Protective effect of candesartan in experimental ischemic stroke in the rat mediated by AT2 and AT4 receptors

Objectives The contribution of the AT(2) and AT(4) angiotensin receptors to the protective role of the AT(1) receptor blocker candesartan in acute ischemic stroke was investigated. Methods Embolic stroke was induced by injection of calibrated microspheres (50 mu m) in the right internal carotid in Sprague-Dawley rats. Results Inhibition of production of endogenous angiotensins by pretreatment for 24 h with lisinopril significantly increased mortality and infarct volume, whereas candesartan for 24 h reduced blood pressure to the same extent but had no deleterious effect. A more sustained pretreatment with candesartan for 5 days significantly decreased mortality, neurological deficit and infarct size. The AT(2) receptor antagonist PD123319 and the AT(4) receptor antagonist divalinal abolished the protective effect of 5 days' AT(1) blockade. Combined blockade of AT(2) and AT(4) in candesartan pretreated rats resulted in an increased mortality, neurological deficit and infarct volume of similar magnitude to lisinopril pretreatment. Coadministration of lisinopril 24 h before surgery completely blunted the protective effect of candesartan pretreatment. Administration of exogenous angiotensin IV (1 nmol) reversed the deleterious effect of lisinopril pretreatment. Conclusion Protection against acute cerebral ischemia induced by AT(1) blockade for 5 days is blood pressure independent and mediated by both AT(2) and AT(4) angiotensin receptors.