Introduction

Bradykinin is a molecule that plays a crucial role in inflammation.  In this review, we will discuss the cellular basis of bradykinin production, function, pathophysiology, and clinical significance. Bradykinin can act as a vasoactive substance along with histamine in inflammation and swelling as it is a potent vasodilator. Bradykinin also plays a significant role in the pathophysiology of C1 esterase inhibitor deficiency and in the clinical application of considering whether to use angiotensin-converting enzyme inhibitors or angiotensin two receptor blockers.[1]

Cellular Level

Bradykinin is a product of the kallikrein-induced breakdown of high-molecular-weight kininogen (HMWK) in the kinin cascade. HMWK also serves as an inducer of the conversion of factor XII to factor XIIa in the intrinsic pathway, or contact activation, of the coagulation cascade. Bradykinin is inactivated by angiotensin-converting enzyme (ACE) in the lungs and kidneys.[2]

Function

Bradykinin plays a prominent role in inflammation. Bradykinin, along with prostaglandins and histamine, are mediators of vasodilation, in which the arteriolar smooth muscle relaxes and, in turn, increases blood flow. This increased blood flow causes the rubor, or redness, and calor, or warmth, components of the inflammation process. Bradykinin, along with prostaglandin E2 (PGE2), also plays a role in the sensitization of sensory nerve endings, which causes the dolor, or pain, the component of the inflammation process. Thus in the process of inflammation, bradykinin causes an increase in vasodilation, an increase in permeability, and an increase in pain.[3]

Pathophysiology

Bradykinin plays a prominent role in the pathophysiology of C1 esterase inhibitor deficiency; this is an autosomal dominant hereditary disease that presents with recurrent episodes of angioedema without urticaria of the face, extremities, oropharynx, and abdomen. It can also cause angioedema of the gastrointestinal tract, which manifests with severe abdominal pain as well as gastrointestinal upset. These episodes of angioedema are often preceded by a period of fatigue and flu-like symptoms. When assessing a patient with angioedema, the airway requires examination, and patient intubation may be necessary.[4] The angioedema in these patients is not responsive to epinephrine or antihistamines. Therefore, the resolution of the angioedema requires treatment with plasma-derived C1 inhibitor or recombinant human C1 inhibitor. If neither of these forms of C1 inhibitor is available for treatment, fresh frozen plasma is a treatment option.[5]

C1 esterase deficiency is a complement regulatory protein deficiency that causes hereditary angioedema. C1 esterase is a protein inhibitor; it inhibits the complement system to prevent spontaneous activation of the complement system. Without the C1 esterase inhibitor, there is unchecked activation of C1, C2, and C4 complement proteins before other inhibitors can stop the cascade.

Angioedema is due to the unregulated activation of kallikrein. This activation of kallikrein increases levels of bradykinin because kallikrein activates bradykinin. This excessive bradykinin induces increased permeability, increased vasodilation, and increased pain.[2] 

Decreased levels of C4 complement characterize this disease because without the C1 esterase inhibitor to inhibit spontaneous activation of the complement system such that there is unchecked activation of C1, C2, and C4, and these complement proteins get consumed as they are activated, decreasing their levels. Thus, decreased C4 and C2 protein levels are the best initial tests. However, C1 inhibitor deficiency would be unlikely if C4 levels were detected to be at normal levels. If the initial test indicates decreased levels of C4 complement protein, a confirmatory diagnostic test should follow, and confirmation of C1 esterase deficiency would show by decreased C1 inhibitor antigenic levels and decreased C1 inhibitor functional levels.

In C1 esterase deficiency, there is an excessive buildup of bradykinin. Therefore, angiotensin-converting enzyme (ACE) inhibitors are contraindicated for patients with this disease, as ACE inhibitors also have the risk of increasing bradykinin further, which would then exacerbate the manifestations of the patient’s C1 esterase deficiency due to excessive inflammation. This exacerbation is because ACE inactivates bradykinin; thus, inhibiting the ACE enzyme inhibits this inactivation, which would allow for the continuation of bradykinin, leading to angioedema.[6]

Clinical Significance

Angiotensin-converting enzyme (ACE) is an enzyme that breaks down and inactivates bradykinin. ACE is present in the lungs and the kidneys and also converts angiotensin I to angiotensin II. This conversion is a crucial step in blood pressure control as angiotensin II causes vasoconstriction and increases blood pressure and constriction of efferent arterioles in the kidneys. Therefore, inhibition of ACE has clinical application as a mechanism for decreasing blood pressure. ACE inhibitors such as captopril, enalapril, lisinopril, and ramipril all inhibit ACE. They are clinically used to manage patients with hypertension, leading to decreased mortality in patients with heart failure, patients with proteinuria, and patients with diabetic nephropathy. ACE inhibitors can reduce heart remodeling that is caused by chronic hypertension. ACE inhibitors are used in patients with chronic kidney disease, such as those with diabetic nephropathy, as they decrease intraglomerular pressure, thereby slowing the thickening of the glomerular basement membrane.

Inhibition of ACE decreases the amount of angiotensin II formed from angiotensin I. This decrease in angiotensin II causes a reduction in the glomerular filtration rate by preventing the constriction of efferent arterioles. This dilation of efferent arterioles causes an increase in renin due to the loss of negative feedback. Inhibition of ACE, however, also inhibits the inactivation of bradykinin. Because bradykinin is a potent vasodilator, the prevention of bradykinin inactivation causes excessive amounts of bradykinin to build up. This increased bradykinin can cause the side effect of angioedema, which can be seen in some patients taking ACE inhibitors and is the reason for the contraindication of ACE inhibitors in C1 esterase deficiency.[7]

Therefore, clinically, angiotensin II receptor blockers (ARB) can be used instead of ACE inhibitors for blood pressure control in hypertensive patients, heart failure, proteinuria, chronic kidney disease, including diabetic nephropathy, or patients with intolerance to ACE inhibitors such as those who have excessive coughing or angioedema.[8] In contrast to ACE inhibitors, angiotensin II receptor blockers, such as losartan, candesartan, and valsartan, selectively block the binding of angiotensin II to the AT1 receptor. Though ultimately, the effects are similar to ACE inhibitors, ARBs do not increase bradykinin as they are not inhibiting ACE. Therefore angioedema is not an adverse effect for patients using ARBs.[9]

FDA has approved medications for treating the acute attacks of hereditary angioedema like c-1 esterase inhibitor concentrate, B2 bradykinin receptor inhibitor, a kallikrein inhibitor, and plasma-free recombinant C1-inhibitor concentrate. FDA-approved prophylaxis to prevent attacks of hereditary angioedema are C1 esterase inhibitor, plasma-derived concentrate of C1-esterase inhibitor, and plasma kallikrein inhibitor (monoclonal antibody).[10][11]