Selective blockade of endothelin-B receptors exacerbates ischemic brain damage in the rat.
OBJECTIVE
Endothelins act through 2 receptors, namely, ET(A) and ET(B). In the cerebral circulation, ET(A) mediates marked and prolonged vasoconstriction, and its blockade increases cerebral blood flow (CBF) and reduces ischemic brain damage. However, the role of ET(B) receptors remains unclear. In this study we examined, in rats, the kinetics of expression of ET(B) and the effects of ET(B) blockade on changes in CBF and brain damage after focal cerebral ischemia and N-methyl-D-aspartate (NMDA)-induced excitotoxic injury.


METHODS
Rats were subjected to transient (60 minutes) focal cerebral ischemia or cortical injection of NMDA. The selective ET(B) antagonist BQ-788 was injected intracerebroventricularly 30 minutes before and 30 minutes after the onset of ischemia. Cortical perfusion was monitored by laser-Doppler flowmetry. The volume of infarction or NMDA-induced cortical lesion was assessed at 24 hours after the insult. The reverse transcription-polymerase chain reaction technique was used to assess ET(B) expression.


RESULTS
Cerebral ischemia failed to alter the expression of ET(B) mRNA in both acute and chronic stages. Administration of BQ-788 resulted in an increase in infarction volume (178%; P<0.05) accompanied by a decrease in residual CBF (-26.7% versus control; P<0.01). In these animals we found a positive correlation between the volume of infarction and the severity of the decrease in CBF. NMDA-induced cortical lesions were not affected by the administration of BQ-788.


CONCLUSIONS
Our results suggest that the ET(B) antagonist BQ-788 induces deleterious effects that are mediated by the reduction of residual blood flow after ischemia and argue that the optimal therapeutic strategy in stroke would be to target the use of selective ET(A) antagonists and not mixed ET(A)/ET(B) antagonists.
Chuquet
Julien
J
Université de Caen, CNRS-UMR 6551, Caen, France. chuquet@cyceron.fr
Benchenane
Karim
K
Toutain
Jérôme
J
MacKenzie
Eric T
ET
Roussel
Simon
S
Touzani
Omar
O
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001783:Blood Flow Velocity / Q000187:drug effects; D002545:Brain Ischemia / Q000139:chemically induced / Q000473:pathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D007276:Injections, Intraventricular; D008297:Male; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000633:toxicity; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects*; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D018690:Excitatory Amino Acid Agonists; D009842:Oligopeptides; D010880:Piperidines; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C086539:BQ 788; D016202:N-Methylaspartate