Bradykinin in Pain & Inflammation + How to Decrease It

You have probably heard that high blood pressure is dangerous. Then it would make sense for anything that lowers blood pressure to be good, right? Not so fast. Enter bradykinin: a compound that lowers your blood pressure, increases inflammation, worsens pain and itchiness, and might even feed a growing tumor. Read on to learn about the two faces of bradykinin.

What is Bradykinin?

Bradykinin is a protein that lowers blood pressure by widening blood vessels. At the same time, it allows water to leak from the vessels into surrounding tissues, which increases inflammation in the area. Bradykinin helps your body to compensate for this movement of water by making you thirsty [1, 2, 3].

Bradykinin also worsens feelings of pain and itchiness triggered in nerve fibers by increasing their sensitivity [4, 5].

Bradykinin vs Histamine

If you’ve read about histamine, then the effects of bradykinin will sound familiar. Bradykinin and histamine are similar compounds with similar functions, but there are important differences between them.

Like bradykinin, histamine widens blood vessels, increases inflammation, and allows fluid from blood vessels to leak into surrounding tissues. Histamine also makes you thirsty and worsens pain and itch. Both bradykinin and histamine are active during allergic reactions such as hay fever [6, 7, 8, 5, 9].

At high concentrations, bradykinin also increases histamine release from inflammatory cells [10, 11].

Because of these similarities and interactions, doctors often assume that these symptoms are caused by histamine and prescribe antihistamine medication. However, some researchers have suggested that iif bradykinin is the culprit, this treatment may not work [5].

Bradykinin interacts with salt in the blood: high sodium increases bradykinin, which in turn signals the kidneys to remove more sodium from the blood. Histamine does not affect the kidneys in this way [12].

Bradykinin has an extremely short half-life of less than 17 seconds. This means that within 17 seconds of bradykinin being released, half of it will have broken down. By contrast, histamine’s half-life may be up to six minutes [13, 14].

Positive Effects of Bradykinin

Although bradykinin may cause problems, it also serves an important purpose in the body.

Bradykinin protects your heart and your nerves from damage. In the heart, it widens vessels and lowers blood pressure, which prevents heart failure and damage caused by high blood pressure. When the spinal cord or other nerves are injured, bradykinin protects nerve cells and prevents them from dying [15, 16].

1) Heart Health and Blood Pressure

High blood pressure can lead to heart failure. Bradykinin widens blood vessels and decreases blood pressure, which can protect the heart and keep it functioning after congestive heart failure [17, 18].

Doctors often take advantage of the protective effects of bradykinin to help patients with heart conditions. Angiotensin-converting-enzyme inhibitors, or ACEIs, are often prescribed to prevent heart failure in people with high blood pressure. ACEIs stop bradykinin from being broken down, and the increased concentration of bradykinin decreases blood pressure [15, 19].

2) Insulin Sensitivity

Bradykinin makes fat and muscle cells more sensitive to insulin, possibly by increasing the activity of insulin receptors on these cells [20].

Insulin resistance, the condition in which cells are not sensitive enough to insulin, develops before and often predicts type 2 diabetes. Because bradykinin increases the insulin sensitivity of certain cells, it may reduce the risk of developing type 2 diabetes. In turn, drugs which increase bradykinin, such as ACEIs, may prevent type 2 diabetes from developing [21, 20].

Negative Effects of Bradykinin

The symptoms shown here are commonly associated with high bradykinin, but many other causes may be at the root. Work with your doctor or other health care professional for an accurate diagnosis and appropriate health management or treatment plan.

Too much bradykinin causes inflammation and worsens feelings of pain. It may even cause dangerous blood pressure drops and feed the growth of a tumor [22, 23, 12, 2].

1) Inflammation

Bradykinin increases inflammation by widening the blood vessels and allowing fluid and cells to leak from the vessels into surrounding tissues. Bradykinin causes the production of histamine and nitric oxide to increase. Histamine allows fluid to leak out of the blood vessels, and nitric oxide relaxes and widens the blood vessels [22, 2, 24, 25, 6, 26].

Inflammation is the first step in wound healing. When it is well-regulated, it allows cells and growth factors to enter an injury site, remove damaged and dead tissues, and regrow new tissues [27].

