Sex-Mediated Response to the Beta-Blocker Landiolol in Sepsis: An Experimental, Randomized Study

Objectives: To investigate any gender effect of the beta-1 adrenergic blocker, landiolol, on cardiac performance and energy metabolism in septic rats, and to explore the expression of genes and proteins involved in this process. Design: Randomized animal study. Setting: University research laboratory. Subjects: Male and female Wistar rats. Interventions: One hour after cecal ligation and puncture, male and female rats were randomly allocated to the following groups: sham male, cecal ligation and puncture male, cecal ligation and puncture + landiolol male, sham female, cecal ligation and puncture female, and cecal ligation and puncture + landiolol female. Cardiac MRI was carried out 18 hours after cecal ligation and puncture to assess in vivo cardiac function. Ex vivo cardiac function measurement and 31P magnetic resonance spectroscopy were subsequently performed using an isovolumic isolated heart preparation. Finally, we assessed cardiac gene and protein expression. Measurements and Main Results: In males, landiolol increased indexed stroke volume by reversing the indexed end-diastolic volume reduction without affecting left ventricle ejection fraction. In females, landiolol did not increase indexed stroke volume and indexed end-diastolic volume but decreased left ventricle ejection fraction. Landiolol had no effect on ex vivo cardiac function and on high-energy phosphate compounds. The effect of landiolol on the gene expression of natriuretic peptide receptor 3 and on protein expression of phosphorylated-AKT:AKT ratio and endothelial nitric oxide synthase was different in males and females. Conclusions: Landiolol improved the in vivo cardiac performance of septic male rats while deleterious effects were reported in females. Expression of natriuretic peptide receptor 3, phosphorylated-AKT:AKT, and endothelial nitric oxide synthase are signaling pathways to investigate to better understand the sex differences in sepsis. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (https://ift.tt/29S62lw). Supported, in part, by Fondation pour la Recherche Médicale (DEA 20150633224), AOP Orphan, Lions Club Marseille Doyen and France Life Imaging (grant ANR-11-INBS-0006). Dr. Mathieu received funding from Fondation Recherche Médicale (DEA20150633224) and Lions club Marseille Doyen. Dr. Singer received funding from AOP Pharma. Dr. Mege disclosed government work. Dr. Leone’s institution received funding from AOP Orphan (provided treatment: landiolol). The remaining authors do not have any potential conflicts of interest. For information regarding this article, Email: marc.leone@ap-hm.fr Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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