Whenrenal blood flow is reduced,juxtaglomerular cells in the kidneys convert the precursorprorenin (already present in the blood) intorenin and secrete it directly into thecirculation. Plasma renin then carries out the conversion ofangiotensinogen, released by theliver, toangiotensin I, which has no biological function on its own.[4] Angiotensin I is subsequently converted to the activeangiotensin II by theangiotensin-converting enzyme (ACE) found on the surface of vascular endothelial cells, predominantly those of thelungs.[5] Angiotensin II has a short life of about 1 to 2 minutes. Then, it is rapidly degraded intoangiotensin III by angiotensinases which are present inred blood cells and vascular beds in many tissues.
Angiotensin III increases blood pressure and stimulatesaldosterone secretion from theadrenal cortex; it has 100% adrenocortical stimulating activity and 40% vasopressor activity of angiotensin II.Angiotensin IV also has adrenocortical and vasopressor activities.
Angiotensin II is a potentvasoconstrictive peptide that causes blood vessels to narrow, resulting in increased blood pressure.[6] Angiotensin II also stimulates the secretion of the hormonealdosterone[6] from theadrenal cortex. Aldosterone causes therenal tubules to increase the reabsorption ofsodium which in consequence causes the reabsorption of water into the blood, while at the same time causing the excretion ofpotassium (to maintainelectrolyte balance). This increases the volume ofextracellular fluid in the body, which also increases blood pressure.
If the perfusion of thejuxtaglomerular apparatus in the kidney'smacula densa decreases, then the juxtaglomerular cells (granular cells, modified pericytes in the glomerular capillary) release theenzymerenin.
Angiotensin I is then converted to anoctapeptide,angiotensin II byangiotensin-converting enzyme (ACE),[9] which is thought to be found mainly in endothelial cells of thecapillaries throughout the body, within the lungs and the epithelial cells of the kidneys. One study in 1992 found ACE in all blood vessel endothelial cells.[10]
Angiotensin I may have some minor activity, but angiotensin II is the major bioactive product. Angiotensin II has a variety of effects on the body:[citation needed]
In the kidneys, angiotensin II constrictsglomerular arterioles, having a greater effect onefferent arterioles than afferent. As with most other capillary beds in the body, the constriction ofafferent arterioles increases the arteriolar resistance, raisingsystemicarterial blood pressure and decreasing the blood flow. However, the kidneys must continue to filter enough blood despite this drop in blood flow, necessitating mechanisms to keep glomerular blood pressure up. To do this, angiotensin II constricts efferent arterioles, which forces blood to build up in the glomerulus, increasing glomerular pressure. Theglomerular filtration rate (GFR) is thus maintained, and blood filtration can continue despite lowered overall kidney blood flow. Because the filtration fraction, which is the ratio of the glomerular filtration rate (GFR) to the renal plasma flow (RPF), has increased, there is less plasma fluid in the downstream peritubular capillaries. This in turn leads to a decreasedhydrostatic pressure and increasedoncotic pressure (due to unfilteredplasma proteins) in the peritubular capillaries. The effect of decreased hydrostatic pressure and increased oncotic pressure in the peritubular capillaries will facilitate increased reabsorption of tubular fluid.
Angiotensin II decreases medullary blood flow through thevasa recta. This decreases the washout of NaCl andurea in the kidneymedullary space. Thus, higher concentrations of NaCl and urea in the medulla facilitate increased absorption of tubular fluid. Furthermore, increased reabsorption of fluid into the medulla will increase passive reabsorption of sodium along the thick ascending limb of theLoop of Henle.
Angiotensin II stimulatesNa+/H+ exchangers located on the apical membranes (faces the tubular lumen) of cells in the proximal tubule and thick ascending limb of the loop of Henle in addition toNa+ channels in the collecting ducts. This will ultimately lead to increased sodium reabsorption.
Angiotensin II stimulates the hypertrophy of renal tubule cells, leading to further sodium reabsorption.
In theadrenal cortex, angiotensin II acts to cause the release ofaldosterone. Aldosterone acts on the tubules (e.g., thedistal convoluted tubules and thecorticalcollecting ducts) in the kidneys, causing them to reabsorb moresodium and water from the urine. This increases blood volume and, therefore, increases blood pressure. In exchange for the reabsorbing of sodium to blood,potassium is secreted into the tubules, becomes part of urine and is excreted.
