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What happens when angiotensin II is increased?

Angiotensin II is a hormone that plays an important role in regulating blood pressure and fluid balance in the body. It is part of the renin-angiotensin-aldosterone system (RAAS) which controls blood volume and systemic vascular resistance. When angiotensin II levels are increased, it can have widespread effects on the cardiovascular system. In this article, we will explore what happens in the body when there are elevated levels of angiotensin II.

Effects on Blood Pressure

One of the main effects of increased angiotensin II is to cause vasoconstriction and raise blood pressure. Angiotensin II stimulates angiotensin type 1 (AT1) receptors located on the muscles surrounding blood vessels. This causes the muscles to contract, making the blood vessels narrower. The end result is an increase in peripheral resistance and blood pressure.

In addition, angiotensin II acts on the adrenal glands to increase the release of aldosterone. Aldosterone is a hormone that promotes sodium and fluid retention by the kidneys. This also leads to an increase in blood volume and pressure. The combined effects of vasoconstriction and fluid retention make angiotensin II a very potent hormone for elevating blood pressure.

Acute vs Chronic Effects on Blood Pressure

The blood pressure raising effects of angiotensin II can occur rapidly in the short-term, or develop more gradually over time with chronic increases in this hormone. In response to acute stressors like hemorrhage or dehydration, angiotensin II levels can increase dramatically within minutes. This helps restore blood pressure by causing intense vasoconstriction.

With prolonged elevation of angiotensin II, such as in cases of hypertension or kidney failure, the effects on blood pressure are more slowly progressive. The chronic vasoconstriction and fluid retention lead to hypertension and end-organ damage over months to years. Acute spikes in angiotensin II have a more immediate and short-lived impact on blood pressure, while chronic elevations have a more gradual but sustained effect.

Effects on Fluid and Electrolyte Balance

In addition to its effects on blood pressure, increased angiotensin II also significantly alters fluid and electrolyte balance in the body. As mentioned, it stimulates aldosterone release which promotes sodium retention and fluid reabsorption in the kidneys. Angiotensin II also decreases renal blood flow which reduces glomerular filtration rate. The combination of direct sodium retention and decreased filtration leads to expanded fluid volume.

There is also increased reabsorption of calcium in renal tubules under the influence of aldosterone. This can potentially lead to hypercalcemia. Angiotensin II also promotes thirst and increased water intake via its effects on the central nervous system. All of these mechanisms act in concert to increase blood volume and cardiac output when angiotensin II levels are elevated.

Impacts on Different Organ Systems

The fluid retaining effects of angiotensin II have widespread impacts on multiple organ systems:

  • Kidneys: decreased renal blood flow and glomerular filtration rate
  • Heart: increased blood volume leads to increased preload and cardiac output
  • Lungs: fluid retention can contribute to pulmonary edema
  • Liver: increased central venous pressure impairs venous drainage

Monitoring fluid status and electrolyte levels is therefore very important when angiotensin II levels are chronically elevated. This helps prevent adverse effects like pulmonary congestion, peripheral edema and hyperkalemia. Prompt treatment with diuretics may be warranted if fluid overload develops.

Effects on Thirst and Vasopressin

Angiotensin II acts centrally to increase thirst sensation and promote drinking behaviors. Within the hypothalamus, it stimulates neurons that are involved in regulating fluid homeostasis. This leads to an increased urge to drink.

Angiotensin II also stimulates the posterior pituitary to release vasopressin (also called antidiuretic hormone or ADH). Vasopressin increases water reabsorption in the collecting ducts of the kidneys, which reduces urine output. Like aldosterone, it works synergistically with angiotensin II to control fluid balance and blood volume. The combined effects of thirst and vasopressin release are aimed at conserving water and correcting volume depletion when angiotensin II levels rise.

Effects on Sympathetic Nervous System

The sympathetic nervous system is activated when there are increased levels of angiotensin II. Within the central nervous system, angiotensin II promotes increased sympathetic outflow via effects on the circumventricular organs. This leads to widespread vasoconstriction, increased cardiac output, and retention of sodium and water.

Angiotensin II also enhances release of norepinephrine from sympathetic nerve endings. This amplifies its pressor effects and helps increase peripheral resistance. Activation of the sympathetic nervous system is one of the key mechanisms by which angiotensin II elevates blood pressure and compensates for volume depletion. It works in tandem with other RAAS hormones like aldosterone and vasopressin to maintain fluid homeostasis.

Effects on Vascular Remodeling

In addition to its short-term effects on vasoconstriction, angiotensin II also promotes vascular remodeling changes when it is chronically elevated. It stimulates growth factors like PDGF (platelet derived growth factor) and TGF-B (transforming growth factor beta) that lead to structural modifications in the vessel wall.

