Which of the following is not one of the ways that angiotensin ii increases arterial blood pressure?

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Introduction

The renin-angiotensin-aldosterone system (RAAS) is a critical regulator of blood volume and systemic vascular resistance. While the baroreceptor reflex responds short-term to decreased arterial pressure, the RAAS is responsible for more chronic alterations. It is composed of three major compounds: renin, angiotensin II, and aldosterone. These three act to elevate arterial pressure in response to decreased renal blood pressure, decreased salt delivery to the distal convoluted tubule, and/or beta-agonism. Through these mechanisms, the body can elevate blood pressure in a prolonged manner.[1][2][3]

Organ Systems Involved

The renin-angiotensin-aldosterone system involves the kidneys, lungs, systemic vasculature, and the brain.[4]

Function

The renin-angiotensin-aldosterone system is primarily associated with blood pressure regulation by modulating blood volume, sodium reabsorption, potassium secretion, water reabsorption, and vascular tone. Other described functions of the RAAS include inflammation, apoptosis, and fibrosis.[5] This article will focus on the role of the RAAS in cardiovascular physiology and blood pressure hemostasis.

Mechanism

Within the afferent arterioles of the kidney, specialized cells called juxtaglomerular (JG) cells contain prorenin. While prorenin is secreted constitutively in its inactive form, activation of JG cells causes the cleavage of prorenin to renin. Activation of these cells occurs in response to decreased blood pressure, beta-activation, or activation by macula densa cells in response to a decreased sodium load in the distal convoluted tubule.[6][7]

Once renin has been released into the blood, it can act on its target, angiotensinogen. Angiotensinogen is produced in the liver and is found continuously circulating in the plasma. Renin then acts to cleave angiotensinogen into angiotensin I. Angiotensin I is physiologically inactive but acts as a precursor for angiotensin II.[5]

The conversion of angiotensin I to angiotensin II is catalyzed by an enzyme called angiotensin-converting enzyme (ACE). ACE is found primarily in the vascular endothelium of the lungs and kidneys. After angiotensin I is converted to angiotensin II, it has effects on the kidney, adrenal cortex, arterioles, and brain by binding to angiotensin II type I (AT1) and type II (AT2) receptors.[8] The effects discussed below are a result of binding to AT receptors. The role of AT receptors is still being investigated, but pertinently, they have been shown to cause vasodilation by nitric oxide generation. In the plasma, angiotensin II has a half-life of 1 to 2 minutes, at which point peptidases degrade it into angiotensin III and IV. Angiotensin III has been shown to have 100% of the aldosterone stimulating effect of angiotensin II but 40% of the pressor effects, while angiotensin IV has further decreased the systemic effect.

In the proximal convoluted tubule of the kidney, angiotensin II acts to increase Na-H exchange, increasing sodium reabsorption. Increased levels of Na in the body act to increase the osmolarity of the blood, leading to a shift of fluid into the blood volume and extracellular space (ECF). This increases the arterial pressure of the patient.

Angiotensin II also acts on the adrenal cortex, specifically the zona glomerulosa. Here, it stimulates the release of aldosterone. In contrast to angiotensin II, aldosterone is a steroid hormone. As a result, it enacts change by binding to nuclear receptors and altering gene transcription. Thus, the effects of aldosterone may take hours to days to begin, while the effects of angiotensin II are rapid. Aldosterone affects sodium reabsorption and potassium excretion at the distal tubule and collecting duct of the nephron.

Aldosterone works by stimulating the insertion of luminal Na channels and basolateral Na-K ATPase proteins. Whether aldosterone results in salt retention without losing potassium or potassium loss without salt retention is described as a paradox because the same stimulus (aldosterone) has the ability to cause seemingly opposite outcomes.[9] The interaction between aldosterone and the mineralocorticoid receptor is influenced by phosphorylation at its binding site. Phosphorylation reduces aldosterone affinity and thereby reduces receptor activation, often described as a “switch” for whether or not mineralocorticoid receptors will react to aldosterone.[10] 

Angiotensin II influences renal epithelial cells, phosphorylation of mineralocorticoid receptors in the intercalated cells of the distal nephron, and inhibits potassium secretion by altering kinase activity, specifically WNK family kinases.[11] As such, the presence or absence of angiotensin II determines whether aldosterone triggers sodium chloride retention without loss of potassium or potassium secretion without significant change in sodium chloride retention.[9]

The effect of angiotensin II on vasoconstriction takes place in systemic arterioles. Here, angiotensin II binds to G protein-coupled receptors, leading to a secondary messenger cascade that results in potent arteriolar vasoconstriction. This acts to increase total peripheral resistance, causing an increase in blood pressure.

