Selective blockade of endothelin-B receptors exacerbates ischemic brain damage in the rat

Abstract

Background and Purpose - Endothelins act through 2 receptors, namely, ETA and ETB. In the cerebral circulation, ETA mediates marked and prolonged vasoconstriction, and its blockade increases cerebral blood flow (CBF) and reduces ischemic brain damage. However, the role of ETB receptors remains unclear. In this study we examined, in rats, the kinetics of expression of ETB and the effects of ETB 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 ETB 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 ETB expression. Results - Cerebral ischemia failed to alter the expression of ETB 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 ETB 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 ETA antagonists and not mixed ETA/ETB antagonists.