However, when inflammation is badly regulated, it can lead to:

• Asthma [28]
• Sinusitis [28]
• Hay fever [9]
• Eczema [28]
• Scarring [27]
• Inflammatory Bowel Disease [28]
• Psoriasis [28]
• Autoimmune diseases [28]
• Arthritis [29]
• Depression [30]
• Cancer [31, 32]
• Many more diseases and chronic conditions [33, 34]

Asthma

Bradykinin may increase long-term inflammation in people with asthma. Cells in the airway produce bradykinin receptors after they are exposed to allergens, viruses, or compounds that promote inflammation such as interleukins. This increase in bradykinin receptors, in turn, increases inflammation in the airway, thereby intensifying this symptom of asthma [35, 36].

Angioedema

Angioedema is the most common symptom of high bradykinin. It is swelling just under the skin, all across the body. This type of swelling may result when bradykinin allows fluid to leak from blood vessels into the skin [37, 38].

Severe angioedema can be fatal, especially when the swelling occurs near the throat. If you experience angioedema, seek immediate medical treatment [39].

2) Pain

Bradykinin increases pain by making the nerves responsible for pain more sensitive. In other words, pressure and temperature levels that would normally be comfortable become painful in the presence of bradykinin [23, 5].

Delayed Muscle Soreness

Bradykinin is released during exercise and triggers the development of muscle soreness one or two days later. Bradykinin receptors increase nerve growth factor in the exercised muscle, and nerve growth factor makes nerves more sensitive to pain. Bradykinin blockers may ease this kind of muscle soreness, but only if taken before exercise [40].

Skin Irritation and Eczema

Over-the-counter and prescription antihistamines are among the most common treatments for the dry, itchy skin caused by eczema. However, a study of 14 people with eczema showed that antihistamines couldn’t reduce the pain and itch caused by bradykinin. Bradykinin receptors can be blocked with medication, but the safety and effectiveness of such treatments are still being studied. Therefore, people with eczema caused by bradykinin may have difficulty finding relief through standard treatments [5, 41, 42, 43].

Nerve Damage

Bradykinin may be responsible for the extreme pain caused by nerve damage, especially after a spinal cord injury. The number of bradykinin receptors more than doubles in injured spinal and other nerve tissue compared to normal, healthy tissues. Bradykinin receptor blockers are likely to be investigated in the future for their potential to treat nerve pain after injury [16].

Endometriosis

In a 2018 study of cells from the uterus, bradykinin increased the production of a compound called endothelin-1, which increases the sensation of pain. These results suggest that bradykinin is involved in the pain caused by reproductive disorders like endometriosis [44].

This theory is extremely new in medical research, with the earliest study published in 2015 [45].

Chronic Pain

Bradykinin makes nerves more sensitive to pain. If bradykinin and its receptors are produced at high levels for a long period of time, chronic pain may result [46, 47, 48].

That bradykinin causes chronic pain in the spine and nerves has been studied for more than a decade. More recently, however, high levels of bradykinin receptors have been associated with other types of chronic pain [48, 49, 50].

3) Bradykinin Cough

Bradykinin can cause a dry cough, especially in people taking a certain type of heart medication.

Angiotensin-converting-enzyme inhibitors, or ACEIs, are a class of drugs used to treat high blood pressure and prevent heart failure. ACEIs block the production of angiotensin II, a hormone that increases blood pressure [19, 51, 52].

One of the most common side effects of ACEIs is a dry cough, which affects up to a third of patients taking this medication for high blood pressure. ACEIs stop bradykinin from being broken down in the blood and tissues. The resulting increase in bradykinin probably triggers this cough [53, 54, 55, 15].

So far, the only treatment guaranteed to stop a bradykinin cough caused by ACEIs is to stop taking ACEIs [56].

In a study of guinea pigs, bradykinin receptors in the lungs made local nerves more sensitive and stimulated a dry cough. This mechanism is very similar to the one that causes increased pain and itchiness [57, 5].

Bradykinin may also cause cough in people who aren’t taking ACEIs, such as those with respiratory infections or asthma. In the future, new treatments for dry cough may block bradykinin [55, 57].

4) Excess Glutamate Release

What is Glutamate?

Glutamate is an extremely important neurotransmitter. The brain needs glutamate to maintain normal function, learn, and form memories. Glutamate release, by itself, is not a negative effect [58, 59].

