The angiotensin type 2 receptor agonist Compound 21 elicits cerebroprotection in endothelin-1 induced ischemic stroke

Joseph, Jason; Mecca, Adam P.; Regenhardt, Robert W; Bennion, Douglas M; Rodríguez, Vermalí; Desland, Fiona; Patel, Neal; Pioquinto, David J.; Unger, Thomas; Katovich, Michael J.; Steckelings, Ulrike Muscha; Sumners, Colin

doi:10.1016/j.neuropharm.2014.01.044

Cited by 59 publications

(49 citation statements)

References 40 publications

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“…Collectively, these studies demonstrate that the level of cardiac fibrosis is significantly reduced with stimulation or overexpression of the AT2R. Recently, the use of this selective non-peptide agonist of AT2R was also shown to provide cerebroprotection in a rodent stroke model, and this cerebroprotective action was attributed to an anti-inflammatory effect (Joseph et al 2014), consistent with findings in the MI model.…”

Section: Possible Mechanisms For Angiotensin II Type 2 Receptor-mediasupporting

confidence: 72%

Is angiotensin II type 2 receptor a new therapeutic target for cardiovascular disease?

Katovich

2014

Experimental Physiology

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Section: Possible Mechanisms For Angiotensin II Type 2 Receptor-mediasupporting

confidence: 72%

Is angiotensin II type 2 receptor a new therapeutic target for cardiovascular disease?

Katovich

2014

Experimental Physiology

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“…Of relevance, several studies have used either the AT2R antagonist, PD123319, or AT2R knockout mice to demonstrate that, at the doses used in the present study, C21 exerts AT2R-specific effects (47)(48)(49)(50). Initial patch-clamp electrophysiological studies revealed that AT2R-expressing neurons in the peri-PVN shared similar general electrophysiological properties to previously described hypothalamic interneurons, including GABAergic ones, such as the expression of a rebound LTS and a mostly linear current/voltage relationship (51,52).…”

Section: Discussionmentioning

confidence: 54%

Angiotensin Type-2 Receptors Influence the Activity of Vasopressin Neurons in the Paraventricular Nucleus of the Hypothalamus in Male Mice

et al. 2016

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It is known that angiotensin-II acts at its type-1 receptor to stimulate vasopressin (AVP) secretion, which may contribute to angiotensin-II-induced hypertension. Less well known is the impact of angiotensin type-2 receptor (AT2R) activation on these processes. Studies conducted in a transgenic AT2R enhanced green fluorescent protein reporter mouse revealed that although AT2R are not themselves localized to AVP neurons within the paraventricular nucleus of the hypothalamus (PVN), they are localized to neurons that extend processes into the PVN. In the present set of studies, we set out to characterize the origin, phenotype, and function of nerve terminals within the PVN that arise from AT2R-enhanced green fluorescent protein-positive neurons and synapse onto AVP neurons. Initial experiments combined genetic and neuroanatomical techniques to determine that γ-aminobutyric acid (GABA)ergic neurons derived from the peri-PVN area containing AT2R make appositions onto AVP neurons within the PVN, thereby positioning AT2R to negatively regulate neuroendocrine secretion. Subsequent patch-clamp electrophysiological experiments revealed that selective activation of AT2R in the peri-PVN area using compound 21 facilitates inhibitory (ie, GABAergic) neurotransmission and leads to reduced activity of AVP neurons within the PVN. Final experiments determined the functional impact of AT2R activation by testing the effects of compound 21 on plasma AVP levels. Collectively, these experiments revealed that AT2R expressing neurons make GABAergic synapses onto AVP neurons that inhibit AVP neuronal activity and suppress baseline systemic AVP levels. These findings have direct implications in the targeting of AT2R for disorders of AVP secretion and also for the alleviation of high blood pressure.

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“…These changes were independent of blood pressure and were reversed by concomitant infusion of PD123319 (92). Moreover, the intra-cerebroventricular or systemic infusion of C21 into stroke-induced normal rats also reduced infarct size and neurological deficits accompanied by reductions in cerebral inflammation, effects that were suppressed by PD123319 (93). Collectively, these studies support the concept that AT2R stimulation could be a potential therapeutic tool for treatment of ischemic stroke or cerebral degenerative diseases.…”

Section: Effects Of At2r Agonists On Brain Functionmentioning

confidence: 99%

AT2 Receptor Activities and Pathophysiological Implications

Matavelli

Siragy

2015

Journal of Cardiovascular Pharmacology

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Although angiotensin II subtype-2 receptor (AT2R) was discovered over two decades ago, its contribution to physiology and pathophysiology is not fully elucidated. Current knowledge suggests that under normal physiologic conditions, AT2R counterbalances the effects of angiotensin II subtype-1 receptor (AT1R). A major obstacle for AT2R investigations was the lack of specific agonists. Most of the earlier AT2R studies were performed using the peptidic agonist, CG42112A, or the non-peptidic antagonist PD123319. CGP42112A is non-specific for AT2R and in higher concentrations can bind to AT1R. Recently, the development of specific non-peptidic AT2R agonists boosted the efforts in identifying the therapeutic potentials for AT2R stimulation. Unlike AT1R, AT2R is involved in vasodilation via release of bradykinin and nitric oxide, anti-inflammation and healing from injury. Interestingly, the vasodilatory effects of AT2R stimulation were not associated with significant reduction in blood pressure. In the kidney, AT2R stimulation produced natriuresis, increased renal blood flow, and reduced tissue inflammation. In animal studies, enhanced AT2R function led to reduction of cardiac inflammation and fibrosis, and reduced the size of the infarcted area. Similarly, AT2R stimulation demonstrated protective effects in vasculature and brain.

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The angiotensin type 2 receptor agonist Compound 21 elicits cerebroprotection in endothelin-1 induced ischemic stroke

Abstract: 2016-12-23T18:47:23

Cited by 59 publications

References 40 publications

Is angiotensin II type 2 receptor a new therapeutic target for cardiovascular disease?

Is angiotensin II type 2 receptor a new therapeutic target for cardiovascular disease?

Angiotensin Type-2 Receptors Influence the Activity of Vasopressin Neurons in the Paraventricular Nucleus of the Hypothalamus in Male Mice

AT2 Receptor Activities and Pathophysiological Implications

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