If Channel Inhibition with Ivabradine Does not Improve Cardiac and Vascular Function in Experimental Septic Shock

• Published in: Shock (Augusta, Ga.) Ga.), 2016-09, Vol.46 (3), p.297-303
• Main Authors: Wei, Chaojie, Kattani, Narimane Al, Louis, Huguette, Albuisson, Eliane, Levy, Bruno, Kimmoun, Antoine
• Format: Article
• Language: English
• Subjects: Animals; Benzazepines; Benzazepines - therapeutic use; Cardiology and cardiovascular system; Cardiovascular Agents; Cardiovascular Agents - therapeutic use; Cecum; Cecum - injuries; Echocardiography; Heart Rate; Heart Rate - drug effects; Hemodynamics; Hemodynamics - drug effects; Human health and pathology; Interleukin-10; Interleukin-10 - blood; Interleukin-6; Interleukin-6 - blood; Life Sciences; Ligation; Ligation - adverse effects; Male; Rats; Rats, Wistar; Shock, Septic; Shock, Septic - blood; Shock, Septic - drug therapy; Tumor Necrosis Factor-alpha; Tumor Necrosis Factor-alpha - blood
• ISSN: 1073-2322; 1540-0514
• DOI: 10.1097/SHK.0000000000000593

OBJECTIVE:Previous studies have suggested that lowering heart rate by selective β1-blockers improves sepsis-induced cardiac and vascular dysfunction primarily by decreasing pro-inflammatory pathways. However, the impact of isolated heart rate reduction on hemodynamics and inflammatory pathways remains unknown. The present study was designed to assess the effects of heart rate reduction by Ivabradine, an If channel inhibitor, on cardiovascular function and inflammatory pathways in peritonitis-induced septic shock in rats. DESIGN:Randomized animal study. SETTING:University research laboratory INTERVENTIONS:Four hours after cecal ligation and puncture (CLP), Wistar rats were randomly allocated to the following groupsCLP (n = 8) and CLP+Ivabradine (n = 8, administered per os four hours after the surgery). Another eight Wistar male rats underwent sham operation. All rats received a continuous infusion of saline (10 ml.kg.h), analgesic (Nalbuphin0.2 mg.kg.h) and antibiotics (Imipenem and Cilastatin Sodium10 mg.kg) four hours after the surgery. Assessment at 18 hours included hemodynamics, in vivo cardiac function by echocardiography and ex vivo vasoreactivity by myography. Circulating cytokine levels (TNF-α, IL-6 and IL-10) were measured by ELISA while cardiac and vascular protein expressions of NF-κB/IκBα/iNOS and Akt/eNOS were assessed by Western blotting. RESULTS:Compared to sham animals, CLP induced tachycardia, hypotension, decreased cardiac output, hyperlactatemia and vascular hypo-responsiveness to vasopressors. Compared to the CLP group, adjunction of Ivabradine decreased the heart rate without any impact on blood pressure, lactatemia or vascular responsiveness to vasopressors. Adjunction of Ivabradine to CLP rats had no impact on TNF-α, IL-6 and IL-10 cytokines, or on the protein expression levels of phosphorylated forms of NF-κB, Akt, eNOS and degradation of IκBα in cardiac and vascular tissues. CONCLUSION:Isolated heart rate reduction by Ivabradine in an experimental model of septic shock does not appear to be associated with any effect on the tested parameters of cardiac function or on vascular responsiveness to vasopressors. Moreover, in this setting, Ivabradine does not alter the circulating levels of selected pro-/anti-inflammatory cytokines or cardiac and vascular NF-κB/IκBα protein expression levels.