Inhibition of endothelin-1 by the competitive ETA receptor antagonist Ro 61-1790 reduces lesion volume after cold injury in the rat

The aim of the present study was to investigate whether endothelin-1 (ET-1) in cerebral arteries is inhibited by the new, non-peptidergic ETA receptor antagonist Po 61-1790 and, if it is, whether that inhibition reduces the lesion volume induced by cold injury in the parietal cortex. In vitro experiments were performed by measuring the isometric contractions of the rat middle cerebral and basilar arteries. A cold lesion was induced in vivo by the application of a pre-cooled (-78 degreesC) copper cylinder (diameter 3 mm) to the intact dura of rats for 6 s. After 24 h, lesion volume was determined by the triphenyltetrazolium method. In vitro, ET-1 (10(-12)-3x10(-7) M) caused a dose-dependent contraction under resting conditions in the middle cerebral and basilar arteries of control rats. Po 61-1790 (3x10(-9) M, 10(-7) M) shifted the concentration-effect curves for ET-1 in a parallel fashion (E-max unaltered). Post-treatment with Po 61-1790 (10(-7)-10(-5) M) also inhibited the prior contraction elicited by ET-1 (3x10(-9) M) significantly. In vitro ET-1 application 3 h after the intracerebroventricular in vivo administration of Po 61-1790 showed that the antagonist had reached the arteries and was bound to their ETA receptors. Intracerebroventricular pre-treatment of Po 61-1790 reduced significantly the lesion volume by 23% after the injury. We conclude that ET-1 is involved in the development of secondary brain damage and that intracerebroventricular treatment with Po 61-1790 reduces the size of the brain lesion caused by cold injury.