http://etsmjournal.biomedcentral.com/articles/10.1186/s13231-016-0022-1
- Mariana Moreira Coutinho Arroja,
- Emma Reid and
- Christopher McCabeEmail authorView ORCID ID profile
Experimental & Translational Stroke Medicine20168:8
DOI: 10.1186/s13231-016-0022-1
© The Author(s) 2016
Received: 22 July 2016
Accepted: 29 September 2016
Published: 7 October 2016
Abstract
The
renin angiotensin system (RAS) consists of the systemic hormone system,
critically involved in regulation and homeostasis of normal
physiological functions [i.e. blood pressure (BP), blood volume
regulation], and an independent brain RAS, which is involved in the
regulation of many functions such as memory, central control of BP and
metabolic functions. In general terms, the RAS consists of two opposing
axes; the ‘classical axis’ mediated primarily by Angiotensin II (Ang
II), and the ‘alternative axis’ mediated mainly by Angiotensin-(1–7)
(Ang-(1–7)). An imbalance of these two opposing axes is thought to exist
between genders and is thought to contribute to the pathology of
cardiovascular conditions such as hypertension, a stroke co-morbidity.
Ischaemic stroke pathophysiology has been shown to be influenced by
components of the RAS with specific RAS receptor antagonists and
agonists improving outcome in experimental models of stroke.
Manipulation of the two opposing axes following acute ischaemic stroke
may provide an opportunity for protection of the neurovascular unit,
particularly in the presence of pre-existing co-morbidities where the
balance may be shifted. In the present review we will give an overview
of the experimental stroke studies that have investigated
pharmacological interventions of the RAS.
Keywords
Acute ischaemic stroke (AIS) Renin angiotensin system (RAS) Angiotensin II (Ang II) Angiotensin-(1–7) (Ang-(1–7)) AT1R blockers AT2R agonists MasR agonistsBackground
In
the UK, stroke is the fourth leading cause of death and one of the
largest contributors towards long-term disability, affecting
approximately 152,000 people every year (https://www.stroke.org.uk; State of the Nation 2015) [1].
In the past 40 years the number of stroke fatalities has been
decreasing, however, it is estimated that over two-thirds of stroke
survivors require daily medical care and over half are left disabled [2], resulting in an annual cost of nearly £4 billion and accounting for approximately 4–6 % of total NHS expenditure [3].
Recombinant
tissue plasminogen activator (rt-PA; Alteplase), is the only
thrombolytic treatment currently available for acute ischaemic stroke
(AIS). It acts by breaking down the clot or thrombus obstructing the
cerebral vessel, thus, re-establishing blood flow. However, it has a
narrow therapeutic time window of 4.5 h from stroke onset, resulting in
only 2–5 % of ischaemic strokes being treated globally, and can have
detrimental side effects, including haemorrhage [4].
Recent results from a number of randomised clinical trials of
mechanical thrombectomy have demonstrated efficacy for this intervention
up to 6 h after stroke onset [5].
The positive results from these trials have reinvigorated the stroke
community and open up new possibilities for adjunctive protective
strategies.
Failure
to translate effective therapeutic strategies from the ‘bench to
bedside’ may partly be attributed to the use of animal models that do
not incorporate non-modifiable risk factors such as gender and many of
the stroke co-morbidities observed in the clinical stroke population,
such as hypertension, diabetes, obesity, etc. For instance, hypertension
is the single most important modifiable risk factor for stroke, acting
as a contributing factor in over 75 % of first time stroke patients [6] with hypertension during acute stroke is associated with poorer clinical outcome [7].
The
renin angiotensin system (RAS), a peptide hormone system intrinsically
involved in blood pressure regulation and blood volume homeostasis in
the circulation, has been shown to be present as a local paracrine
system in the brain [8]. The RAS is reported to be involved in the pathology of AIS and its risk factors [8, 9],
therefore, emerging as a potential therapeutic target. This review
discusses the therapeutic potential of the RAS following AIS,
emphasising the importance of cerebral RAS receptor targeting and its
relevance in the presence of known stroke risk factors.
Brain RAS: classical and alternative axis
In
the circulation, a drop in blood pressure (systemic hypotension) and/or
blood volume results in juxtaglomerular cells within the kidneys to
release renin (protease) whereas increased blood pressure (hypertension)
inhibits renin release under normal circumstances. Circulating
angiotensinogen is hydrolysed by renin to produce Angiotensin I (Ang I),
which is then further converted by angiotensin converting enzyme (ACE)
to generate biological active octapeptide, Ang II (Fig. 1). Ang II, a potent vasoconstrictor, acts by stimulating Ang II type 1 and type 2 receptors (AT1R and AT2R) [10]. Ang II exhibits a higher affinity to the widely expressed AT1R
whereby it exerts its main physiological effects by constricting blood
vessels, increasing BP, and stimulating aldosterone release from adrenal
glands, promoting water and salt reabsorption in the kidneys, thus,
raising blood volume levels [10].
In the last decade, an ‘alternative axis’ has been identified involving
the monocarboxypeptidase, ACE2, the biologically active peptide
Ang-(1–7) and its G-protein coupled receptor, Mas (MasR). Ang-(1–7) is
formed by the direct actions of ACE2 on Ang II or via ACE2 induced
cleavage of Ang I, generating the nine amino acid peptide Ang-(1–9),
which is further converted to Ang (1–7) by ACE or peptidases such as
neprilysin (NEP) [8].
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