Norepinephrine (NE) Modulates Active Caspase‐3 Expression and Increase Susceptibility of Cardiomyocytes for Voltage‐stimulated Deformation during Sepsis

Abstract

In the present study, we tested the hypothesis that the progression of sepsis from 1 to 7‐days modulates the NE‐induced alterations in caspase‐3 and the time for deformation (TDEF) of adult rat ventricular myocytes (ARVM). Male Sprague‐Dawley rats (350–400g) were randomized into sham, 1‐, 3‐ and 7‐day sepsis groups. Sepsis and sham‐sepsis was induced using 200 mg/kg cecal inoculum and 5% dextrose water i.p., respectively. Isolated ARVMs were subjected to 5Hz stimulation using the IonOptix edge detection system to record TDEF (cutoff time 300s). The concentration of myocardial NE and the expression of active caspase‐3 were determined using immunochemical assay in the myocardial tissue samples. The cell viability of the NE‐treated septic ARVMs was significantly reduced (42%) compared to (26%) in the sham NE‐treated ARVMs. When stimulated, the septic ARVMs produced a progressive decrease in TDEF in the 1‐day (195±38s), 3‐day (156±22s) and 7‐day (101±28s) groups compared to the sham (206±28s) group. The NE‐treated septic ARVMs significantly decreased TDEF in both the sham and septic ARVMs. A significant increase in the myocardial NE levels was observed in the septic groups. We observed that the increased duration of sepsis significantly elevated the myocardial active caspase‐3, which was further upregulated by NE. The data suggest that an NE‐induced decrease in the TDEF correlated with the upregulated expression of active caspase‐3. We concluded that active caspase‐3 may increase the susceptibility of NE‐treated ARVMs for voltage‐stimulated deformation during progression of polymicrobial sepsis. (This work was supported by NHLBI # 66016).