REVERSAL OF SUBARACHNOID HEMORRHAGE-INDUCED VASOCONSTRICTION WITH AN ENDOTHELIN RECEPTOR ANTAGONIST

INCREASED CONCENTRATIONS OF the vasoconstrictor endothelin have recent ly been demonstrated in the cerebrospinal fluid after subarachnoid hem orrhage (SAH). This observation is consistent with the hypothesis that SAH-induced vasospasm is mediated in part by enhanced constriction du e to endothelin. To investigate this issue, an endothelin receptor ant agonist (ETant), cyclo(D-Asp-L-Pro-D-Val-L-Leu-D-Trp), was tested for its ability to reverse vasoconstriction after SAH. A transclival surgi cal approach to the basilar artery in rabbits was used, and the arteri al diameter was measured continuously by videomicroscopy. Rabbits were divided randomly into six groups: 1) normal rabbits treated with 40 n mol/L ETant only; 2) normal rabbits treated with 50 mmol/L KCI, then 5 0 mmol/L KCI + 40 nmol/L ETant; 3) normal rabbits treated with 20 nmol /L endothelin-1 (ET-1), then 20 nmol/L ET-1 + 40 nmol/L ETant; 4) rabb its treated with 20 nmol/L ET-1 only; 5) rabbits subjected to SAH and treated with 40 nmol/L ETant; and 6) rabbits subjected to SAH and trea ted with artificial cerebrospinal fluid only. In normal (non-SAH) rabb its, ETant: 1) had little or no effect on resting tone; 2) did not rev erse potassium-induced constrictions; and 3) substantially reversed en dothelin-induced constrictions. The diameter of normal rabbit basilar arteries was 832.1 +/- 20.0 mum (mean +/- standard error). After SAH ( double hemorrhage model), the mean diameter was 517.4 +/- 18.3 mum. Th e addition of ETant reversed this SAH-induced constriction by 70.7%. T hese findings support the hypothesis that increased activation of ET-1 receptors in the basilar artery contributes to cerebral vasospasm aft er SAH and that the constricted state may be reversed by the applicati on of ETant.