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 of 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 micrograms.kg-1.h-1 i.v.) was infused for 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 (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.
Weitzberg
E
E
Department of Anaesthesiology, Karolinska Hospital, Stockholm, Sweden.
Lundberg
J M
JM
Rudehill
A
A
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology*; D016232:Endothelins / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D004731:Endotoxins / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D004926:Escherichia coli; D006339:Heart Rate / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000037:antagonists & inhibitors; D008168:Lung / Q000098:blood supply / Q000378:metabolism; D009478:Neuropeptide Y / Q000097:blood; D009638:Norepinephrine / Q000097:blood; D012772:Shock, Septic / Q000378:metabolism* / Q000503:physiopathology; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D016232:Endothelins; D004731:Endotoxins; D008070:Lipopolysaccharides; D009478:Neuropeptide Y; D004008:Diclofenac; D009638:Norepinephrine