Comparisons of the effects of anesthesia and stress on release of tumor necrosis factor-alpha, leptin, and nitric oxide in adult male rats

Bacterial lipopolysaccharide (LPS) stimulates massive release of tumor necrosis factor-alpha (TNF-alpha) together with nitric oxide (NO) and a lessor release of leptin. We hypothesized that other types of stress such as that of surgery might also release these cytokines and NO. Adult male rats were anesthetized with ketamine/acepromazine/xylazine anesthesia (90 + 2 + 6 mg/ml, respectively) and an external jugular catheter was inserted for removal of blood samples (0.6 ml) at various times postoperatively. Plasma TNF-alpha was almost undetectable in decapitated rats and was near zero immediately following the placement of the jugular catheter (time zero t0]). As the rats awakened from anesthesia, there was a rise in TNF-alpha at 30 min that peaked at 2 hr with a 400-fold increase and then precipitously declined 40-fold to a level still greater than zero at 3 hr. At 6 hr on the following morning, TNF-alpha values were near zero, but following connection of tubing and withdrawal of the initial blood sample, there was a 100-fold increase 1 hr later, followed by a decline over the next 3 hr. In contrast, plasma NO/NO2] from decapitated rats was 117 microM. Values at tO were decreased and plummeted 4-fold within 30 min, then rose slightly in the ensuing 3 hr. At 6 hr on the next day NO3/NO2] values were lower than at tO and declined gradually during the next 4 hr. Leptin gradually declined from pre-operative concentrations, reaching a minimum at 3 hr and its concentration was unaffected by the bleeding stress of the second day. We conclude that release of TNF-alpha, NO3/NO2], and leptin are neurally controlled since plasma levels of all three declined as a result of anesthesia. TNF-alpha secretion was remarkably stress responsive, whereas NO release appeared to be suppressed by the combined operative and bleeding stress, and leptin was stress unresponsive.