Anesthesia Pharmacology:  Vasoactive Peptides

Kinins

• Overview:

  • Kinins: potent vasodilator peptides

  • Kinins formed from kininogens, catalyzed by kallikreins (or kininogenases)

  • Kallikreins-kinin: similar to renin angiotensin system in certain respects

• Kallikreins

  • Localization: kallikreins

    • Plasma

    • Tissues: kidneys, pancreas, intestine, salivary glands, sweat glands

    • Serine proteases (catalytically similar to trypsin, chymotrypsin, thrombin, elastase, plasmin)

  • Kallikrein precursor

    • Prekallikrein produced by the liver

    • Kallikreins in some glands exist as Prekallikreins

    • Prekallikrein is conveted to kallikrein

      • Conversion catalyzed by: trypsin, Hageman factor, kallikrein itself (possibly)

• Kininogens

  • Kininogens are precursors of kinins; kallikreins substrate

  • Localization of kininogens

    • Plasma

      1. Two forms:

         1. Low molecular weight (LMW)kininogen

         2. High molecular weight (HMW) kininogen

      2. HMW form (15-20% of total plasma kininogen) remains in the blood: substrate for plasma kallikrein

      3. LMW form: crosses capillary walls -- substrate for tissue kallikreins

    • Lymph

    • Interstitial fluid

     

• Tissue and plasma Kinin formation

  • Three kinins

    • Bradykinin

    • Lysylbradykinin

    • Methionyllysylbradykinin

  • Bradykinin released by plasma kallikreinin

  • Lysylbradykinin released by glandular kallikrein

  • Methionyllysylbradykinin released by pepsins and pepsin-like enzymes

  • Preferred substrate for plasma kallikrein

    • HMW kininogen

  • Preferred substrate for tissue kallikrein

    • LMW kininogen

  • Bradykinin: major plasma kinin

  • Lysylbradykinin: major urinary kinin

  • Methionyllysylbradykinin: found in acid urine (acid activates uropepsinogen, catalyzing release of methionyllysylbradykinin from urinary kininogens

• Kinins: Physiological Effects

  • Cardiovascular

    • Vasodilation: vascular beds:

      • Heart

      • Kidney

      • Intestine

      • Skeletal muscle

      • Lver

    • Mechanism of Action (possible): vasodilation

      1. Drect effect of kinins on arteriolar, vascular smooth muscle

      2. Mediated by nitric oxide (EDRF)

      3. Mediated by vasodilator prostaglandins (PGE₂ and PGI₂)

    • Vasoconstriction: vascular beds

      • Venous smooth muscle

      • Mechanism of Action: vasoconstriction

        1. Direct venous smooth muscle stimulation

        2. Release of venoconstrictor prostaglandins (PGF_2-a )

      • Visceral smooth muscle

    • Blood Pressure Effects

      • Hypotensive response (brief)

      • Reflex tachycardia, positive inotropism: increased cardiac output compensates

      • Arteriolar dilation:  Mechanism of Action --

        1. Increase in capillary bed pressure and flow

        2. Promotes fluid transfer from blood to tissue (increased capillary permeability may occur because of endothelial cell contraction which widens intercellular junctions)

           1. Increased venous pressure (following venous constriction) also promotes fluid transfer to tissue.

           2. Edema may result

  • Endocrine and Exocrine Gland Effects

    • Prekallikreins and kallikreins present in:

      1. Kidney

      2. Pancreas

      3. Intestine

      4. Salivary glands

      5. Sweat glands

    • Enzymes or kinins may diffuse from organs to blood, acting as local regulators of blood flow

    • Kinins may (because of smooth muscle effects) influence salivary and pancreatic ducts tone; and may influence gastrointestinal motility

    • Kinins affect transepithelial transport of:

      1. Water

      2. Electrolytes

      3. Amino acids

      4. Glucose

    • Kallikreins may be involved in physiological activation of prohormones, i.e. proinsulin and prorenin

  • Kinins and Inflammation

    • Kallikreins and kinins: produce inflammatory symptoms

  • Kinins and Sensory Nerves

    • Potent pain-producing (intradermal application)

    • Mechanism of Action: stimulation of nociceptive afferents.

Reid, I.A., Vasoactive Peptides, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 287-303.