Angiotensin II also upregulates adhesion molecules like VCAM-1 and ICAM-1 that recruit inflammatory cells such as monocytes and lymphocytes. These inflammatory cells penetrate the vessel wall and stimulate fibrosis and hyperplasia. Over time, this leads to thickening of vessel walls and narrowing of the vascular lumen. The arteries become stiffer and less compliant.

These vascular remodeling effects contribute to the development of hypertension and end-organ damage associated with prolonged elevation of angiotensin II. The vascular changes exacerbate the vasoconstrictive effects. Reversing the remodeling process is one of the major benefits of RAAS blockade in hypertension management.

Effects on Aldosterone Release

A key effect of increased angiotensin II is to stimulate aldosterone synthesis and release from the adrenal cortex. Aldosterone is a mineralocorticoid hormone that acts on the kidneys to increase sodium and water reabsorption, which increases blood volume. Angiotensin II stimulates aldosterone release by acting on angiotensin type 1 (AT1) receptors in the zona glomerulosa of the adrenals.

When angiotensin II levels are elevated due to low blood pressure or volume depletion, more aldosterone is released to help restore blood volume and pressure through sodium retention. This acute effect is beneficial in correcting hypotension. However, chronic aldosterone release driven by high angiotensin II levels can lead to fluid overload and hypertension.

RAAS inhibitors like ACE inhibitors and ARBs reduce aldosterone release by blocking the upstream formation of angiotensin II or directly antagonizing AT1 receptors. This helps reduce the sodium retaining effects of aldosterone when angiotensin II levels are chronically high.

Aldosterone Release vs Sensitivity

In certain conditions like primary aldosteronism, angiotensin II levels may be normal but the adrenal glands are hypersensitive to its effects. Smaller than normal amounts of angiotensin II trigger excessive aldosterone release. Primary aldosteronism is treated by blocking aldosterone effects directly rather than upstream RAAS inhibition. This highlights that both the level of angiotensin II and tissue sensitivity are important in determining aldosterone secretion.

Effects on Endothelial Function

The vascular endothelium helps regulate vascular tone and structure by releasing relaxing factors like nitric oxide (NO) and constricting factors like endothelin-1 (ET-1). Angiotensin II impairs endothelial function by tipping this balance in favor of vasoconstriction.

It reduces endothelial nitric oxide release through multiple mechanisms. First, it stimulates production of reactive oxygen species like superoxide anion, which quench and degrade nitric oxide. Secondly, it upregulates expression of caveolin-1, which inhibits endothelial nitric oxide synthase activity.

Angiotensin II also increases release of the potent vasoconstrictor endothelin-1. This further tips the balance towards vasoconstriction. The net result is a reduction in endothelium-dependent vasodilation and unopposed vasoconstriction. This contributes to the increased peripheral resistance induced by angiotensin II.

Endothelial Dysfunction and RAAS Inhibitors

RAAS inhibition with drugs like ACE inhibitors and ARBs has been shown to improve endothelial dysfunction in conditions with elevated angiotensin II. These agents reduce vascular oxidative stress and increase nitric oxide bioavailability. They also reduce endothelin-1 levels. Thus, the vascular benefits of RAAS inhibitors are due in part to reversing the adverse effects of angiotensin II on the endothelium.

Effects on Atherosclerosis

Chronic elevation of angiotensin II promotes development of atherosclerosis through several mechanisms. First, the endothelial dysfunction it induces reduces nitric oxide levels and predisposes to platelet activation and thrombosis. Secondly, the increased oxidative stress caused by angiotensin II damages the endothelium.

Angiotensin II also stimulates migration of monocytes into the vessel intima and their differentiation into lipid-laden foam cells that form the atherosclerotic plaque. It activates growth factors like PDGF that cause smooth muscle proliferation within the plaque. Over time, these effects accelerate formation of atherosclerotic lesions.

Clinical Trials in Atherosclerosis

Multiple clinical trials have demonstrated that RAAS inhibition with ACE inhibitors or ARBs can reduce atherosclerotic complications like myocardial infarction and stroke. These drugs mitigate the plaque-destabilizing effects of angiotensin II. Their atheroprotective effects are at least partly mediated by improving endothelial function and reducing oxidative stress and inflammation.

Effects on Myocardial Hypertrophy and Fibrosis

In addition to the vasculature, elevated angiotensin II also adversely affects cardiac structure and function. It stimulates cardiomyocyte hypertrophy, which increases left ventricular wall thickness and mass. Angiotensin II also promotes cardiac fibrosis by enhancing fibroblast proliferation and collagen deposition.

