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Specific Inhibition of Brain Angiotensin III Formation as a New Strategy for Prevention of Heart Failure After Myocardial Infarction

Leenen, Frans H. H., MD, PhD, FRCPC, FAHA*; Ahmad, Monir, MD, PhD*; Marc, Yannick, PhD†,‡; Llorens-Cortes, Catherine, PhD

Journal of Cardiovascular Pharmacology: February 2019 - Volume 73 - Issue 2 - p 82–91
doi: 10.1097/FJC.0000000000000638
Original Article
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Aims: Inhibition of brain angiotensin III by central infusion of aminopeptidase A (APA) inhibitor firibastat (RB150) inhibits sympathetic hyperactivity and heart failure in rats after myocardial infarction (MI). This study evaluated effectiveness of systemic treatment with firibastat compared with 1R blocker">AT1R blocker, losartan.

Methods and Results: MI was induced by ligation of left coronary artery in male Wistar rats. Rats were treated from 1 to 5 weeks after MI in protocol 1 with vehicle, or firibastat at 50 mg/kg/d subcutaneously (s.c.) or 150 mg/kg/d oral, once daily, and in protocol 2, with vehicle, firibastat 150 mg/kg or losartan 50 mg/kg oral twice daily. At 5 weeks, left ventricle function was evaluated by echocardiography and Millar catheter. After MI, rats developed moderate severe heart failure. Both s.c. and oral firibastat inhibited brain APA and attenuated left ventricle dysfunction. Oral firibastat and losartan similarly improved left ventricular end diastolic pressure. However, whereas firibastat improved dP/dtmax, losartan lowered dP/dtmax and left ventricular peak systolic pressure, and increased plasma creatinine by ~50%. On the other hand, losartan more effectively inhibited cardiac fibrosis.

Conclusion: Inhibition of the brain renin–angiotensin system by oral APA inhibitor is at least as effective as oral 1R blocker">AT1R blocker to inhibit cardiac dysfunction after MI but without hypotension or renal dysfunction.

*Brain and Heart Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada;

Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, INSERM U1050/CNRS UMR7241, Center for Interdisciplinary Research in Biology, College de France, Paris, France; and

Quantum Genomics, Paris, France.

Reprints: Frans H. H. Leenen, MD, PhD, FRCPC, FAHA, University of Ottawa, Heart Institute, Room H-3229A, 40 Ruskin St, Ottawa, ON K1Y 4W7, Canada (e-mail: fleenen@ottawaheart.ca).

F. H. H. Leenen holds the Pfizer Chair in Hypertension Research, an endowed chair supported by Pfizer Canada, University of Ottawa Heart Institute Foundation, and Canadian Institutes of Health Research. Research was supported by operating grants from Quantum Genomics, Paris, France, Canadian Institute of Health Research, Grant # FRN:MOP-136923, “Institut National de la Santé et de la Recherche Médicale,” College de France, and National Agency for Research Lab Com CardioBAPAI, ANR-14-LAB6-001.

Y. Marc is an employee of Quantum Genomics. F. H. H. Leenen is a member of the Scientific Advisory Board of Quantum Genomics. The remaining authors have no conflicts of interests to disclose.

All experiments were performed at the University of Ottawa Heart Institute, Ottawa, Ontario, Canada. F. H. H. Leenen designed the experiments, interpreted the data, and wrote all drafts of the manuscript. M. Ahmad performed all experiments, analyzed the data, wrote parts of the first draft of the manuscript, and reviewed drafts of the manuscript. Y. Marc performed the brain APA assays and reviewed drafts of the manuscript. C. Llorens-Cortes codesigned the experiments, cointerpreted the data, and revised drafts of the manuscript.

Received July 30, 2018

Accepted September 17, 2018

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