However, too much glutamate can lead to health problems. Brain and nerve damage and diseases like epilepsy, depression, multiple sclerosis, ALS, and Alzheimer’s have been linked to high glutamate levels [60, 61, 62, 63, 64].

Too much glutamate has also been linked to some cancers, chronic pain, diabetes, and migraines [65, 66, 67, 68].

Bradykinin and Glutamate

Bradykinin increases the amount of glutamate that is released in the brain and nerves. As a result, most of glutamate’s effects will be more intense when bradykinin levels are high [47].

However, bradykinin also seems to protect nerve cells when too much glutamate is released. In multiple studies, bradykinin appeared to slow down cell death in animal brains after they had suffered a stroke. In one study, bradykinin increased the survival rate of rat eye cells exposed to toxic levels of glutamate [16, 69].

On the other hand, bradykinin and glutamate both make nerves more sensitive. While bradykinin might protect against the damage caused by glutamate, it will worsen the pain [23, 66, 46].

5) Low Sodium and Blood Pressure Drops

Bradykinin levels increase in the kidneys when the blood passing through contains high levels of sodium. Bradykinin then increases the amount of sodium that the kidneys filter out of the blood and into the urine. In this way, bradykinin helps maintain the balance of salt in the blood [12, 70].

High levels of bradykinin may cause the kidneys to filter out too much sodium. Sodium, like bradykinin, regulates blood pressure: when sodium levels drop, so does blood pressure. What’s more, mice genetically modified to produce high levels of human bradykinin in their kidneys have low blood pressure [12, 71].

If there is too much bradykinin and not enough sodium in the blood, blood pressure may drop dangerously low [12].

Paradoxically, in dogs, a very low sodium diet quickly increased the amount of bradykinin in the kidneys. So not only can bradykinin increase with high levels of sodium in the blood, but also with very low levels of sodium in the blood [72, 73, 74].

When Blood Pressure is Too Low

You may have heard that high blood pressure is dangerous and that you should work to lower it. However, excessively low blood pressure can also be hazardous to your health.

Sudden drops in blood pressure can cause:

• Dizziness [75]
• Fainting [76]
• Blurred vision [77]
• Ringing in the ears [77]
• Uncontrolled eye movements [77]
• Balance difficulties [77]
• Nausea [78]
• Fatigue [78]
• Irregular heartbeat [78]
• Headaches [78]

Drops in blood pressure are common in people who have difficulty maintaining healthy blood pressure overall. That is, many people who experience spikes of high blood pressure also have sudden blood pressure drops. These spikes and drops often predict heart problems and diabetes [76].

Low blood pressure and decreased brain function have been linked together in people with Parkinson’s disease, though it’s not yet clear whether one causes the other [79].

6) Tumor Growth

When a tumor begins to grow, it needs new blood vessels to spread. These new vessels bring nutrients that eventually render the tumor cancerous. Unfortunately, bradykinin increases the growth rate of these new vessels and possibly of tumors [2].

New cancer treatments may target bradykinin receptors to reduce cancerous vessel growth, which may prevent the tumor from becoming dangerous. In test tubes, several compounds that block bradykinin stopped breast cancer cells from growing or outright killed them. Bradykinin blockers were even more powerful than traditional chemotherapy drugs [80].

Although promising, more research is needed to understand how bradykinin blockers work and to make sure they’re safe [80].

7) Autoimmune Diseases

Autoimmune diseases begin when a person’s immune system attacks parts of their own body. Rheumatoid arthritis, multiple sclerosis, and type 1 diabetes are all autoimmune diseases. The symptoms of many such diseases include inflammation and pain caused by bradykinin and its receptors. In the future, drugs developed to treat autoimmune diseases may target bradykinin receptors [81].

Lupus Nephritis

Systemic lupus erythematosus, also called SLE or simply lupus, is an autoimmune disease that causes chronic inflammation, cell death, and organ damage. Roughly half of all people with SLE develop lupus nephritis, which specifically affects the kidneys. For many of these people, lupus nephritis is the first sign of SLE [82, 83].

Bradykinin may worsen the symptoms of lupus nephritis by increasing inflammation and the number of immune cells entering the kidneys. Therefore, some researchers believe that new treatments for lupus nephritis may block bradykinin receptors [84].

