Norepinephrine induces systolic failure and inhibits antiapoptotic genes in a polymicrobial septic rat model

Aims: We examined the effect of norepinephrine (NE) infusion on left ventricular function and apoptotic genes during progression of polymicrobial sepsis. Methods: Male Sprague-Dawley rats (350-400g) were made septic by intraperitoneal (i.p.) administration of 200mg/kg cecal inoculum. Sham animals received 5% dextrose water, i.p. Echocardiography was performed at baseline, 3days and 7days post-sepsis/sham. NE (0.6µgkg-1h-1) was infused for 2h, before the end of day 3 of echocardiography. At the end of day 7, rats were euthanized and heart tissues harvested for isolation of total RNA. PCR was performed using RT2 profiler™ PCR array PARN-012 (Rat apoptosis array; SuperArray, MD) using RT2 Real-Time™ SYBR Green PCR master mix PA-012. Key findings: NE-infusion resulted in a significant decrease in the left ventricular ejection fraction (EF) (62.56 ± 2.07 from the baseline 71.11 ± 3.23, p< 0.05) and fractional shortening (FS) (39.90 ± 2.64 from the sham group 54.41 ± 2.19, p< 0.05) at 7. days post-sepsis, respectively. Super Array data revealed that during sepsis, tumor necrosis factor (TNF-α) (2.85 ± 0.07 fold, p< 0.0001), anti-apoptotic molecules, Prok2 (16.07 ± 0.48 fold, p< 0.0001) and interleukin-10 (IL-10) (23.5 ± 0.57 fold, p< 0.0001) were up regulated at day 1. At 7-days post-sepsis, CD40lg (2.49 ± 0.54 fold, p< 0.08) and Birc1b (17.8 ± 0.58 fold, p< 0.0001) were up regulated compared to the sham, 1 and 3-days post-sepsis groups. Significance: The data suggest that upregulation of a series of pro-apoptotic molecules could be responsible for systolic and diastolic dysfunction during 3 and 7. days post sepsis.