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

Abstract

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 (350–400 g) were made septic by intraperitoneal (i.p.) administration of 200 mg/kg cecal inoculum. Sham animals received 5% dextrose water, i.p. Echocardiography was performed at baseline, 3 days and 7 days post-sepsis/sham. NE (0.6 μg kg − 1 h − 1 ) was infused for 2 h, 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 RT 2 profiler™ PCR array PARN-012 (Rat apoptosis array; SuperArray, MD) using RT 2 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.