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 hy poxia have been studied in mice using the following experimental model s: hypobaric hypoxia induced by low atmospheric pressure, histotoxic h ypoxia induced by 12.5 mg/kg KCN i.p., and complete ischemia induced b y 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 followi ng i.c.v. administration of ET-1 (5 pmol/mouse) and ET-3 (10 pmol/mous e). ET-1 (1-5 pmol/mouse) and ET-3 (5-25 pmol/mouse) showed a dose-dep endent increase in the survival/gasping time in all models of hypoxia. The effect reached its maximum between 15 and 30 min after ET adminis tration and lasted for about 120 min. ET-1 and ET-3 did not significan tly change the brain levels of 6-keto-PGF1alpha and TxB2. The protecti ve effect of ET-1 and ET-3 was unexpected, because endothelins (ETs) a re the most potent vasoconstrictors known, and in doses close to those used in this study they cause vasoconstriction and decrease in cerebr al blood flow. The protection was not likely to be due either to stimu lation of the endogenous release of prostacyclin (PGI2) or to a decrea se in the deleterious prostanoid thromboxane A2 (TxA2). Additional exp eriments are necessary to explain the cerebroprotective effects of ET- 1 and ET-3.