Reversal of Subarachnoid Hemorrhage-induced Vasoconstriction with an Endothelin Receptor Antagonist

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Abstract

ABSTRACT

INCREASED CONCENTRATIONS OF the vasoconstrictor endothelin have recently been demonstrated in the cerebrospinal fluid after subarachnoid hemorrhage (SAH). This observation is consistent with the hypothesis that SAH-induced vasospasm is mediated in part by enhanced constriction due to endothelin. To investigate this issue, an endothelin receptor antagonist (ETant), cyclo(D-Asp-L-Pro-D-Val-L-Leu-D-Trp), was tested for its ability to reverse vasoconstriction after SAH. A transclival surgical approach to the basilar artery in rabbits was used, and the arterial diameter was measured continuously by videomicroscopy. Rabbits were divided randomly into six groups: 1) normal rabbits treated with 40 nmol/L ETant only; 2) normal rabbits treated with 50 mmol/L KCl, then 50 mmol/L KCl + 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) rabbits 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 treated with artificial cerebrospinal fluid only. In normal (non-SAH) rabbits, ETant: 1) had little or no effect on resting tone; 2) did not reverse potassium-induced constrictions; and 3) substantially reversed endothelin-induced constrictions. The diameter of normal rabbit basilar arteries was 832.1 ± 20.0 μm (mean ± standard error). After SAH (double hemorrhage model), the mean diameter was 517.4 ± 18.3 μm. The addition of ETant reversed this SAH-induced constriction by 70.7%. These findings support the hypothesis that increased activation of ET-1 receptors in the basilar artery contributes to cerebral vasospasm after SAH and that the constricted state may be reversed by the application of ETant.

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