Finally, angiotensin II acts on the brain. Here, it has three effects. First, it binds to the hypothalamus, stimulating thirst and increasing water intake. Second, it stimulates the release of antidiuretic hormone (ADH) by the posterior pituitary. ADH, or vasopressin, acts to increase water reabsorption in the kidney by inserting aquaporin channels at the collecting duct. Finally, angiotensin II decreases the sensitivity of the baroreceptor reflex. This diminishes baroreceptor response to an increase in blood pressure, which would be counterproductive to the goal of the RAAS.

The net effect of these interactions is an increase in total body sodium, total body water, and vascular tone.

Clinical Significance

The renin-angiotensin-aldosterone system acts to manage blood volume and arteriolar tone on a long-term basis. While minor and rapid shifts are typically managed via the baroreceptor reflex, the RAAS can alter blood volume chronically. Though the RAAS serves a critical function, it can be activated inappropriately in several conditions that may then lead to the development of hypertension. For example, renal artery stenosis results in a decreased volume of blood reaching one (or both) kidneys. As a result, the juxtaglomerular cells will sense a decrease in blood volume, activating the RAAS. This can lead to an inappropriate elevation of circulating blood volume and arteriolar tone due to poor renal perfusion.[12][4]

Pharmacologically, the RAAS is a frequently manipulated system in managing heart failure, hypertension, diabetes mellitus, and acute myocardial infarction. ACE inhibitors (e.g., enalapril), angiotensin receptor blockers (ARBs, e.g., losartan), and aldosterone antagonists (e.g., spironolactone) all act to decrease the effect of the RAAS.

The varied mechanisms of these drugs allow their utilization in different scenarios. ACE inhibitors inhibit the action of angiotensin-converting enzymes, thus decreasing the production of angiotensin II. ARBs act to block AT receptors, thus inhibiting angiotensin’s effect while maintaining normal levels of the compound. Aldosterone inhibitors have two specific varieties. The first (e.g., spironolactone or eplerenone) act as aldosterone antagonists. These work by preventing the binding of aldosterone to binding sites in the kidney, preventing insertion of Na channels. The second (e.g., amiloride or triamterene) group act to block the inserted Na channels in the distal convoluted tubule.

A common use for ACE inhibitors or ARBs is in managing hypertension. In these cases, blocking or decreasing levels of angiotensin II will lead to a reduction in blood pressure. They achieve this goal by decreasing sodium and water reabsorption, leading to a reduction in blood volume, and decreasing arteriolar tone. In addition, these drugs are often used in the management of diabetes mellitus. Patients with diabetes mellitus often have renal manifestations such as proteinuria due to excess glucose damaging the glomerulus. Using ACE inhibitors or ARBs can decrease efferent arteriolar tone, leading to a reduction in pressure on the glomerulus. Thus, they are frequently used for the prevention of worsening diabetic nephropathy.

References

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Bernstein KE, Khan Z, Giani JF, Cao DY, Bernstein EA, Shen XZ. Angiotensin-converting enzyme in innate and adaptive immunity. Nat Rev Nephrol. 2018 May;14(5):325-336. [PMC free article: PMC6192041] [PubMed: 29578208]

Arroyo JP, Ronzaud C, Lagnaz D, Staub O, Gamba G. Aldosterone paradox: differential regulation of ion transport in distal nephron. Physiology (Bethesda). 2011 Apr;26(2):115-23. [PubMed: 21487030]

Wagner CA. Effect of mineralocorticoids on acid-base balance. Nephron Physiol. 2014;128(1-2):26-34. [PubMed: 25377117]

Shibata S, Arroyo JP, Castañeda-Bueno M, Puthumana J, Zhang J, Uchida S, Stone KL, Lam TT, Lifton RP. Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation. Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15556-61. [PMC free article: PMC4217463] [PubMed: 25313067]

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