Impact of the endothelin-A receptor antagonist BQ 610 on microcirculation in global cerebral ischemia and reperfusion.

The role of endogenous endothelin-1 in mediating microcirculatory disturbances after global cerebral ischemia was investigated in Mongolian gerbils. The pial microcirculation was studied by intravital fluorescent microscopy before, during, and up to 3 h after occlusion of both carotid arteries for 15 min. Pretreatment was achieved with the peptidergic selective endothelin-A (ET-A) receptor antagonist BQ 610. The neurological outcome was assessed daily for up to 4 days. The antagonist attenuated postischemic leukocyte-endothelium interactions in postcapillary venules, in particular the number of rolling leukocytes was found to be reduced (13.0+/-9.4 x 100 microm(-1) min(-1) in the control vs. 2.0+/-2.5 in the experimental group, P<0.05). The local microvascular perfusion, measured by the arterio-venous transit time, was improved during reperfusion by BQ 610 (1.3+/-0.5 s in the control vs. 0.7+/-0.2 s in the experimental group, P<0.05). The neurological deficit was significantly reduced in animals treated with the ET-A antagonist (P<0.05). The inhibition of the postischemic inflammatory reaction and the reversal of the delayed hypoperfusion may account for the improved neurological outcome. These observations suggest that application of endothelin-A antagonists may be a useful approach to interfere with derangements in cerebral ischemia/reperfusion.