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Inhibitory effects of diclofenac on the endotoxin shock response in relation to endothelin turnover in the pig
Author(s) -
Weitzberg E.,
Lundberg J. M.,
Rudehill A.
Publication year - 1995
Publication title -
acta anaesthesiologica scandinavica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.738
H-Index - 107
eISSN - 1399-6576
pISSN - 0001-5172
DOI - 10.1111/j.1399-6576.1995.tb05592.x
Subject(s) - medicine , diclofenac , arachidonic acid , endothelin receptor , endocrinology , shock (circulatory) , endothelium , endothelins , endothelin 1 , pharmacology , biology , enzyme , biochemistry , receptor
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 (15μg·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.