RAAS and ACEIs

Discovery of RAAS occurred more than a century ago when in 1898, Tigerstedt1 and Bergmann demonstrated the existence of a substance (subsequently named renin) in crude extracts of rabbit renal cortex that caused a sustained increase in arterial pressure. Further understanding of RAAS pathway was brought forth by discovery of ANG-I  and II by Skeggs  and colleagues in 1950s. Finally, corticalhormone Aldosterone was discovered whose release was mediated via Ang-II and there by establishing the role of RAAS system in the regulation of blood pressure, fluid and electrolyte balance in the body. 

Fig 1 

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 Components of RAAS

 

The renin-angiotensin-aldosterone hormonal cascade begins with the biosynthesis of renin by the juxtaglomerular cells (JG) that line the afferent (and occasionally efferent) arteriole of the renal glomerulus. Renin regulates the initial and rate-limiting step of the RAAS cascade, i.e., converting angiotensinogen, formed constitutively in liver to Ang-I. The Ang-I is hydrolyzed by angiotensin- converting enzyme (ACE) to Ang-II, a biologically active, potent vasoconstrictor. ACE, an exopeptidase, and is localized on the plasma membranes of various tissues including vascular endothelial cells. ACE metabolizes a number of other peptides, including the vasodilator peptides bradykinin and kallikrein, to inactive metabolites.

 

Alternative pathways exist that convert angiotensinogen directly to Ang-II, such as tissue plasminogen activator,  cathepsin G , and tonin, whereas Ang-I is also catalyzed to Ang-II by chymase and cathepsin G part of which forms the basis of “Ang-II escape.” Ang-II once formed acts on the adrenal cortex and causes the release of aldosterone. The net effects include vasoconstriction, sodium and water retention, increased arterial blood pressure and increased myocardial contractility, which in combination increase the effective circulating volume. Apart from the classical pathway there is increasing evidence that the reninangiotensin system (RAAS) functions at tissue level in a paracrine or autocrine manner (Paul et al., 2006).  The physiologic role of tissue RAAS is complementary to the classical circulating RAAS and serves as a mechanism for long-term maintenance of balance at the tissue level between opposing effects mediated by the system (e.g., growth promotion and inhibition in the heart and vasculature).

 

Dysregulation of RAAS in Cardiovascular Disorders

 

Cardiovascular disorders have been postulated as a continuum that starts with presence of risk factors in an individual and produce endothelial dysfunction and atherosclerosis. Once established both lead to various cardiovascular events ultimately leading to MI, stroke, heart failure (HF), end stage renal disease (ESRD) or death. Dysregulation of RAAS has been implicated in affecting  every stage of this continuum  (Figure 1 ). above. 

 

Roles of RAAS activation

RAAS has been shown to be associated with both primary and secondary hypertension. Certain forms of secondary hypertension, including renin secreting neoplasms, renovascular hypertension (e.g., renal artery stenosis), malignant hypertension, pheochromocytoma, and primary hyperaldosteronism are supposed to be a direct consequence of increased RAAS activity. In patients with primary (essential) hypertension, the plasma renin activity   (PRA) can be high, normal, or low.  Activation of local RAAS has been implicated in “Low-renin” hypertension which is commonly seen in the elderly, diabetics and those with chronic renal parenchymal disease.

Atherosclerosis and endothelial dysfunction

The endothelium maintains vascular homeostasis through a network of complex interactions with vessel wall cells and lumen and plays a key role in the regulation of vascular tone, platelet adhesion and aggregation, inflammation and cell proliferation. The endothelial dysfunction that results from presence of multiple cardiovascular risk factors upregulates

 

Ang-II levels which triggers responses in vascular smooth muscle cells that lead to proliferation, migration and a phenotypic modulation, resulting in

production of growth factors and extracellular matrix,  all contributing to neointima formation and development of atherosclerotic process. These effects are mediated by the reactive release of vasoactive substances (Thromboxane A2, free radicals, endothelin, prostacyclin). Ang II, elaborated by activated endothelial ACE, impairs nitric oxide bioactivity, by increasing production of superoxide radicals (O2–) (that scavenge nitric oxide) and reduce both endothelium-dependent vasodilation and migration of

 

smooth muscle cells into in time.  The accumulation of ACE and metalloproteinase in the shoulder region of the vulnerable plaque may contribute to increased local circumferential stress and plaque instability, and hence may be implicated in acute complications by promoting plaque rupture and a hyperthrombotic state. ACEIs reduce CV risk through cardioprotective and vasoprotective effects (Figure 2 ) by blocking both the circulating & tissue RAS, inhibiting the formation of Ang-II as well as preventing the degradation of bradykinin, thereby  enhancing release of NO by the endothelium.

 Image

RAAS as therapeutic Targets

The effects of angiotensins are exerted through specific heptahelical G-protein coupled receptors. The four subtypes of angiotensin receptors are AT , AT , AT  and AT .

1 2 3 4

Most of the biological effects of Ang-II are mediated by AT 

receptors whose gene contains a polymorphism that may be associated with hypertension,  hypertrophic cardiomyopathy, coronary artery vasoconstriction and aortic stiffness. Functional roles of AT  receptors which are  widely disturbed in fetal tissues than adults are poorly defined. They may exert antiproliferative, proapoptotic, vasodilatory and antihypertensive & ECM modification effects.

The function of AT  receptor is unknown. However, AT   receptor may be involved in modulation of endothelial function.

 

 References 
1- Preventive Cardiology Journal ( volume 3rd ) 

2- . Tigerstedt R, Bergman P. Niere und Kreislauf. Skand Arch Physiol. 1898;8:223–71.

3. Skeggs LT Jr, Lentz KE, Kahn JR, Shumway NP, Woods KR. The amino acid sequence of hypertensin. II. J Exp Med. 1956;104:193–7.
4. Johnston CI, Risvanis J. Preclinical pharmacology of angiotensin II receptor antagonists: update and outstanding issues. Am J Hypertens. 1997;10:306S–10S.

5. Paul M, Poyan Mehr A, Kreutz R. Physiology of local reninangiotensin systems.
Physiol Rev. 2006;86:747–803.
6. Dzau V, Braunwald E. Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement. Am Heart J. 1991;121:1244–63.

 

About Dr.Nabil Paktin

Cardiologist , M.D.,F.A.C.C.

Posted on September 15, 2013, in Uncategorized. Bookmark the permalink. 1 Comment.

  1. ahmad haroon musleh

    besides, it is thought that a small amount of renin is released from the infarcted area and this amount is being inhibited by ACE inhibitors as well.

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