These effects are mediated by angiotensin II stimulation of growth factors like TGF-beta as well as the increased aldosterone levels it causes. The myocardial hypertrophy and scarring that develop can lead to diastolic heart failure and arrhythmias. Blocking the RAAS can reverse some of this adverse cardiac remodeling.

Effects on Kidney Structure and Function

The kidneys are directly damaged by sustained increases in angiotensin II through multiple pathways. It causes constriction of the efferent arterioles which increases glomerular pressure and promotes glomerulosclerosis. It stimulates TGF-beta and collagen production which causes renal fibrosis.

Angiotensin II also enhances kidney leukocyte infiltration and inflammation. Over time, these effects lead to nephron loss and chronic kidney disease. RAAS inhibitors like ACE inhibitors or ARBs confer renoprotective benefits in proteinuric kidney disease by mitigating the angiotensin II-mediated damage. They improve outcomes in conditions like diabetic nephropathy.

Effects in Diabetic Patients

Diabetic patients often have elevated activity of the RAAS system. This contributes to their increased risk of hypertension, vascular damage, kidney disease and heart failure. Angiotensin II levels are often high in these patients due to volume depletion from glycosuria. Diabetes also causes tissue dysregulation of the RAAS.

Hyperglycemia promotes angiotensin II formation by the kidney and other organs. Angiotensin II also increases insulin resistance which worsens glycemic control. All of these effects are detrimental in diabetes. RAAS inhibition with ACE inhibitors or ARBs has proven benefits in diabetic patients by offsetting the adverse effects of high angiotensin II activity.

Benefits in Diabetic Nephropathy

ACE inhibitors and ARBs are considered first-line therapy in patients with diabetic nephropathy and proteinuria. They counteract the blood pressure raising effects of angiotensin II and also confer direct renoprotective benefits. ARBs reduce progression of diabetic kidney disease better than other antihypertensive agents. Thus, RAAS inhibition has a vital role in preserving kidney function in diabetic patients.

Genetic Factors Related to Angiotensin II

Genetic polymorphisms related to the RAAS system may influence an individual’s risk from elevated angiotensin II levels. Gene variants affecting angiotensin converting enzyme (ACE) levels have been widely studied.

Individuals with the DD genotype of the ACE gene have higher ACE levels and more rapid angiotensin II formation. They tend to experience greater blood pressure reduction from ACE inhibitor therapy. ACE gene testing is being studied to guide personalized use of RAAS inhibitors.

Polymorphisms in the angiotensin receptor gene AGTR1 may also impact sensitivity to angiotensin II effects. Genetic screening may someday help identify individuals who require more aggressive RAAS blockade based on their genetic profile. More research is needed in this area.

Testing for Angiotensin II Levels

While direct measurement of angiotensin II levels is not routinely performed in clinical practice, tests are available in specialized research settings. Blood samples may be obtained and plasma angiotensin II levels measured using radioimmunoassay techniques. Normal plasma concentrations are generally 10-20 pg/mL at rest.

However, angiotensin II has important local tissue effects that may not be reflected in circulating levels. Testing its concentration in isolated vessels provides a functional assessment of its vasoconstrictor effects. Genetic proxies like ACE gene variants are also being used as indirect biomarkers of angiotensin II activity. These methods may provide insight into the clinical effects of angiotensin II excess or deficiency.

Risks Related to Very High Angiotensin II

Markedly elevated angiotensin II levels have detrimental effects on multiple organ systems and can be severely detrimental, especially when the increase is acute. Risks related to very high angiotensin II include:

  • Hypertensive crisis with malignant hypertension
  • Acute kidney injury and renal failure
  • Pulmonary edema due to acute fluid overload
  • Accelerated atherosclerosis and atherothrombosis
  • Acute heart failure due to increased afterload
  • Encephalopathy and stroke due to malignant hypertension

Very high angiotensin II levels require urgent medical treatment to reduce RAAS overactivity, control blood pressure, and prevent end-organ damage. Prompt therapy with RAAS blockers, diuretics and antihypertensive agents may be life-saving by mitigating these risks.


Angiotensin II is a potent hormone that plays an important role in maintaining cardiovascular and renal homeostasis. However, excess activation of the RAAS system and elevated angiotensin II has widespread adverse effects. It raises blood pressure, alters fluid and electrolyte balance, and promotes end-organ damage in the vasculature, kidneys and heart.

Careful RAAS modulation with blockers like ACE inhibitors or ARBs can offset these negative effects, especially in high-risk conditions like hypertension, kidney disease and diabetes. A deeper understanding of the molecular and genetic determinants of angiotensin II action may further improve personalized management in the future.