How is bradykinin synthesized?
Bradykinin is generated from kininogen through the action of kallikrein.
- Kininogen: A precursor protein circulating in the blood.
- Kallikrein: An enzyme; in the kidneys, it is located in the cells of the distal tubules.
- Bradykinin: The active peptide produced by this enzymatic cascade.
Physiological effects: what does bradykinin target?
This peptide participates in the regulation of hemodynamics and water-electrolyte balance, ultimately leading to a decrease in blood pressure.
- Vascular effects: Exerts a vasodilatory action. It dilates small arterioles and precapillary sphincters, increases venous return, and enhances blood shunting into the venous system via arteriovenous anastomoses. It alters vascular tone and increases the permeability of vessel walls.
- Renal effects: Increases renal blood flow and alters vascular permeability. It reduces sodium ion ($Na^+$) reabsorption in the renal tubules directly or via the inhibition of aldosterone, increasing the urinary excretion of water, as well as $K^+$, $Na^+$, and $Cl^-$ ions.
- Neuropeptide effects: In experimental studies (in the presence of cycloheximide), bradykinin was shown to restore a blocked defensive reflex.
Role in the pathogenesis of inflammation and pain
Bradykinin is a classic inflammatory mediator. Endothelial injury, such as that caused by antigen-antibody complexes, triggers the activation of the kinin-kallikrein system.
- Exudation and thrombosis: Due to increased vascular permeability, plasma leaks into the interstitial tissues. A reduction in plasma volume relative to the number of erythrocytes leads to sludging, impaired hemorheology, and intravascular thrombosis. Bradykinin also interacts with the coagulation and fibrinolytic systems.
- Cellular reactions: The peptide stimulates phagocyte chemotaxis, activates Hageman factor (factor XII), promotes collagenogenesis, and stimulates cyclooxygenase.
- Nociception: Bradykinin acts as an activator of vanilloid receptors alongside protons, ATP, and other vanilloids. It sensitizes nociceptors to external stimuli and, in certain conditions like acute inflammation, can directly trigger pain. Tissue accumulation of bradykinin is implicated in labor pain, while local symptoms during viral respiratory infections are driven by inflammatory mediators, particularly bradykinins.
Clinical significance and pharmacology
- Iatrogenic cough and angioedema: ACE inhibitors block the degradation of kinins. The resulting accumulation of bradykinin in tissues is responsible for dry cough and angioedema; ACE inhibitor-induced cough develops in 5–20% of patients.
- Reduced efficacy of local anesthesia: In inflamed tissue, bradykinin and other mediators lower the pain threshold. Hyperemia, increased vascular permeability, and tissue edema accelerate the washout and dilution of local anesthetics, diminishing their duration and efficacy.
- Amniotic fluid embolism: Particulate elements of amniotic fluid, including meconium and epithelial squamous cells, irritate pulmonary vascular interoreceptors. This triggers a massive release of endogenous mediators, including bradykinin.
- Antitussive therapy: Specific combination therapies containing antibodies to bradykinin, morphine, and histamine are sometimes utilized to manage dry, non-productive coughs.