Angiotensin II Type 2 Receptor Stimulation Initiated After Stroke Causes Neuroprotection in Conscious Rats

Abstract

A ngiotensin II (Ang II) can bind to several receptor subtypes, thus, influencing an array of cardiovascular functions in the body. However, the 2 major receptor subtypes are the angiotensin II type 1 receptor (AT 1 R), which is thought to be responsible for most of the biological and pathological actions of Ang II, and the angiotensin II type 2 receptor (AT 2 R), which mainly opposes the actions of the AT 1 R.1 Several largescale clinical trials 2,3 have indicated that the use of AT 1 R antagonists as a method of blood pressure control in high-risk patients improves cardiac and vascular events, which results in a reduced risk of secondary events such as stroke. This is consistent with experimental studies reporting that central or peripheral pretreatment with an AT 1 R antagonist reduces postischemic inflammation and the size of the cerebral infarction together with improved behavioral symptoms. [4][5][6][7][8] Importantly, neuroprotection has been demonstrated to occur even with nonhypotensive doses of AT 1 R blockers. 9 The postulated nonvascular mechanisms of neuroprotection include inhibition of neuronal apoptosis 5 and reduced neuronal loss associated with inhibition of superoxide production and inflammation, 10 although there is likely to be a contribution from the AT 2 R during AT 1 R blockade.6,7 Indeed, several groups have reversed neuroprotection induced during AT 1 R blockade with the coadministration of an AT 2 R antagonist, suggesting that the AT 2 R is a pivotal component in the therapeutic action of AT 1 R antagonists. 6,7 In addition, mice lacking the AT 2 R show poorer outcome after stroke and are less receptive to the protective influence of AT 1 R antagonists.11,12 Thus, there is accumulating indirect evidence that suggests that the AT 2 R may have a cerebroprotective role during stroke, although little is known about direct AT 2 R stimulation in the brain.In this context, we have recently examined the neuroprotective effect of direct AT 2 R stimulation after intracerebroventricular (ICV) administration of the AT 2 R agonist CGP42112 in a conscious rat model of stroke. Our results indicate that, even in the absence of AT 1 R blockade, direct stimulation of the central AT 2 R for 5 days before and for 3 days after stroke dramatically reduces subsequent damage, both histologically and behaviorally, such that at 72 hours after stroke injury is minimal. 13 Given that patients normally present for treatment after a cerebrovascular event, a clinically relevant treatment needs to be effective when administered after a stroke has occurred. To this end, the current proof-of-principle study investigated the potential neuroprotective role of See Editorial Commentary, pp 1391-1392Abstract-We have demonstrated previously that pretreatment with an angiotensin II type 2 receptor (AT 2 R) agonist is neuroprotective against a subsequent stroke independent of any changes in blood pressure. Therefore, in the current study, we have examined the potential neuroprotective effect of AT 2 R stimulation initiated aft...

Neuroprotection after Traumatic Brain Injury in Heat-Acclimated Mice Involves Induced Neurogenesis and Activation of Angiotensin Receptor Type 2 Signaling

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“…46 Importantly, recent elegant studies show that AT 2 R stimulation induces neuroprotection in conscious rats either before or after induction of stroke, a common consequence of hypertension. 47 Clearly, tissue protection is strongly emerging as a potential therapeutic application of pharmacological AT 2 R activation in humans.…”