The Renin-Angiotensin-Aldosterone System (RAAS) is a hormone system that regulates long-term blood pressure. It uses a sequence of hormones and enzymes to manage blood volume and blood vessel constriction in response to pressure drops or changes in fluid balance. By controlling sodium and water levels and influencing vascular tone, the RAAS maintains stable blood flow to the body’s organs.
The RAAS Activation Cascade
The RAAS cascade is initiated by triggers within the kidneys. When specialized juxtaglomerular cells detect a drop in blood pressure or sodium concentration, they release the enzyme renin into the bloodstream. The release of renin is the rate-determining step of the process. The system remains inactive in individuals with normal blood pressure and stable salt levels.
Once in the blood, renin acts on angiotensinogen, a protein produced by the liver. Renin cleaves a portion of the angiotensinogen molecule to form angiotensin I. At this stage, angiotensin I is biologically inactive and serves as a precursor molecule that requires further conversion.
The transformation of angiotensin I occurs primarily in the lungs. As blood flows through lung capillaries, it encounters Angiotensin-Converting Enzyme (ACE). ACE is found on the surface of endothelial cells and converts angiotensin I into angiotensin II, the main active hormone of the RAAS. This conversion creates the molecule that drives the system’s effects on blood pressure.
Physiological Effects of RAAS Hormones
The effects of the RAAS are driven by angiotensin II, which has multiple targets. One of its primary actions is causing widespread vasoconstriction, the narrowing of small arteries (arterioles). By constricting these vessels, angiotensin II increases total peripheral resistance, which directly elevates systemic blood pressure.
Beyond its direct effect on blood vessels, angiotensin II also acts on the adrenal glands, which are located on top of the kidneys. It specifically stimulates a region of these glands called the adrenal cortex, prompting the release of another hormone, aldosterone. Angiotensin II also travels to the brain, where it can stimulate the hypothalamus to trigger the sensation of thirst and a desire for salt, encouraging an increase in fluid and sodium intake.
Aldosterone’s role is to regulate the body’s sodium and water balance. It acts on the kidneys’ distal tubules and collecting ducts, where it promotes the reabsorption of sodium from urine back into the bloodstream. Because water follows sodium via osmosis, this retention expands total blood volume, which further contributes to an increase in blood pressure.
Dysregulation of the RAAS
While the RAAS manages acute changes in blood pressure, its chronic overactivation can lead to health problems. When the system is persistently engaged, its short-term benefits become detrimental. The constant vasoconstriction from high angiotensin II levels leads to a sustained increase in peripheral resistance, a hallmark of chronic high blood pressure (hypertension).
This elevated pressure is compounded by aldosterone’s effect on blood volume, which places a greater load on the heart and blood vessels. Over time, this sustained high pressure can damage the endothelial lining of arteries. It can also cause the muscular walls of the heart and vessels to thicken and stiffen, a process known as remodeling.
The consequences of a chronically overactive RAAS extend to major organs. The constant high pressure and volume overload can strain the heart, contributing to the development of heart failure. The heart must work harder to pump blood against the increased resistance, leading to enlargement and weakening of the heart muscle. The kidneys can also be damaged, impairing their filtration function and potentially leading to chronic kidney disease.
Pharmacological Targeting of the RAAS
Understanding the RAAS cascade has led to medications that treat hypertension and heart failure by interrupting the system. These drugs are among the most prescribed for cardiovascular conditions and work by targeting specific steps in the pathway. By blocking the cascade, these medications reduce the effects of angiotensin II and aldosterone, lowering blood pressure and reducing strain on the heart.
One common class of these drugs is Angiotensin-Converting Enzyme (ACE) inhibitors. Medications like ramipril and lisinopril block the action of ACE, the enzyme that converts angiotensin I to angiotensin II. This reduces the amount of angiotensin II in the body, leading to less vasoconstriction and lower aldosterone production. The result is vasodilation and reduced sodium retention, which lowers blood pressure.
Another class of drugs is the Angiotensin II Receptor Blockers (ARBs). Unlike ACE inhibitors, ARBs allow angiotensin II to be produced but block it from binding to its AT1 receptors on blood vessels and other tissues. By preventing angiotensin II from activating these receptors, ARBs stop its vasoconstrictor and aldosterone-releasing effects. Other medications, like aldosterone antagonists, work further down the cascade by blocking aldosterone’s action on the kidneys, promoting sodium and water excretion.