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 l esion volume induced by cold injury in the parietal cortex. In vitro experi ments were performed by measuring the isometric contractions of the rat mid dle 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 determin ed 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 fashio n (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 a dministration of Po 61-1790 showed that the antagonist had reached the arte ries and was bound to their ETA receptors. Intracerebroventricular pre-trea tment of Po 61-1790 reduced significantly the lesion volume by 23% after th e injury. We conclude that ET-1 is involved in the development of secondary brain damage and that intracerebroventricular treatment with Po 61-1790 re duces the size of the brain lesion caused by cold injury.