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.
Lehmberg
Jens
J
Department of Neurosurgery, Albert-Ludwigs-University, Freiburg i.B., Germany. lehmberg@nz.ukl.uni-freiburg.de
Putz
Christiane
C
Fürst
Monika
M
Beck
Jürgen
J
Baethmann
Alexander
A
Uhl
Eberhard
E
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D002545:Brain Ischemia / Q000378:metabolism*; D002339:Carotid Arteries / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D004730:Endothelium, Vascular / Q000378:metabolism; D005849:Gerbillinae; D007249:Inflammation / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D009842:Oligopeptides / Q000494:pharmacology*; D010841:Pia Mater / Q000098:blood supply; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*; D013997:Time Factors
D065128:Endothelin Receptor Antagonists; D009842:Oligopeptides; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C087220:BQ 610