Deans' stroke musings

Changing stroke rehab and research worldwide now.Time is Brain!Just think of all the trillions and trillions of neurons that DIE each day because there are NO effective hyperacute therapies besides tPA(only 12% effective). I have 493 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.

What this blog is for:

Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It's quite disgusting that this information is not available from every stroke association and doctors group.
My back ground story is here:http://oc1dean.blogspot.com/2010/11/my-background-story_8.html

Friday, October 7, 2016

Therapeutic potential of the renin angiotensin system in ischaemic stroke

There really is no point in doing any stroke research. None ever seems to be followed up to create stroke protocols. Let's just save the money and continue to let our stroke survivors deal with this by themselves. Would following this fix the Capillaries that don't open due to pericytes?
http://etsmjournal.biomedcentral.com/articles/10.1186/s13231-016-0022-1
Experimental & Translational Stroke Medicine20168:8
DOI: 10.1186/s13231-016-0022-1
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 agonists

Background

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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