How the Renin-Angiotensin System Controls Blood Pressure

The renin-angiotensin system involves a balance between two pathways

The renin-angiotensin system (RAS) is a group of related hormones that act together to regulate blood pressure and control inflammation. It is called a system because each part influences the other parts and all are necessary for the whole to function correctly.

The renin-angiotensin system, working together with the kidneys, is a vitally important part of the body's blood pressure regulation system. More specifically, this is done through the classical renin-angiotensin-aldosterone system (RAAS) pathway.

A doctor writing a prescription
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Inappropriate activation of the classical pathway can also lead to some harmful effects such as hypertension, which is sustained high blood pressure, and the development of vascular disease. However, the renin-angiotensin system also promotes protective, anti-inflammatory responses through its alternative renin-angiotensin pathway.

Together, the classical and alternative RAS pathways create responses that oppose one another, but balance out their effects.

How the Classical RAS Pathway Works

The important members of the classical RAS pathway are:

  • Renin
  • Angiotensin I
  • Angiotensin II
  • Angiotensin converting enzyme 1 (ACE1)
  • Aldosterone

Renin

When blood pressure drops for any reason, special cells in the kidney detect the change and release renin into the bloodstream. Renin by itself does not really affect blood pressure.

Instead, it floats around and converts angiotensinogen into angiotensin I. Angiotensinogen is a molecule that is primarily produced by the liver and circulates throughout the bloodstream. It is not able to alter the blood pressure as a precursor molecule. It must be transformed into the active form of angiotensin.

Angiotensin I

Angiotensin I also does not affect blood pressure much itself. Instead, most angiotensin I is converted to angiotensin II, a much more powerful hormone that does cause large changes in blood pressure.

Angiotensin-converting enzyme 1

This second conversion, which produces angiotensin II, happens mainly in the lungs via the action of a molecule called an angiotensin-converting enzyme. More specifically, it is called angiotensin-converting enzyme 1 (ACE1). This conversion can be blocked by drugs called ACE Inhibitors, an important type of high blood pressure medication.

Angiotensin II

Angiotensin II is a very powerful hormone that can act directly on blood vessels, causing them to become narrow, or constrict, to increase blood pressure. It has another important function as well—stimulating the release of aldosterone.

Aldosterone

Aldosterone is a hormone that helps increase blood pressure by causing the kidneys to retain both salt and water, which over time increases the amount of fluid in the body. This increase, in turn, raises blood pressure.

Classical RAA System Pathway

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Other Effects of the RAA Pathway: Neural and Renal

Aside from the blood vessels, angiotensin II can also bind to receptors located in different areas of the body. It regulates blood pressure by sending messages to the brain and the kidneys to help raise blood pressure.

Neural effects

Angiotensin II stimulates an area in the brain called the "thirst center" to help increase blood pressure. This thirst center is located in a part of the brain called the hypothalamus. When the thirst center is told by angiotensin II that the blood pressure is too low, it creates a sensation of thirst. Drinking water, then, increases the fluid volume in the body and raises blood pressure.

Angiotensin II also stimulates the body's "fight-or-flight response" to help increase blood pressure. This response, which is usually activated during stressful situations, causes the heart to pump more quickly and forcefully to increase the circulating volume and the blood pressure.

Renal effects

Thirst is not the only message from the brain in response to low blood pressure. Angiotensin II also tells the hypothalamus to increase the production of a protein called antidiuretic hormone. This hormone travels from the brain to the kidneys and tells the kidneys to reabsorb water from the urine.

Angiotensin II also acts directly on the kidneys to further help increase blood pressure and blood flow by telling the kidneys to:

  • Constrict its small blood vessels to help increase blood pressure
  • Increase sodium and water retention
  • Regulate the rate the kidney filters fluid

As a long-term regulator of blood pressure, the classical RAS pathway has a constant baseline level of activity, and actually works much like the gas pedal of a car. Constant pressure on the gas pedal is required to keep the car moving forward, even when you just want to go at the same speed.

If you need to, though, you can press the pedal down suddenly in order to quickly speed up. Likewise, constant activity in the classical RAS pathway keeps blood pressure steady over the long term, but sudden bursts of action are possible when a quick response is required.

The Classical RAS Pathway and High Blood Pressure

The classical RAS pathway is known to be an important factor in heart disease. One heart disease that is common in the United States is chronic high blood pressure, also known as hypertension. According to the Centers for Disease Control and Prevention (CDC), hypertension affects approximately half of adults in the United States.

Some people with hypertension have no identifiable cause. This is referred to as primary, or essential, hypertension. Other people have hypertension due to secondary causes. Secondary hypertension can be caused by hormonal imbalances in the classical RAS pathway. For example, a tumor in the adrenal gland can release excessive amounts of aldosterone and lead to fluid retention and high blood pressure.

Many scientific papers, conference presentations, and textbooks have been written about the importance of the classical RAS pathway in blood pressure regulation. This is an area of research still being pursued by scientists more than 50 years after the discovery of the system.

