Bradykinin Notes PDF

Bradykinin 10/21/2024 Bradykinin Peptides act as autacoid that act locally to produce pain, vasodilation, and increased vascular permeability. But can also have beneficial effects (e.g: heart, kidney, circulation) Most of their activity is due to stimulation of potent mediators such as p...

Bradykinin 10/21/2024 Bradykinin Peptides act as autacoid that act locally to produce pain, vasodilation, and increased vascular permeability. But can also have beneficial effects (e.g: heart, kidney, circulation) Most of their activity is due to stimulation of potent mediators such as prostaglandins, NO, or endothelium-derived hyperpolarizing factors (EDHF) 10/21/2024  Bradykinins: biosynthesis Kallikreins Type: Serine proteases Location: Plasma and tissues (kidney, pancreas, intestine, sweat, and salivary glands) Function: Convert kininogen into kinin Kininogens Substrates for kallikrein with two forms: High-molecular weight kininogen Found in plasma Substrate for plasma kallikrein Low-molecular weight kininogen Found in tissues Substrate for tissue kallikrein Kinins Two major types in humans: Bradykinin Lys-bradykinin (Kallidin) Metabolism: Rapidly degraded by kininases, also by ACE 10/21/2024 Bradykinin receptors: B1 and B2 are types of GPCRs B2 Receptor Expression: Found in most normal tissues Ligands: Binds to bradykinin and kallidin Function: Mediates most effects of bradykinin B1 Receptor Induction: Triggered by inflammatory mediators Role: Active in inflammatory conditions 10/21/2024 Bradykinins effects Cardiovascular: Vasodilation by activating its B2 receptor on endothelial cells → generation of NO, vasodilator prostaglandins eg: PGE2 and PGI. Cardioprotective effect: Anti-proliferative effect of Protect the heart against ischemia, reperfusion injury Protect against myocardial infarction and stroke (via stimulation of tissue plasminogen activator (tPA) release Pain: Stimulates the sensory neurons and provoke the release of neuropeptides, such as: substance P, neurokinin A, and calcitonin gene-related peptide Inflammation: Vasodilation Increase permeability in the microcirculation Increase hydrostatic pressure gradient Edema Stimulation of nerve ending All the above will lead to a “wheal and flare” response to intradermal injection of BK: redness, local heat, swelling and pain 10/21/2024 Bradykinins effects Kidney: Kinins increase renal blood flow (due to vasodilation) Causes natriuresis by inhibiting sodium reabsorption Non-vascular smooth muscle Contraction in the intestinal, urinal, and bronchial smooth muscle Could be implicated in allergic airway disorders such as asthma and rhinitis: kinin causes bronchospasm in asthmatic patients but not in normal individuals 10/21/2024 Bradykinins effects Hereditary angioedema: A rare genetic disorder that result in the activation of kallikrein and increased formation of bradykinin: Increasing vascular permeability and other actions causes recurrent episodes of angioedema of the airways, GI, extremities, and genitalia Can be treated with drugs that inhibit the formation or action of bradykinin 10/21/2024 Drugs that target BK ACE Inhibitors (ACEIs) Function: Block conversion of ANGI to ANGII and inhibit bradykinin degradation Increased bradykinin contributes to: beneficial protective effects Adverse Effects: Common: Chronic, non-productive cough Rare: Angioedema Kinin Receptor Antagonists Icatibant Type: Selective B2 receptor antagonist Use: Approved for hereditary angioedema-related swelling Fasitibant Status: Under investigation Focus: Intra-articular injection for knee osteoarthritis-alleviate inflammation and pain through bradykinin pathway modulation. 10/21/2024 10/21/2024 Natriuretic peptides 10/21/2024