ALTERATION OF THE PHYSIOLOGICAL-RESPONSES TO INDOMETHACIN BY ENDOTOXIN TOLERANCE IN THE RAT - A POSSIBLE ROLE FOR CENTRAL VASOPRESSIN

1. Previous studies suggest that arginine vasopressin (AVP) is released into the ventral septal area (VSA) of the rat brain during the antipyresis induced by the cyclo-oxygenase inhibitor indomethacin. In addition, there is evidence for increased AVP transmission in the VSA of animals having a reduced pyretic response following three intravenous injections of bacterial endotoxin (LPS) (endotoxin tolerant). Since ventral septal AVP receptors can also become 'sensitized' following exposure to AVP, we questioned whether the antipyretic action of indomethacin would increase, via an action involving central AVP, if this drug were administered into LPS-tolerant rats. 2. Intraperitoneal indomethacin (7.5 mg kg(-1)) was effectively antipyretic when administered 2 h after an intravenous challenge with LPS (50 mu g kg(-1)) into conscious unrestrained rats. This dose of indomethacin had no effect on the core temperature of non-febrile rats given intravenous 0.9% pyrogen-free saline. 3. Three intravenous injections of LPS over a period of 3 days resulted in rats that were tolerant to the pyrogenic effects of LPS. When indomethacin was administered 2 h following the third LPS injection, a dose-dependent hypothermia was observed. This effect was age dependent, as profound hypothermia was seen in 8 week but not 20 week old rats. 4. A mortality rate of 41% (P = 0.02) was observed within 24 h of indomethacin treatment in 8 week old tolerant rats compared with 0% in 8 week old non-tolerant and 20 week old tolerant rats. 5. The hypothermic and lethal effects of intraperitoneal indomethacin were not observed in young rats pretreated with bilateral microinjections of an AVP V-1 receptor antagonist within the VSA, whereas hypothermia and lethal effects were seen in saline pretreated controls. 6. These results indicate that the physiological effects of indomethacin are dramatically altered in LPS-tolerant rats and that endogenous AVP may have a role in this process. The lack of indomethacin-induced deleterious effects in older rats indicates an age susceptibility to the antipyretic drug reminiscent of that seen in humans with Reye's syndrome.