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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 HH, MD, PhD1; Ahmad, Monir, MD, PhD1; Marc, Yannick, PhD2,3; Llorens-Cortes, Catherine, PhD2

doi: 10.1097/FJC.0000000000000638
Original Article: PDF Only

Aims: Inhibition of brain angiotensin III by central infusion of aminopeptidase A (APA) inhibitor firibastat (RB150) inhibits sympathetic hyperactivity and heart failure (HF) in rats post myocardial infarction (MI). The present study evaluated effectiveness of systemic treatment with firibastat compared to 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 post MI in protocol 1 with vehicle, or firibastat at 50 mg/kg/day sc or 150 mg/kg/day oral, once daily and in protocol 2, with vehicle, firibastat 150 mg/kg or losartan 50 mg/kg oral twice daily. At 5 weeks, LV function was evaluated by echocardiography and Millar catheter.

Post MI, rats developed moderate severe HF. Both sc and oral firibastat inhibited brain APA and attenuated LV dysfunction. Oral firibastat and losartan similarly improved LVEDP. However, whereas firibastat improved dP/dt max, losartan lowered dP/dtmax and LVPSP, and increased plasma creatinine by ∼ 50%. On the other hand, losartan more effectively inhibited cardiac fibrosis.

Conclusion: Inhibition of brain RAS by oral APA inhibitor is at least as effective as oral 1R blocker">AT1R blocker to inhibit cardiac dysfunction post MI but without hypotension or renal dysfunction.

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

2 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

3 Quantum Genomics, Paris, France.

Address of corresponding author: Frans HH Leenen, MD, PhD, FRCPC, FAHA, University of Ottawa Heart Institute, Rm H-3229A, 40 Ruskin Street, Ottawa, Ontario, Canada, K1Y 4W7, Telephone (613) 696-7361, Fax: (613) 696-7242, Email: fleenen@ottawaheart.ca

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