The details of the renin-angiotensin-aldosterone system continue to be investigated and could help us further understand:

  • Why people develop primary (essential) hypertension
  • Why some people don't respond well to typical high blood pressure treatment
  • Why some people with high blood pressure develop more complications than others

For example, Black patients with high blood pressure often don't respond as well to ACE inhibitors as to other medicines. This is likely because African-Americans have a different level of activity in their renin-angiotensin-aldosterone system, which makes them less sensitive to drugs that work by blocking the system

RAA Inhibitors and High Blood Pressure

Several effective high blood pressure treatments have been developed as a direct result of our understanding of the renin-angiotensin-aldosterone system.

  • ACE inhibitors stop the conversion of angiotensin I to angiotensin II.
  • Angiotensin receptor blockers (ARBs) prevent angiotensin II from binding to blood vessels and causing vasoconstriction.
  • Water pills, or diuretics, help to get rid of fluid by telling the body excrete water and sodium through urination.

While we have a better understanding of how to manage chronic high blood pressure, the fine details of the renin-angiotensin-aldosterone system are still being discovered.

How the Alternative RAS Pathway Works

Eventually, angiotensin I, angiotensin II, and aldosterone are broken down into other molecules. Some of these other molecules act in a closely related alternative pathway that counteracts the effects of the classical pathway. Important members of the alternative pathway include:

  • Angiotensin-converting enzyme 2
  • Angiotensin-(1-7)
  • Angiotensin-(1-9)

While the classical RAS pathway controls blood pressure and body fluid, it also has a complementary negative effect on the body that promotes inflammation. Some of the inflammatory responses of the classical RAS pathway include:

  • Blood vessel narrowing, or constriction
  • Increase in lung inflammatory responses
  • Increase in cell stress responses
  • Increase in arrhythmias or abnormal heartbeats
  • Increase in insulin resistance

The alternative RAS pathway opposes the effects of angiotensin II by lowering blood pressure. It also has anti-inflammatory responses. Some of these responses include:

  • Blood vessel relaxation, or dilation
  • Maintains blood flow and oxygenation in the lung
  • Reduction in cell stress responses
  • Relaxation of the heart’s coronary vessels
  • Decrease in insulin resistance

You can think of the alternative RAS system as a brake on the classical RAA pathway. Because the classical and alternative RAA pathways oppose one another, they act to balance out their systemic effects.

The RAA System and COVID-19

The Coronavirus disease 2019 (COVID-19), or SARS-CoV-2, led to a global outbreak that affected nearly 200 million people worldwide as of July 2021. The disease is associated with severe complications in people who have pre-existing cardiovascular diseases, such as hypertension and diabetes.

The renin-angiotensin system plays an important role in the COVID-19 infectious disease process.

The SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE 2) as a "receptor" and cellular entry point to infect a wide range of cells in the body. More specifically, ACE 2, which is embedded in the surfaces of cells, is recognized by spike proteins on the COVID-19 virus. This recognition leads to a lock-and-key relationship that opens the door for the virus to enter.

COVID-19 virus binds ACE 2 to enter cells

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Angiotensin-converting enzyme 2 (ACE2)

Although ACE 2 protects against the harmful inflammatory effects of angiotensin II, in the presence of the COVID-19 virus, ACE 2 is unable to serve in this protective manner. It is preoccupied with facilitating viral entry into cells. This leads to a reduction in anti-inflammatory responses and worsening of COVID-19 symptoms and infection.

Frequently Asked Questions

How quickly does the RAA system work?

The RAA system involves a cascade of events that are triggered by different hormones. While the effects of some hormones are rapid, such as that of angiotensin II, others, such as aldosterone, take hours to days. The net effect of the RAA system is to elevate blood pressure in a prolonged manner.

Why is the RAA system important?

The RAA system is one of the most important hormonal response systems in the body because it regulates blood pressure, fluid balance, electrolyte balance (sodium and potassium), and a balance between inflammatory and anti-inflammatory effects. The RAA system has also been demonstrated to play a role in the infectious disease process of COVID-19.

What functions does the RAA system help maintain?

The classical RAA pathway leads to blood vessel constriction and blood pressure elevation. It can also eventually lead to systemic inflammation and organ damage. The alternative RAA pathway, on the other hand, leads to blood vessel relaxation and blood pressure reduction. It has anti-inflammatory effects and can lead to organ protection. The two pathways counteract but balance one another. An imbalance may have an effect on the COVID-19 infectious disease process.

A Word From Verywell

The RAA System is well-characterized in cardiovascular diseases such as hypertension, heart failure, and renal disease. Several medications that inhibit the classical RAA pathway have been developed and effectively help to reduce the progression of vascular diseases.

The RAA inhibitors also indirectly affect the alternative RAA pathway and the infectious disease process of COVID-19. It is important to speak with your medical provider about the risks and benefits of treatment with RAA inhibitors.

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