INHIBITORY EFFECTS OF DICLOFENAC ON THE ENDOTOXIN-SHOCK RESPONSE IN RELATION TO ENDOTHELIN TURNOVER IN THE PIG

During sepsis vasoactive arachidonic acid metabolites of the cyclo-oxy genase pathway and the endothelium-derived vasoconstrictor endothelin- 1 (ET-1) are released. The effects cyclo-oxygenase pathway inhibition by diclofenac on the endotoxin shock response and ET-1 turnover, were investigated in five groups of pigs. In the first group (n = 7; contro ls) endotoxin (15 mu g.kg(-1).h(-1) i.v.) was infused far two hours. I n a second endotoxin group (n = 7), the animals were pretreated with d iclofenac (3 mg.kg(-1) i.v.). In a third group (n = 7), high-dose ET-1 was infused (20 pmol.kg(-1).min(-1) i.v.) and in a fourth group (n = 7), the ET-1 infusion was preceded by diclofenac. In a fifth group in (n = 4), a low and intermediate dose of ET-1 (0.2 and 4 pmol.kg(-1).mi n(-1)) was infused. A significant increase in ET-1-like immunoreactivi ty (LI) plasma levels was observed in both endotoxin groups, but in th e diclofenac group the increase was comparatively delayed. Furthermore , this group showed a more stable haemodynamic course and in the bipha sic increase of pulmonary vascular resistance seen in endotoxin contro ls, the initial peak was abolished by diclofenac. Exogenous ET-1 infus ion indicated that not only locally released but possibly also circula ting ET-1 could be a mediator of vascular responses to endotoxin. Indi cations of release from the lungs were seen during endotoxin infusion. Diclofenac had no effect on basal ET-1-LI plasma levels or on the dis appearance rate from plasma of ET-1-LI and the haemodynamic changes se en on ET-1 infusion. The inhibition of cyclo-oxygenase pathway by dicl ofenac resulted in prevention of the initial pulmonary hypertension an d a delayed increase in plasma ET-1-LI levels in porcine endotoxin sho ck and this latter effect is not due to an increased rate of disappear ance from plasma but rather to a decreased release of ET-1.