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This study investigated the effect of post-stroke, direct AT2-receptor (AT2R) stimulation with the non-peptide AT2R-agonist compound 21 (C21) on infarct size, survival and neurological outcome after middle cerebral artery occlusion (MCAO) in mice and looked for potential underlying mechanisms. C57/BL6J or AT2R-knockout mice (AT2-KO) underwent MCAO for 30 min followed by reperfusion. Starting 45 min after MCAO, mice were treated once daily for 4 days with either vehicle or C21 (0.03 mg/kg ip). Neurological deficits were scored daily. Infarct volumes were measured 96 h post-stroke by MRI. C21 significantly improved survival after MCAO when compared to vehicle-treated mice. C21 treatment had no impact on infarct size, but significantly attenuated neurological deficits. Expression of brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor B (TrkB) (receptor for BDNF) and growth-associated protein 43 (GAP-43) were significantly increased in the peri-infarct cortex of C21-treated mice when compared to vehicle-treated mice. Furthermore, the number of apoptotic neurons was significantly decreased in the peri-infarct cortex in mice treated with C21 compared to controls. There were no effects of C21 on neurological outcome, infarct size and expression of BDNF or GAP-43 in AT2-KO mice. From these data, it can be concluded that AT2R stimulation attenuates early mortality and neurological deficits after experimental stroke through neuroprotective mechanisms in an AT2R-specific way. Key message • AT2R stimulation after MCAO in mice reduces mortality and neurological deficits.• AT2R stimulation increases BDNF synthesis and protects neurons from apoptosis.• The AT2R-agonist C21 acts protectively when applied post-stroke and peripherally.

Abstract-Pulse wave velocity (PWV), a direct marker of arterial stiffness, is an independent cardiovascular risk factor.Although the angiotensin II type 1 receptor blockade belongs to major antihypertensive and cardioprotective therapies, less is known about the effects of long-term stimulation of the angiotensin II type 2 receptor. Previously, compound 21, a selective nonpeptide angiotensin II type 2 receptor agonist improved the outcome of myocardial infarction in rats along with anti-inflammatory properties. We investigated whether compound 21 alone or in combination with angiotensin II type 1 receptor blockade by olmesartan medoxomil could prevent PWV increase and aortic remodeling in N -nitro-L-argininemethyl ester (L-NAME)-induced hypertension. Male adult Wistar rats (nϭ65) were randomly assigned to control, L-NAME, L-NAMEϩcompound-21, L-NAMEϩolmesartan, and L-NAMEϩolmesartanϩcompound-21 groups and treated for 6 weeks. We observed that L-NAME hypertension was accompanied by enhanced PWV, increased wall thickness, and stiffness of the aorta, along with elevated hydroxyproline concentration. Olmesartan completely prevented hypertension, PWV and wall thickness increase, and the increase of aortic stiffness and partly prevented hydroxyproline accumulation. Compound 21 partly prevented all of these alterations, yet without concomitant prevention of blood pressure rise. Although the combination therapy with olmesartan and compound 21 led to blood pressure levels, PWV, and wall thickness comparable to olmesartan-alone-treated rats, only in the combination group was complete prevention of increased hydroxyproline deposition achieved, resulting in even more pronounced stiffness reduction. We conclude that chronic angiotensin II type 2 receptor stimulation prevented aortic stiffening and collagen accumulation without preventing hypertension in rats with inhibited NO synthase. These effects were additive to angiotensin II type 1 receptor blockade, yet without additional blood pressurelowering effect, and they seem to be NO and blood pressure independent. Key Words: L-NAME Ⅲ vascular remodeling Ⅲ arterial stiffness Ⅲ pulse wave velocity Ⅲ renin-angiotensin system Ⅲ hypertension A rterial hypertension is a highly prevalent and still insufficiently controlled medical condition leading to severe cardiovascular complications. 1,2 One of the main contributors to the cardiovascular risk in these patients is the associated target organ damage. Augmented pulse wave velocity (PWV), which is considered to be the best and direct marker of arterial stiffness, 3 is regarded as an indicator of subclinical organ damage by current European guidelines for hypertension treatment. 4 The effects of current antihypertensive treatment on PWV have been investigated with various outcomes. The angiotensin II type 1 receptor (AT 1 R) antagonists, together with angiotensin-converting enzyme inhibitors, belong to the gold standard cardioprotective therapies. 5,6 In a study on 113 hypertensives, 2-to 3-year treatment with candesartan produced a l...

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