Endothelin Receptor Antagonist Preserves Microvascular Perfusion and Reduces Ischemic Brain Damage Following Permanent Focal Ischemia |
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Authors: | Dawson Deborah A Sugano Hidenori McCarron Richard M Hallenbeck John M Spatz Maria |
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Institution: | (1) Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892;(2) Present address: Cerebrus Ltd, 613 Reading Road, Winnersh, Wokingham, RG41 5UA, United Kingdom;(3) Resuscitative Medicine Department, Naval Medical Research Center, Bethesda, Maryland, 20889;(4) Stroke Branch, NINDS, National Institutes of Health, 36 Convent Drive, MSC 4128, Bethesda, MD, 20892-4128 |
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Abstract: | Synthesis and release of the potent vasoconstrictor peptide endothelin-1 (ET-1) increases following cerebral ischemia and has previously been shown to mediate the delayed hypoperfusion associated with transient global ischemia. In this study we assessed the impact of ET-1 on perfusion and infarct volume in a focal model of cerebral ischemia by use of the selective ET(A) receptor antagonist Ro 61-1790 (affinity for ET(A) receptor 1000 fold greater than ETB receptor). Control rats subjected to permanent middle cerebral artery occlusion (MCAO) showed extensive reductions in microvascular perfusion 4 h post-MCAO that were significantly attenuated by Ro 61-1790 pretreatment (10 mg/kg, i.v.). Ro 61-1790 concomitantly and significantly reduced the ischemic lesion volume in the same animals. This effect was maintained 24 h post-MCAO providing that the animals received additional i.v. injections of 5 mg/kg Ro 61-1790 at 5 h and 8 h after MCAO. These findings demonstrate that ET(A) receptor antagonism partially preserves tissue perfusion following focal ischemia and that this effect is associated with significant neuroprotection. The results also support the hypothesis that vasoactive mediators, and ET-1 in particular, are important contributors to the pathogenesis of cerebral ischemic injury. |
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Keywords: | Endothelin-1 cerebral ischemia microvascular perfusion ET-1 receptor antagonist spontaneously hypertensive rat |
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