Angiotensin AT ₂ Receptor Stimulation Causes Neuroprotection in a Conscious Rat Model of Stroke

Abstract

Background and Purpose-The angiotensin II type 2 receptor (AT 2 R) is implicated to be neuroprotective in stroke, although this premise has not been directly tested. Therefore, we have examined the neuroprotective effect of AT 2 R stimulation after intracerebroventricular administration of AT 2 R agonist CGP42112 in a conscious rat model of stroke. Methods-Spontaneously hypertensive rats were treated with either CGP42112 (0.1 to 10 ng/kg/min intracerebroventricularly) alone or in combination with the AT 2 R antagonist PD123319 (36 ng/kg/min intracerebroventricularly) beginning 5 days before stroke induction. A focal reperfusion model of stroke was induced in conscious spontaneously hypertensive rats by administering endothelin-1 to the middle cerebral artery through a surgically implanted cannula. Behavioral tests were used to assess the severity of neurological deficit as a result of the ischemic event. Cortical and striatal infarct volumes were measured 72 hours poststroke. Results-Blood pressure was unaffected by treatments. CGP42112 dose-dependently reduced cortical infarct volume poststroke, and PD123319 abolished the neuroprotective effect of CGP42112. PD123319 had no effect on infarct volume alone. These results were consistent with the behavioral findings, indicating that CGP42112 reduced motor deficit on the ledged beam test at 72 hours poststroke and immunohistochemical analyses showing that CGP42112 increased neuronal survival and minimized the loss of AT 2 R expression in the infarcted region. Conclusion-Based on infarct, behavioral, and immunohistochemical data, these results indicate that centrally administered CGP42112 exhibits a neuroprotective effect, which was independent of blood pressure. Thus, for the first time, we have shown that central AT 2 R stimulation is neuroprotective in a conscious rat model of stroke.

Angiotensin II Type 2 Receptor Agonists as Therapies for Ischemic Stroke

“…7 Candesartan has a similar effect, although it lowers blood pressure, 8 making it difficult to separate the effects of the drug from the beneficial effects of lowering blood pressure. Positive effects of AT 2 R activation have been shown previously by the authors of the current study, and in 2009 McCarthy et al 9 showed that CGP42112 reduces the damage caused by cerebral ischemia when administered 5 days before the ischemic insult. Importantly, as with the current study, the beneficial effects of AT 2 R activation were observed without the concomitant inhibition of the AT 1 R, suggesting that AT 2 R agonists can overcome the powerful detrimental effects of AT 1 R activation.…”

“…One study using the filament occlusion model of ischemic stroke suggests that AT 2 R expression is increased after the induction of cerebral ischemia; these receptors were expressed only in neurons and appeared to promote neurite outgrowth. 7 Conversely, in the previous study from McCarthy et al, 9 it appears that AT 2 R expression is reduced after cerebral ischemia. The reason for this disparity in the results observed could be many fold and include the method of the induction of ischemia, the region of the brain studied, and the strain of rat used.…”

A Single β-Amino Acid Substitution to Angiotensin II Confers AT 2 Receptor Selectivity and Vascular Function

“…20 Clearly, there is an unmet need to develop a range of AT 2 R agonists to examine class effects of AT 2 R agonists directly in a number of cardiovascular diseases including heart failure 25 and stroke. 26 The majority of previous studies that have reported on novel Ang II peptides have examined binding profiles in a range of tissues with varying proportions of AT 1 R and AT 2 R, often with no functional correlate to assess functionality. In the present study, using homogenous ATRtransfected cell lines, we have shown that individual ␤-amino acid substitutions were well tolerated for AT 2 R binding but not for AT 1 R binding, suggesting the constraints on AT 1 R binding are more strict than AT 2 R. Consistent with these findings, alanine or glycine scans of Ang II caused only minor changes in AT 2 R binding affinity, whereas there was sometimes marked reduction in AT 1 R binding.…”

Response to Letter by Tsuda

“…1 We reported that chronic treatment with AT 2 receptor (AT 2 R) agonist CGP42112 prevented brain ischemic injury in conscious spontaneously hypertensive rat. We showed evidence that AT 2 R stimulation preserved neuronal architecture and motor function, while suggesting that a local vasodilator component would likely contribute to the neuroprotection demonstrated.…”

“…11 An antioxidant action of AT 2 R has also been highlighted, with AT 2 R knockout mice exhibiting elevated levels of superoxide production after stroke, 12 a finding that is consistent with the reduction in superoxide production in infarcted tissue that we noted in response to CGP42112. 1 Thus, it is likely that there are multiple components to neuroprotection induced during AT 2 R stimulation, and the potential contribution of endothelial NO synthase and NO availability to this effect should not be ignored.…”