Sex-mediated response to landiolol, a ß1 selectif adrenergic blocker, in myocardial dysfunction during sepsis

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Rationale Gender affects the hemodynamic and immune responses to infection while the adrenergic system plays a key role in sepsis. Gender-dependent effects of adrenergic modulation with beta-blockers remain undetermined. To investigate any gender effect of the ß 1 -adrenergic blocker, landiolol, on cardiac performance and energy metabolism in septic rats, and to explore the expression of candidate genes involved in this process. One hour after cecal ligation and puncture (CLP), male and female rats were randomized to receive landiolol (0.1 mg/kg/min) or n-saline (10 mL/kg/h). Six groups were studied: sham male, CLP male, CLP + landiolol male, sham female, CLP female and CLP + landiolol female. Cardiac magnetic resonance imaging (MRI) was carried out 18 h after CLP to assess in vivo cardiac function and molecular pathways were identified by a transcriptomic approach. In males, landiolol increased indexed stroke volume (SVi) by reversing the CLP-induced reduction of indexed end-diastolic volume (EDVi) without affecting left ventricle ejection fraction (LVEF). In females, landiolol did not increase SVI and EDVi, but decreased LVEF. At Hour 20, hearts were frozen for quantification of gene and cardiac protein expressions. In males, landiolol reversed the CLP-induced pathways for inflammation, apoptosis, metabolism, oxidative stress and calcium transport. Data are under analysis for females but preliminary results showed already some differences for example for the NPR3 and Endothelin-1 receptors. Only in males, CLP affected the pAKT:AKT ratio and eNOS expression, while landiolol reversed its effect. Landiolol improved the in vivo cardiac performance of septic male rats, in association with an improvement in diastolic function. However, in septic females, treatment with landiolol resulted in deleterious effects. Ongoing analysis of these signaling pathways will aid better understanding of sex differences occurring in sepsis.