Non-AT1-receptor-mediated protective effect of angiotensin against acute ischaemic stroke in the gerbil

Abstract

Previous studies have shown that angiotensin II (Ang II), by mediating rapid recruitment of collateral circulation, has a protective effect in the setting of acute ischaemia. In an experimental model of acute cerebral ischaemia in the gerbil, Fernandez et al. have reported that the mechanism of the protective effect of Ang II is blood pressure (BP)-independent,1 and that the AT 1-receptor antagonist, losartan, but not the ACE inhibitor (ACE-I), enalapril, decreases mortality following unilateral carotid artery ligation. 2 The aim of this study was to examine the reproducibility of the respective effects of losartan and enalapril, and to verify that these differential effects are drug class-related. Acute cerebral ischaemia was induced in anaesthetised gerbils by unilateral carotid ligation. The effect of pretreatment with two different ACE-I (enalapril and lisinopril), and two different AT 1-receptor antagonists (losartan and candesartan), administered orally or intravenously, on mortality were compared. Kaplan-Meier survival curves at day three were analysed by a log-rank test. Pretreatment with both enalapril and lisinopril significantly decreased survival at day three compared with controls, while the AT1-receptor antagonists losartan and candesartan, despite similarly lowering BP, did not increase mortality. Coadministration of losartan and enalapril increased mortality to the same extent as enalapril alone. This study confirms that Ang II contributes to protective mechanisms against acute cerebral ischaemia through non AT1-receptor-mediated, BP-independent effects.

Angiotensin AT1-receptor blockers and cerebrovascular protection: do they actually have a cutting edge over angiotensin-converting enzyme inhibitors?

“…Our group confirmed this finding by comparing in the same model the effect of previous administration of candesartan or losartan with lisinopril or enalapril, respectively, at the same hypotensive dose [34]: whereas the ACEIs decreased survival (25 vs 18%) compared with saline controls, the AT1RBs improved survival (65 vs 60%). Furthermore, preadministration of an ACEI combined with an AT1RB resulted in the same deleterious effect as with ACEI alone.…”

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

“…In contrast to the protective effect of AT 1 blockade that requires several days of pretreatment, the deleterious effect of ACE inhibition can be observed with pretreatment of short duration (i.e. 30 min prior to ischemia induction when administered intravenously [35]), an observation consistent with the very rapid decrease in circulating levels of endogenous AngII following administration of an ACEI [37]. Taken together our findings strongly support the conclusion that the protective effect of AT 1 blockade is mediated by angiotensins acting through non-AT 1 receptors.…”

“…30 min before, both similarly worsened mortality at day 3 [35]. Hamai et al [8] have directly compared the effect of candesartan and enalapril, both at nonhypotensive and hypotensive doses, in the model of permanent MCAO in the mouse.…”

Managing the patient at risk for a second stroke

“…Combination of the two treatments, however, abolished the protective effects of the losartan, indicating that, in part at least, the protective effects are mediated by selective stimulation of the AT 2 receptor. Similarly, survival after ischaemic stroke in gerbils is prolonged by pretreatment Managing the patient at risk for a second stroke Weber S43 with either losartan or candesartan, but not by enalapril or lisinopril [27].…”