STUDIES ON THE EFFECTS OF ENDOTHELIN-1 (ET-1) AND ENDOTHELIN-3 (ET-3) IN BRAIN HYPOXIA AND ON THE PARTICIPATION OF BRAIN PROSTANOIDS IN THEIR ACTIONS

The effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) in brain hypoxia have been studied in mice using the following experimental models: hypobaric hypoxia induced by low atmospheric pressure, histotoxic hypoxia induced by 12.5 mg/kg KCN i.p., and complete ischemia induced by decapitation. ET-1 and ET-3 were injected intracerebroventricularly (i.c.v.) 15 min before the tests. Forebrain tissue concentrations of 6-keto-PGF1alpha and thromboxane B2 (TxB2) were measured 15 min following i.c.v. administration of ET-1 (5 pmol/mouse) and ET-3 (10 pmol/mouse). ET-1 (1-5 pmol/mouse) and ET-3 (5-25 pmol/mouse) showed a dose-dependent increase in the survival/gasping time in all models of hypoxia. The effect reached its maximum between 15 and 30 min after ET administration and lasted for about 120 min. ET-1 and ET-3 did not significantly change the brain levels of 6-keto-PGF1alpha and TxB2. The protective effect of ET-1 and ET-3 was unexpected, because endothelins (ETs) are the most potent vasoconstrictors known, and in doses close to those used in this study they cause vasoconstriction and decrease in cerebral blood flow. The protection was not likely to be due either to stimulation of the endogenous release of prostacyclin (PGI2) or to a decrease in the deleterious prostanoid thromboxane A2 (TxA2). Additional experiments are necessary to explain the cerebroprotective effects of ET-1 and ET-3.