Angiotensin II causes the release of anti-diuretic hormone (ADH),[6] also calledvasopressin – ADH is made in the hypothalamus and released from the posteriorpituitary gland. As its name suggests, it also exhibits vaso-constrictive properties, but its main course of action is to stimulate reabsorption of water in the kidneys. ADH also acts on thecentral nervous system to increase an individual's appetite for salt, and to stimulate the sensation ofthirst.
These effects directly act together to increase blood pressure and are opposed byatrial natriuretic peptide (ANP).
Locally expressed renin–angiotensin systems have been found in a number of tissues, including thekidneys,adrenal glands, theheart,vasculature andnervous system, and have a variety of functions, includinglocal cardiovascular regulation, in association or independently of the systemic renin–angiotensin system, as well as non-cardiovascular functions.[9][11][12] Outside the kidneys, renin is predominantly picked up from the circulation but may be secreted locally in some tissues; its precursor prorenin is highly expressed in tissues and more than half of circulating prorenin is of extrarenal origin, but its physiological role besides serving as precursor to renin is still unclear.[13] Outside the liver, angiotensinogen is picked up from the circulation or expressed locally in some tissues; with renin they form angiotensin I, and locally expressedangiotensin-converting enzyme,chymase or other enzymes can transform it into angiotensin II.[13][14][15] This process can be intracellular or interstitial.[9]
In the adrenal glands, it is likely involved in theparacrine regulation ofaldosterone secretion; in the heart and vasculature, it may be involved in remodeling or vascular tone; and in thebrain, where it is largely independent of the circulatory RAS, it may be involved in local blood pressure regulation.[9][12][16] In addition, both thecentral andperipheral nervous systems can use angiotensin for sympathetic neurotransmission.[17] Other places of expression include the reproductive system, the skin and digestive organs. Medications aimed at the systemic system may affect the expression of those local systems, beneficially or adversely.[9]
In thefetus, the renin–angiotensin system is predominantly a sodium-losing system,[citation needed] as angiotensin II has little or no effect on aldosterone levels. Renin levels are high in the fetus, while angiotensin II levels are significantly lower; this is due to the limited pulmonary blood flow, preventing ACE (found predominantly in the pulmonary circulation) from having its maximum effect.[citation needed]
Flowchart showing the clinical effects of RAAS activity and the sites of action of ACE inhibitors and angiotensin receptor blockers.
Inhibitors of angiotensin-converting enzyme are often used to reduce the formation of the more potent angiotensin II.Captopril is an example of an ACE inhibitor. ACE cleaves a number of other peptides, and in this capacity is an important regulator of thekinin–kallikrein system, as such blocking ACE can lead to side effects.[18]
Atrial natriuretic peptide: When the atrium stretches, blood pressure is considered to be increased and sodium is excreted to lower blood pressure.
Bainbridge reflex: In response to stretching of the right atrium wall, heart rate increases, lowering venous blood pressure.
Baroreflex: When the stretch receptors in the aortic arch and carotid sinus increase, the blood pressure is considered to be elevated and the heart rate decreases to lower blood pressure.
Antidiuretic hormone: The hypothalamus detects the extracellular fluid hyperosmolality and the posterior pituitary gland secretes antidiuretic hormone to increase water reabsorption in the collecting duct.
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^Rogerson FM, Chai SY, Schlawe I, Murray WK, Marley PD, Mendelsohn FA (July 1992). "Presence of angiotensin converting enzyme in the adventitia of large blood vessels".J. Hypertens.10 (7):615–620.doi:10.1097/00004872-199207000-00003.PMID1321187.S2CID25785488.
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^Patil J, Heiniger E, Schaffner T, Mühlemann O, Imboden H (April 2008). "Angiotensinergic neurons in sympathetic coeliac ganglia innervating rat and human mesenteric resistance blood vessels".Regulatory Peptides.147 (1–3):82–87.doi:10.1016/j.regpep.2008.01.006.PMID18308407.S2CID23123825.
^Gradman A, Schmieder R, Lins R, Nussberger J, Chiangs Y, Bedigian M (2005). "Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients".Circulation.111 (8):1012–1018.doi:10.1161/01.CIR.0000156466.02908.ED.PMID15723979.
^Richter WF, Whitby BR, Chou RC (1996). "Distribution of remikiren, a potent orally active inhibitor of human renin, in laboratory animals".Xenobiotica.26 (3):243–254.doi:10.3109/00498259609046705.PMID8730917.
^Tissot AC, Maurer P, Nussberger J, Sabat R, Pfister T, Ignatenko S, et al. (March 2008). "Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study".Lancet.371 (9615):821–827.doi:10.1016/S0140-6736(08)60381-5.PMID18328929.S2CID15175992.
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