Centrally administered angiotensin‐(1–7) increases the survival of stroke‐prone spontaneously hypertensive rats

Abstract

New Findings r What is the central question of this study?Activation of angiotensin-converting enzyme 2, resulting in production of angiotensin-(1-7) and stimulation of its receptor, Mas, exerts beneficial actions in a number cardiovascular diseases, including ischaemic stroke. A potential beneficial role for angiotensin-(1-7) in haemorrhagic stroke has not previously been reported. r What is the main finding and its importance?Central administration of angiotensin-(1-7) into stroke-prone spontaneously hypertensive rats, a model of haemorrhagic stroke, increases lifespan and improves the neurological status of these rats, as well as decreasing microglial numbers in the striatum (implying attenuation of cerebral inflammation). These actions of angiotensin-(1-7) have not previously been reported and identify this peptide as a potential new therapeutic target in haemorrhagic stroke.Angiotensin-(1-7) [Ang-(1-7)] exerts cerebroprotective effects in ischaemic stroke, and this action is associated with a blunting of intracerebral inflammatory processes and microglial activation. Given that intracerebral inflammation and microglial activation play key roles in the mechanism of injury and brain damage in both ischaemic and haemorrhagic stroke, we have investigated the potential beneficial actions of Ang-(1-7) in stroke-prone spontaneously hypertensive rats (spSHRs), an established animal model of hypertensioninduced haemorrhagic stroke. Angiotensin-(1-7) was administered by continuous infusion via the intracerebroventricular route for 6 weeks into spSHRs fed a high-sodium (4%) diet, starting at 49 days of age. This treatment resulted in a significant increase in survival of the spSHRs. Median survival was 108 days in control, artificial cerebrospinal fluid-infused spSHRs and 154 days in Ang-(1-7)-treated spSHRs. This effect was partly reversed by intracerebroventricular infusion of the Mas receptor blocker, A779. This Ang-(1-7) treatment also decreased the number of haemorrhages in the striatum, improved neurological status (reduced lethargy), decreased the number of microglia in the striatum and tended to increase neuron survival at the same site. Importantly, infusions of Ang-(1-7) had no effect on kidney pathology, heart pathology, body weight, serum corticosterone levels or blood pressure. This study is the first to demonstrate the cerebroprotective actions of Ang-(1-7), including increased survival time, in spSHRs. As such, these data reveal a potential therapeutic target for haemorrhagic stroke.

Effects of Diabetic Hyperglycemia on Central Ang-(1-7)-Mas-R-nNOS Pathways in Spontaneously Hypertensive Rats

“…Prior studies have shown that central chronic administration of Ang-(1-7) increases survival of stroke-prone SHR rats, and improves cerebral blood flow, neurological deficits and brain ischemic tolerance evoked by middle carotid artery occlusion in rats [23,25]. These effects are not accompanied with changes of arterial BP [23,25], indicating that outcomes of Ang-(1-7) are likely independent of changes in BP.…”

“…These effects are not accompanied with changes of arterial BP [23,25], indicating that outcomes of Ang-(1-7) are likely independent of changes in BP. Consistent with the prior findings, in the current report, ICV injection of Ang-(1-7) fails to significantly alter BP in non-diabetic SHR animals; however, it lowers SBP in diabetic SHR animals.…”

“…Thus, in this report, the rats were divided into four groups as: WKY control; WKY with STZ; SHR control and SHR with STZ, respectively. In an additional experiment, Ang-(1-7) (75 µg/kg twice a day) and A779 (150 µg daily) were given via ICV injection [23,25] and tempol (50 mg/kg i.p. daily) was given for 4 weeks.…”

Protective axis of the renin–angiotensin system in the brain

“…Ang-(1-7) stimulates NO release and up-regulates eNOS (endothelial NOS) expression in ischaemic tissues following focal cerebral ischaemia/reperfusion in rats [56]. The cerebroprotective effect elicited by Ang-(1-7) has also been described in stroke-prone SHRs [57]. Intracerebroventricular infusion of Ang-(1-7) increased the survival time in these rats.…”

Genetics of aging and longevity

“…Известно, что контролируемое вме-шательство в активность ангиотензина-(1-7) приводит к существенному увеличению длительности жизни крыс с гипертензией за счет снижения у них повреждений и по-давления воспаления в головном мозге (Regenhardt et al, 2014). Инъекции рекомбинантного ACE2 также оказали положительное влияние.…”