The effects of bosentan on cerebral blood flow and histopathology following middle cerebral artery occlusion in the rat.
The involvement of endothelins in the cerebrovascular events which follow a focal ischemic insult in the rat was explored in the present study. Intravenous (i.v.) administration of bosentan (3, 15 and 30 mg/kg), an endothelin ETA and ETB receptor antagonist, prior to middle cerebral artery occlusion in the rat did not significantly alter cortical perfusion in these rats. A 62 +/- 3% reduction in laser doppler flow was observed 10 min after middle cerebral artery occlusion in the vehicle-treated group compared to a 49 +/- 5% reduction in laser doppler flow in the group receiving 15 mg/kg bosentan. Pre-treatment with intravenous bosentan (15 mg/kg) prior to middle cerebral artery occlusion in the rat also failed to elicit significant alterations in the reduction in regional cerebral blood flow (frontal cortex; 81 +/- 13 ml/100 g/min) and subsequent hemispheric volume of ischemic damage observed (94 +/- 9 mm3) compared to the vehicle treated animals (68 +/- 9 ml/100 g/min, 113 +/- 5 mm3, respectively). Minimal changes were also observed in these endpoints, when a 15 mg/kg dose of bosentan was administered following middle cerebral artery occlusion. In conclusion bosentan failed to expose a major role for endothelins in focal ischemic pathology in the rat.
McAuley
M A
MA
Wellcome Surgical Institute, University of Glasgow, Scotland, UK.
Breu
V
V
Graham
D I
DI
McCulloch
J
J
D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives; D001157:Arterial Occlusive Diseases / Q000503:physiopathology*; D001345:Autoradiography; D000077300:Bosentan; D002545:Brain Ischemia / Q000503:physiopathology; D002250:Carbon Radioisotopes; D002536:Cerebral Arteries / Q000187:drug effects / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000098:blood supply; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D065128:Endothelin Receptor Antagonists; D007553:Isotope Labeling; D017078:Laser-Doppler Flowmetry; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000134:cerebrospinal fluid / Q000494:pharmacology*
D002250:Carbon Radioisotopes; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D000077300:Bosentan; D000983:Antipyrine; C008135:iodoantipyrine