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If the RAS is abnormally active, blood pressure will be too high. There are several types of drugs which includes ACE inhibitors, ARBs, and renin inhibitors that interrupt different steps in this system to improve blood pressure. These drugs are one of the primary ways to control high blood pressure, heart failure, kidney failure, and harmful effects of diabetes.
Renin activates the renin-angiotensin system by cleaving angiotensinogen, produced by the liver, to yield angiotensin I, which is further converted into angiotensin II by ACE, the angiotensin-converting enzyme primarily within the capillaries of the lungs.
In the kidneys, angiotensin II constricts glomerular arterioles, having a greater effect on efferent arterioles than afferent. As with most other capillary beds in the body, the constriction of afferent arterioles increases the arteriolar resistance, raising systemicarterial 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. The glomerular 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 decreased hydrostatic pressure and increased oncotic pressure (due to unfiltered plasma 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 the vasa recta. This decreases the washout of NaCl and urea in the kidney medullary 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 the Loop of Henle.
Angiotensin II stimulates / 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 to 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 the adrenal cortex, angiotensin II acts to cause the release of aldosterone. Aldosterone acts on the tubules (e.g., the distal convoluted tubules and the corticalcollecting ducts) in the kidneys, causing them to reabsorb more sodium 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), also called vasopressin - ADH is made in the hypothalamus and released from the posterior pituitary 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 the central nervous system to increase an individual's appetite for salt, and to stimulate the sensation of thirst.
Locally expressed renin-angiotensin systems have been found in a number of tissues, including the kidneys, adrenal glands, the heart, vasculature and nervous system, and have a variety of functions, including local cardiovascular regulation, in association or independently of the systemic renin-angiotensin system, as well as non-cardiovascular functions. 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. Outside the liver, angiotensinogen is picked up from the circulation or expressed locally in some tissues; with renin they form angiotensin I, and locally expressed angiotensin-converting enzyme, chymase or other enzymes can transform it into angiotensin II. This process can be intracellular or interstitial.
In the adrenal glands, it is likely involved in the paracrine regulation of aldosterone secretion; in the heart and vasculature, it may be involved in remodeling or vascular tone; and in the brain, where it is largely independent of the circulatory RAS, it may be involved in local blood pressure regulation. In addition, both the central and peripheral nervous systems can use angiotensin for sympathetic neurotransmission. 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.
Fetal renin-angiotensin system
In the fetus, the renin-angiotensin system is predominantly a sodium-losing system, 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.
Flowchart showing the clinical effects of RAAS activity and the sites of action of ACE inhibitors and angiotensin receptor blockers.
ACE 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 the kinin-kallikrein system, as such blocking ACE can lead to side effects.
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