Neuromodulatory role of angiotensin-(1–7) in the central nervous system

Abstract

Ang-(1-7) [angiotensin-(1-7)] constitutes an important functional end-product of the RAS (renin-angiotensin system) endogenously formed from AngI (angiotensin I) or AngII (angiotensin II) through the catalytic activity of ACE2 (angiotensin-converting enzyme 2), prolyl carboxypeptidase, neutral endopeptidase or other endopeptidases. Ang-(1-7) lacks the pressor, dipsogenic or stimulatory effect on aldosterone release characteristic of AngII. In contrast, it produces vasodilation, natriuresis and diuresis, and inhibits angiogenesis and cell growth. At the central level, Ang-(1-7) acts at sites involved in the control of cardiovascular function, thus contributing to blood pressure regulation. This action may result from its inhibitory neuromodulatory action on NE [noradrenaline (norepinephrine)] levels at the synaptic cleft, i.e. Ang-(1-7) reduces NE release and synthesis, whereas it causes an increase in NE transporter expression, contributing in this way to central NE neuromodulation. Thus, by selective neurotransmitter release, Ang-(1-7) may contribute to the overall central cardiovascular effects. In the present review, we summarize the central effects of Ang-(1-7) and the mechanism by which the peptide modulates NE levels in the synaptic cleft. We also provide new evidences of its cerebroprotective role.

Estrogen regulation of the brain renin-angiotensin system in protection against angiotensin II-induced sensitization of hypertension

“…The protective effects of ANG-(1-7) are mediated by actions on both the brain and peripheral tissues (11,28). Feng et al reported that brain overexpression of ACE2 attenuated ANG II-induced hypertension, at least partly, by increasing AT 2 R, MasR, and nitric oxide synthase (NOS) mRNA expression and nitric oxide production in the brain of male mice (9).…”

Protective axis of the renin–angiotensin system in the brain

“…For instance, Ang-(1-7) induces similar responses to AngII on BP regulation when it is injected into the RVLM, NTS or CVLM, although these effects are elicited through different mechanisms and receptor subtypes [40,41]. In contrast, Ang-(1-7) exerts opposite actions to those displayed by AngII on baroreflex sensitivity and ischaemic injury [21,29,30]. Up until now, there has been no clear explanation for this differential effect for Ang-(1-7).…”

“…The CVLM receives direct baroreceptor input from the NTS and exerts a modulatory action on RVLM neurons via a short inhibitory pathway, thus having a sympato-inhibitory action [25,26]. It has been shown that Ang-(1-7) is as effective as AngII on BP regulation when injected into the RVLM or CVLM (see [29]). Despite both peptides eliciting similar responses with respect to BP when injected into the RVLM or CVLM, differential actions on the baroreflex control of heart rate have been reported [39].…”

“…In opposition to AngII, Ang-(1-7) has been shown to facilitate the baroreflex control of heart rate (for a review, see [29]). Accordingly, central infusion of an Ang-(1-7) antagonist blunted the baroreflex sensitivity in normotensive rats, but not in SHRs, whereas central infusion of an AT 1 R (AngII type 1 receptor) antagonist facilitated the sensitivity of the baroreceptor control of heart rate in both strains [30].…”

“…In contrast, Ang-(1-7) elicits an inhibitory neuromodulatory response in the brain noradrenaline system by acting at three levels: synthesis, release and uptake. Ang-(1-7), acting in sympathetic neurons through Mas receptor or AT 2 R stimulation, induces a decrease in neurotransmitter synthesis and release, as well as an increase in noradrenaline uptake, leading to a decrease in neurotransmitter levels in the synaptic cleft [29]. The Ang-(1-7)-stimulated noradrenaline uptake is the result of Ang-(1-7) action solely on neurons, since Mas receptors were shown to be present in neurons and not in astroglia [21], another cell assisting in the termination of signalling molecules that diffuse away from the synapse.…”