Blockade and Reversal of Endothelin-Induced Constriction in Pial Arteries From Human Brain

Abstract

Background and Purpose —Substantial evidence now implicates endothelin (ET) in the pathophysiology of cerebrovascular disorders such as the delayed vasospasm associated with subarachnoid hemorrhage and ischemic stroke. We investigated the ET receptor subtypes mediating vasoconstriction in human pial arteries. Methods —ET receptors on human pial and intracerebral arteries were visualized with the use of autoradiography, and the subtypes mediating vasoconstriction were identified by means of wire myography. Results —ET-1 was more potent than ET-3 as a vasoconstrictor, indicating an ET _A -mediated effect. Similarly, the selective ET _B agonist sarafotoxin S6c had no effect on contractile action at concentrations up to 30 nmol/L. The nonpeptide ET _A receptor antagonist PD156707 (3 to 30 nmol/L) caused a parallel rightward shift of the ET-1–induced response, yielding a pA ₂ of 9.2. Consistent with these results, PD156707 (30 nmol/L) fully reversed an established constriction in pial arteries induced by 1 nmol/L ET-1, while the selective ET _B receptor antagonist BQ788 (1 μmol/L) had little effect. The calcium channel blocker nimodipine (0.3 to 3 μmol/L) significantly attenuated the maximum response to ET-1 in a concentration-dependent manner without changing potency. In agreement with the functional data, specific binding of [ ¹²⁵ I] PD151242 to ET _A receptors was localized to the smooth muscle layer of pial and intracerebral blood vessels. In contrast, little or no [ ¹²⁵ I]BQ3020 binding to ET _B receptors was detected. Conclusions —These data indicate an important role for ET _A receptors in ET-1–induced constriction of human pial arteries and suggest that ET _A receptor antagonists may provide additional dilatory benefit in cerebrovascular disorders associated with raised ET levels.