Causes of High Bradykinin

Bradykinin is part of numerous pathways in a healthy person. As such, high levels of bradykinin can have many causes. The ones shown here are commonly associated with high bradykinin, but this may not be an exhaustive list. Work with your doctor or other health care professional for an accurate diagnosis and health management plan.

Heart Medication

As discussed in the bradykinin cough section, people with high blood pressure are often prescribed angiotensin-converting-enzyme inhibitors, or ACEIs. ACEIs raise bradykinin by preventing its breakdown [19, 15].

Genetics

Some people may be at risk for high or low bradykinin based on their DNA. For more, see the section bradykinin genetics below [50, 85].

Too Much Salt

Bradykinin signals the kidneys to filter more sodium out of the blood. The higher the level of sodium, the more bradykinin will be released [12, 70].

Brain Injury

Bradykinin levels will normally increase during inflammation, as part of the wound healing process. In particular, the dramatic increase in bradykinin after brain and nerve injury protects the tissues and aids repair [16].

Factors that Could Decrease Bradykinin

Most importantly, work with your doctor to treat any underlying conditions causing your high bradykinin levels. You may try the additional strategies listed below if you and your doctor determine that they could be appropriate. None of these strategies should ever be done in place of what your doctor recommends or prescribes.

Furthermore, the precise links between diet, lifestyle choices, and bradykinin have been poorly studied. Much of the limited evidence on factors that decrease bradykinin comes from animal studies, which may not translate at all to human health.

As such, there is no clinical data to recommend any of these strategies to lower bradykinin in humans. Rather than attempting to lower bradykinin, it’s important to talk to your doctor and address any underlying conditions that may be causing an increase in bradykinin.

Diet Choices

Avoid Salty Foods

High levels of sodium in the blood will increase bradykinin. Salty foods may, therefore, cause bradykinin levels to rise [12].

Supplements

Linseed or flaxseed oil may decrease inflammation caused by bradykinin and histamine. Linseed oil contains a very high percentage of alpha-linolenic acid, an omega-3 fatty acid, which acted against bradykinin and histamine in rodents [86].

Ginger may decrease some of bradykinin’s negative effects. One component of ginger, 6-shogaol, blocks the production of inositol triphosphate in tissue studies. Bradykinin normally stimulates the production of inositol triphosphate, so this effect suggests that 6-shogaol may decrease bradykinin [87, 88, 89].

Areca nut (betel) is used to relieve migraines in parts of India. In a rat study, an extract from this nut significantly decreased the inflammation caused by bradykinin. However, chewing betel has been linked to numerous health problems, including oral cancer. As such, while special extracts or formulations may be developed in the future, we recommend strongly against chewing betel [90].

High-Fat Diets

In rats, a diet high in fish and soybean oils reduced the amount of bradykinin released in inflamed tissue. This result suggests that a diet high in healthy fats (PUFAs) should be further investigated in the context of bradykinin [91].

Overall, diets rich in healthy fats (like omega 3s) may decrease bradykinin and inflammation [86].

Lifestyle Choices

Avoid Tobacco

Tobacco, both in cigarette smoke and in smokeless forms, makes blood vessels more sensitive to the leakiness caused by bradykinin and increases inflammation in the lungs. Avoiding tobacco smoke may help decrease the inflammatory effect of bradykinin [92, 93, 94].

Limitations and Caveats

Unfortunately, research on bradykinin often takes a back seat to other inflammatory markers such as histamine, and human studies are limited. Much of the available data comes from animal studies, cell studies, or human studies with very few participants. Some data about the effects of blood sodium on bradykinin are contradictory and have yet to be fully explained.

Furthermore, many links between diet, lifestyle choices, and bradykinin have not been explicitly studied. Future research will likely clarify the relationship between diet, lifestyle, and bradykinin.

Genetics of Bradykinin

The two bradykinin receptors, B1 and B2, are encoded in genes called BDKRB1 and BDKRB2. These receptors, and especially B1, are expressed in higher amounts in inflamed and injured tissue [95].

These two genes have been associated with differences in baseline blood pressure. One version of the BDKRB1 gene, common in people of Han Chinese ancestry, is associated with chronic high blood pressure [96].

Animal studies have shown that deleting the BDKRB1 gene entirely reduced the symptoms of inflammatory disease [97].