; heart rate, 70 beats/min; and respiratory rate, 22 breaths/min on room air. On physical examination, the patient was afebrile, alert, and oriented. There was mild conjunctival pallor. Cardiac examination revealed a normal S 1 and S 2 with a 2/6 holosystolic nonradiating murmur loudest at the apex, no additional rubs, and no jugular venous distension. Lungs were clear to auscultation except for bibasilar inspiratory crackles. The remainder of the physical examination findings were unremarkable. Chest radiography showed mild cardiomegaly, pulmonary venous hypertension, and small bilateral pleural effusions with bibasilar atelectasis.A urinalysis demonstrated 4 to 10 white blood cells per high-power field (hpf) (1-10/ hpf) and 51 to 100 red blood cells (RBCs)/hpf (<3/hpf), with less than 25% noted to be dysmorphic, accompanied by occasional granular casts. The predicted urinary protein value was 3281 mg/24 hours. The urine sample was orange and cloudy.

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Atypical reactions associated with use of angiotensin‐converting enzyme inhibitors and apheresis

Abstract: Patients receiving ACE inhibitor therapy who are undergoing therapeutic plasma exchange with albumin replacement solutions are at high risk (100%) for atypical reactions. It is recommended that ACE inhibitors be withheld for at least 24 hours before that procedure.

Cited by 132 publications

References 10 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

65-Year-Old Woman With Shortness of Breath and Dark Urine

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