Renin Angiotensin System

By Devansh MehtaM.PHARM.(PHARMACOLOGY)

M.B.A.(Pharmaceutical Marketing and Hospital Administration)B.Pharmacy

Contact No.:+91-8171552727

Its also called as RAAS system

• The renin–angiotensin system (RAS) or the renin–angiotensin–aldosterone system (RAAS) is a hormone system that regulatesblood pressure and fluid balance.

• When renal blood flow is reduced, juxtaglomerular cells in the kidneys convert the prorenin already present in the blood into renin and secrete it directly into the circulation. Plasma renin then carries out the conversion of angiotensinogen released by the liver toangiotensin I. Angiotensin I is subsequently converted to angiotensin II by the enzyme angiotensin-converting enzyme found in the lungs. Angiotensin II is a potent vaso-active peptide that causes blood vessels to constrict, resulting in increased blood pressure.Angiotensin II also stimulates the secretion of the hormone aldosterone from the adrenal cortex. Aldosterone causes the tubules of the kidneys to increase the reabsorption of sodium and water into the blood. This increases the volume of extracellular fluid in the body, which also increases blood pressure.

• If the renin–angiotensin–aldosterone system is abnormally active, blood pressure will be too high. There are many drugs that interrupt different steps in this system to lower blood pressure. These drugs are one of the main ways to control high blood pressure (hypertension), heart failure, kidney failure, and harmful effects of diabetes.

• The system can be activated when there is a loss of blood volume or a drop in blood pressure (such as in hemorrhage or dehydration). This loss of pressure is interpreted by baroreceptors in the carotid sinus. In alternative fashion, a decrease in the filtrate NaCl concentration and/or decreased filtrate flow rate will stimulate the macula densa to signal the juxtaglomerular cells to release renin.

• If the perfusion of the juxtaglomerular apparatus in the kidney's macula densa decreases, then the juxtaglomerular cells (granular cells, modified pericytes in the glomerular capillary) release the enzyme renin.

• Renin cleaves a zymogen, an inactive peptide, called angiotensinogen, converting it into angiotensin I.

• Angiotensin I is then converted to angiotensin II by angiotensin-converting enzyme (ACE), which is thought to be found mainly in lung capillaries. One study in 1992 found ACE in all blood vessel endothelial cells.

• Angiotensin II is the major bioactive product of the renin-angiotensin system, binding to receptors on intraglomerular mesangial cells, causing these cells to contract along with the blood vessels surrounding them and causing the release of aldosterone from the zona glomerulosa in the adrenal cortex. Angiotensin II acts as an endocrine,autocrine/paracrine, and intracrine hormone.

Cardiovascular effects

• It is believed that angiotensin I may have some minor activity, but angiotensin II is the major bio-active product. Angiotensin II has a variety of effects on the body:

• Throughout the body, it is a potent vasoconstrictor of arterioles.• In the kidneys, AII 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 systemic arterial 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 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 Na+/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 to Na+ channels in the collecting ducts. This will ultimately lead to increased sodium reabsorption

• In the adrenal cortex, it acts to cause the release of aldosterone. Aldosterone acts on the tubules (e.g., the distal convoluted tubules and the cortical collecting 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.

• Release of anti-diuretic hormone (ADH),[3] 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.

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.

• The renin-angiotensin-aldosterone system (RAAS) plays an important role in regulating blood volume and systemic vascular resistance, which together influence cardiac output and arterial pressure. As the name implies, there are three important components to this system: 1) renin, 2) angiotensin, and 3) aldosterone. Renin, which is primarily released by the kidneys, stimulates the formation of angiotensin in blood and tissues, which in turn stimulates the release of aldosterone from the adrenal cortex.

• Renin is a proteolytic enzyme that is released into the circulation primarily by the kidneys. Its release is stimulated by:

sympathetic nerve activation (acting through β1-adrenoceptors)renal artery hypotension (caused by systemic hypotension or renal artery stenosis)decreased sodium delivery to the distal tubules of the kidney.

• Juxtaglomerular (JG) cells associated with the afferent arteriole entering the renal glomerulus are the primary site of renin storage and release. A reduction in afferent arteriole pressure causes the release of renin from the JG cells, whereas increased pressure inhibits renin release.

• Beta1-adrenoceptors located on the JG cells respond to sympathetic nerve stimulation by releasing renin. Specialized cells (macula densa) of distal tubules lie adjacent to the JG cells of the afferent arteriole. The macula densa senses the concentration of sodium and chloride ions in the tubular fluid.

• When NaCl is elevated in the tubular fluid, renin release is inhibited. In contrast, a reduction in tubular NaCl stimulates renin release by the JG cells. There is evidence that prostaglandins (PGE2 and PGI2) stimulate renin release in response to reduced NaCl transport across the macula densa.

• When afferent arteriole pressure is reduced, glomerular filtration decreases, and this reduces NaCl in the distal tubule. This serves as an important mechanism contributing to the release of renin when there is afferent arteriole hypotension, which can be caused by systemic hypotension or narrowing (stenosis) of the renal artery that supplies blood flow to the kidney.

• When renin is released into the blood, it acts upon a circulating substrate, angiotensinogen, that undergoes proteolytic cleavage to form the decapeptide angiotensin I. Vascular endothelium, particularly in the lungs, has an enzyme,angiotensin converting enzyme (ACE), that cleaves off two amino acids to form the octapeptide, angiotensin II (AII), although many other tissues in the body (heart, brain, vascular) also can form AII.

• AII has several very important functions:• Constricts resistance vessels (via AII [AT1] receptors) thereby

increasing systemic vascular resistance andarterial pressure• Stimulates sodium transport (reabsorption) at several renal tubular

sites, thereby increasing sodium and water retention by the body• Acts on the adrenal cortex to release aldosterone, which in turn acts

on the kidneys to increase sodium and fluid retention

• Stimulates the release of vasopressin (antidiuretic hormone, ADH) from the posterior pituitary, which increases fluid retention by the kidneys• Stimulates thirst centers within the brain• Facilitates norepinephrine release from sympathetic nerveendings

and inhibits norepinephrine re-uptake by nerve endings, thereby enhancing sympathetic adrenergic function• Stimulates cardiac hypertrophy and vascular hypertrophy