THE EFFECT OF BOSENTAN, A NEW POTENT ENDOTHELIN RECEPTOR ANTAGONIST, ON THE PATHOGENESIS OF CEREBRAL VASOSPASM

USING THE CANINE chronic cerebral vasospasm model, we studied the effects of a potent new nonpeptidic endothelin-1 (ET1) receptor antagonist, bosentan (Ro 47-0203, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzenesulfonamide). Endothelin (ET) receptors are composed of the ET(A) receptors and the ET(B) receptors; ET1 acts on both of these receptors. Although it has been previously thought that the ET(A) receptor mediates vasoconstriction, whereas the ET(B) receptor mediates vasodilation, recent evidence suggests that ET(B) receptor also contributes to vasoconstriction. Because bosentan is a mixed antagonist that acts on both receptors, its use might indicate whether or not ET is involved in the pathogenesis of cerebral vasospasm. In this study, beagle dogs received a double injection of autologous arterial blood into the cisterna magna at 2-day intervals (i.e., on Days 0 and 2). The diameter of the basilar artery (BA) was angiographically examined up to Day 7. A total of 24 dogs were randomly allocated to either the treatment group or the no-treatment group. Eight dogs were treated with 10 mg/kg bosentan by a one-dose injection into a central venous catheter. Bosentan was given twice a day starting immediately after the first subarachnoid hemorrhage far 6 days until Day 5. Sixteen dogs served as controls, with untreated subarachnoid hemorrhage. After the injection of bosentan, blood pressure decreased by about 25 mm Hg for a few minutes and then returned to normal. In the dogs treated with bosentan, the BA spasm on Day 7 was significantly ameliorated compared with the BA spasm in the untreated dogs. in treated dogs, the BA diameter decreased by 21 +/- 15% (mean +/- standard deviation, n = 8), whereas the BA diameter decreased by 49 +/- 8% (n = 16) in the untreated dogs (P < 0.01). The ET1 content in the plasma was higher in the treated dogs than in the untreated dogs, but the ET1 content in the cerebrospinal fluid was not different in the two groups. These results suggest that ET1 is involved in the development of chronic cerebral vasospasm via both ET(A) and ET(B) receptors.