Sexual dimorphism in myocardial tumor necrosis factor-α and cardiac function during endotoxin tolerance

Preconditioning is injury-induced protection against subsequent injury and may be induced by a variety of stimuli. Both males and females may be preconditioned; however, if females are relatively protected against the initial insult, is their preconditioning threshold higher? We hypothesized that preconditioning injury threshold differences may exist between genders, which may be associated with differences in myocardial inflammatory monokine production. Male and female Sprague-Dawley rats (n = 3-5/group) were given intraperitoneal injections of 125 or 500 μg/kg Salmonella typhimurium lipopolysaccharide (ETX) or 0.4 mL normal saline (NS; 154 mmol/L NaCl). After 24 hours, another injection of 500 μg/kg ETX (injury dose) or NS was given, and the animals were incubated an additional 1 or 6 hours. The rats were anesthetized and myocardial function evaluated via the Langendorff perfusion model. Tumor necrosis factor-α (TNF-α), interleukin-(IL)-1β, and IL-6 were measured in 1-hour animals via an enzyme-linked immunosorbent assay. Nonpreconditioned rats (PC-) received NS followed by ETX. Preconditioned rats received either 125 μg/kg ETX (PC+125) or 500 μg/kg ETX (PC+500) followed by injury dose ETX. PC+125 and PC+500 males, as well as PC+500 females, were preconditioned and retained cardiac function similar to shams. PC+125 females were not preconditioned with this stimulus and had a decrease in cardiac function similar to PC- rats. Furthermore, PC+125 and PC+500 males, and PC+500 females had decreased release of TNF-α after preconditioning, while PC- animals and PC+125 females did not. Males and females can be preconditioned by endotoxin; however the preconditioning threshold is higher in females than males.