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 release d into the ventral septal area (VSA) of the rat brain during the antip yresis induced by the cyclo-oxygenase inhibitor indomethacin. In addit ion, there is evidence for increased AVP transmission in the VSA of an imals having a reduced pyretic response following three intravenous in jections of bacterial endotoxin (LPS) (endotoxin tolerant). Since vent ral septal AVP receptors can also become 'sensitized' following exposu re to AVP, we questioned whether the antipyretic action of indomethaci n would increase, via an action involving central AVP, if this drug we re administered into LPS-tolerant rats. 2. Intraperitoneal indomethaci n (7.5 mg kg(-1)) was effectively antipyretic when administered 2 h af ter 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 s aline. 3. Three intravenous injections of LPS over a period of 3 days resulted in rats that were tolerant to the pyrogenic effects of LPS. W hen indomethacin was administered 2 h following the third LPS injectio n, a dose-dependent hypothermia was observed. This effect was age depe ndent, 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 o f 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 hypot hermic and lethal effects of intraperitoneal indomethacin were not obs erved in young rats pretreated with bilateral microinjections of an AV P V-1 receptor antagonist within the VSA, whereas hypothermia and leth al effects were seen in saline pretreated controls. 6. These results i ndicate that the physiological effects of indomethacin are dramaticall y 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.