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-oxygenase 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; controls) endotoxin (15 mu g.kg(-1).h(-1) i.v.) was infused far two hours. In a second endotoxin group (n = 7), the animals were pretreated with diclofenac (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).min(-1)) was infused. A significant increase in ET-1-like immunoreactivity (LI) plasma levels was observed in both endotoxin groups, but in the diclofenac group the increase was comparatively delayed. Furthermore, this group showed a more stable haemodynamic course and in the biphasic increase of pulmonary vascular resistance seen in endotoxin controls, the initial peak was abolished by diclofenac. Exogenous ET-1 infusion indicated that not only locally released but possibly also circulating ET-1 could be a mediator of vascular responses to endotoxin. Indications of release from the lungs were seen during endotoxin infusion. Diclofenac had no effect on basal ET-1-LI plasma levels or on the disappearance rate from plasma of ET-1-LI and the haemodynamic changes seen on ET-1 infusion. The inhibition of cyclo-oxygenase pathway by diclofenac resulted in prevention of the initial pulmonary hypertension and a delayed increase in plasma ET-1-LI levels in porcine endotoxin shock and this latter effect is not due to an increased rate of disappearance from plasma but rather to a decreased release of ET-1.