Bradykinin

Bradykinin

• Bradykinin is a peptide that acts as an autacoid, influencing various bodily functions.
• Bradykinin’s activity is primarily stimulated by potent mediators: prostaglandins, nitric oxide (NO), and endothelium-derived hyperpolarizing factors (EDHF).

Bradykinin: Biosynthesis

• Kallikreins are serine proteases found in plasma and tissues.
• They convert kininogen into kinin.
• There are two forms of kininogen: high-molecular weight kininogen (found in plasma) and low-molecular weight kininogen (found in tissues).
• The two major types of kinins in humans are bradykinin and Lys-bradykinin (Kallidin).
• Kinins are rapidly degraded by kininases and angiotensin-converting enzyme (ACE).

Bradykinin Receptors

• Bradykinin receptors are G protein-coupled receptors (GPCRs).
• The B2 receptor is found in most normal tissues.
• It binds to bradykinin and kallidin, mediating most of bradykinin's effects.
• The B1 receptor is triggered by inflammatory mediators and is active in inflammatory conditions.

Bradykinin Effects

• Cardiovascular:
  • Bradykinin causes vasodilation by activating its B2 receptor on endothelial cells, triggering the release of NO and vasodilator prostaglandins such as PGE2 and PGI2.
  • Bradykinin has cardioprotective effects, including anti-proliferative effects.
  • It protects the heart against ischemia and reperfusion injury.
  • It helps prevent myocardial infarction and stroke through stimulation of tissue plasminogen activator (tPA) release.
• Pain:
  • Bradykinin stimulates sensory neurons and provokes the release of neuropeptides such as substance P, neurokinin A, and calcitonin gene-related peptide.
• Inflammation:
  • Bradykinin causes vasodilation and increased permeability in the microcirculation.
  • It increases hydrostatic pressure gradient, leading to edema.
  • It stimulates nerve endings.
  • These effects result in a "wheal and flare" response to intradermal injection of bradykinin: redness, local heat, swelling, and pain.
• Kidney:
  • Bradykinin increases renal blood flow due to vasodilation.
  • It causes natriuresis by inhibiting sodium reabsorption.
• Non-vascular Smooth Muscle:
  • Bradykinin causes contraction of intestinal, urinary, and bronchial smooth muscle.
  • It may be implicated in allergic airway disorders such as asthma and rhinitis. Bradykinin causes bronchospasm in asthmatic patients but not in normal individuals.
• Hereditary Angioedema:
  • This rare genetic disorder results in increased activation of kallikrein and bradykinin formation.
  • Increased vascular permeability and other actions lead to recurring episodes of angioedema in the airways, gastrointestinal tract, extremities, and genitalia.

Drugs that Target Bradykinin

• ACE Inhibitors (ACEIs):
  • ACEIs block the conversion of angiotensin I (ANGI) to angiotensin II (ANGII) and inhibit bradykinin degradation.
  • Increased bradykinin may contribute to beneficial protective effects, but it can also cause adverse effects.
  • Common side effect: Chronic, non-productive cough.
  • Rare side effect: Angioedema.
• Kinin Receptor Antagonists:
  • Icatibant:
    • A selective B2 receptor antagonist approved for hereditary angioedema-related swelling.
  • Fasitibant:
    • Under investigation for intra-articular injection for knee osteoarthritis to alleviate inflammation and pain through bradykinin pathway modulation.

Natriuretic peptides

• The text provides information on bradykinin and its effects and does not cover natriuretic peptides.