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

Abstract

The aim of the present study was to investigate whether endothelin-1 (ET-1) in cerebral arteries is inhibited by the new, non-peptidergic ET(A) receptor antagonist Ro 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 degrees C) 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. Ro 61-1790 (3x10(-9) M, 10(-7) M) shifted the concentration-effect curves for ET-1 in a parallel fashion (Emax unaltered). Post-treatment with Ro 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 Ro 61-1790 showed that the antagonist had reached the arteries and was bound to their ET(A) receptors. Intracerebroventricular pre-treatment of Ro 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 Ro 61-1790 reduces the size of the brain lesion caused by cold injury.

Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist clinically effective for the treatment of cerebral vasospasm. Part I: Inhibitory effect on endothelinA receptor—mediated contraction

“…4,32 Similar affinities of ET-1 and clazosentan to the ET A receptor have also been described, albeit with quantitative differences, in the isolated canine coronary artery 42 and in the rat BA. 13 The data emphasize the necessity for the characterization of ET receptor antagonists in the specific vasculature of their potential therapeutic field.…”

Endothelin-1 Is Increased in Cerebrospinal Fluid and Associated with Unfavorable Outcomes in Children after Severe Traumatic Brain Injury

“…Under homeostatic conditions, the role of ET-1 in regulating CBF appears minimal; however, under pathological conditions, ET-1 synthesis is increased in the cerebrovascular endothelium, and ET-B receptors are upregulated after injury (Andresen et al, 2006). Endothelial-derived ET-1 reduces CBF and is associated with clinical vasospasm and secondary neurological injury due to its high potency and long duration of action (Gorlach et al, 2001). In animal models of TBI, including pediatric models, brain ET-1 concentrations increase two-to threefold (Steiner et al, 2004), and are associated with prolonged vasoconstriction (Armstead, 2004).…”

Candidate neuroinflammatory markers of cerebral autoregulation dysfunction in human acute brain injury

“… 83 The upregulation of ET-1 after brain injury is associated with clinical vasospasm and secondary injury likely because of its efficiency and long-lasting vasoconstriction effects. 84 The source of ET-1 over-production has been investigated, with active astrocytes and endothelial cells being key candidates. 85 Theoretically, treatment aimed at decreasing ET-1 levels would be advantageous in increasing CBF and ameliorating some of ET-1’s harmful effects.…”