KININS -THEIR PHYSIOLOGICAL ROLE
Kinins are endogenous biological peptides that have potent vasodilatory properties. These are formed from Kininogens by the action of enzymes Kallikreins. KALLIKREINS: -These are present in plasma and several other tissues (Kidneys, Pancreas, Intestine, Sweat glands and Salivary glands). -These are in inactivated state as prekallikreins and are converted to active kallikrein by action of Trypsin, Hageman factor and preformed kallikrein. KININOGENS: -These are precursors of Kinins and mark their presence in plasma, lymph and interstitial fluid. -Two types of Kininogens are present in plasma a Low Molecular Weight (LMW Kininogen) form and High Molecular Weight form (HMW kininogen). -LMW Kininogen serves as substrate for tissue kallikreins as it easily crosses the capillary walls. KININS: There are three important Kinins viz. Bradykinin, Lysylbradykinin and Methionyllysylbradykinin. The latter two have bradykinin as the basic structure. Different enzymes synthesize their respective Kinins from a kininogen. -Bradykinin is formed by plasma kallikrein -Lysylbradykinin by tissue kallikreins and -Methionyllysylbradykinin by pepsin and pepsin like enzymes. -Bradykinin is the major form in plasma and the urinary form being Lysylbradykinin. BIOLOGICAL EFFECTS: EFFECTS ON CARDIOVASCULAR SYSTEM: -These peptides produce marked Vasodilation in vascular beds of heart, kidney, intestine, skeletal muscle and liver. This relaxation produced may be attributed to their direct inhibitory action on the arteriolar smooth muscle or caused by release of nitric oxide or vasodilatory prostaglandins (PGE2 and PGI2). -Kinins cause direct venoconstriction. EFFECTS ON ENDOCRINE AND EXOCRINE GLANDS: Since the kallikreins are present in glands they are released into the secretory fluids of these glands. From here they diffuse into blood flow and act as local mediators in regulating blood flow. They modulate the tone of the salivary and pancreatic ducts and help regulate GI motility. Also influence transepithelial transport of water, electrolytes, glucose and amino acids in GIT and Kidney. ROLE IN INFLAMMATION: These are produced soon after tissue injury and are essential in the manifestation and maintenance of prominent signs of inflammation such redness, local heat, swelling and pain. Effects on Sensory nerves Stimulate the nociceptive afferent nerve fibers and there by play an important role in eliciting pain in the skin and viscera. KININ RECEPTORS: B1 and B2 are the two receptors through which these peptides mediate their biological action. They are distributed on the membranes of the target tissues. These receptors are classified based on the potencies of the agonists. Bradykinin has more affinity towards B2 receptors followed by lys-bradykinin and then by met-lys-bradykinin. B1 Receptors- These receptors have very limited distribution in mammalian tissues and have few known functional roles. Knockout mice that lack these receptors suggest that these receptors are primarily implicated in the inflammatory response and in long term effects such as collagen synthesis and cell multiplication. The main transduction mechanism is through G-protein coupled receptors. By activation of Gi/Go family it results in Adenylate cyclase inhibition and by activation of Gq/G11 family Phospholipase C stimulation. B2 Receptors- These are also G-protein coupled receptors and have multiple transduction events. By activation of, Gs family of proteins it leads to Adenylate cyclase inhibition or the Gi/Go family leads to Phospholipase C stimulation or Gq/G11 family results in Phospholipase A2 stimulation. These are involved in calcium mobilization, chloride transport, formation of nitric oxide. METABOLISM OF KININS: These are metabolized rapidly by nonspecific exo/endo-peptidases commonly called as 'Kininases' and as a consequence have short half lives of about 15seconds. Two kininases are well characterized viz. Kininase I synthesized in Liver which is a carboxypeptidase and Kininase II present in plasma and vascular endothelial cells through out the body. Reference:: Basic and Clinical Pharmacology, 11th Edition, Tata Mc Graw Hill publications, By Bertram G. Katzung, Pg:298-301.