Synthesis and receptor interactions of active peptides generated by the kallikrein-kinin and renin-angiotensin systems. Bradykinin is generated by the action of plasma kallikrein on high-molecular-weight (HMW) kininogen, whereas kallidin (Lys1-bradykinin) is released by the hydrolysis of low-molecular-weight (LMW) kininogen by tissue kallikrein. Kallidin and bradykinin are the natural ligands of the B2 receptor but can be converted to corresponding agonists of the B1 receptor by removal of the C-terminal Arg by kininase I–type enzymes: the plasma membrane–bound carboxypeptidase M (CPM) or soluble plasma carboxypeptidase N (CPN). Kallidin or [des-Arg10]-kallidin can be converted to the active peptides bradykinin or to [des-Arg9]-bradykinin by aminopeptidase cleavage of the N-terminal Lys residue. In a parallel fashion, the inactive decapeptide angiotensin I is generated by the action of renin on the plasma substrate angiotensinogen. By removal of the C-terminal His–Leu dipeptide, angiotensin-converting enzyme (ACE) generates the active peptide angiotensin II (AngII). These two systems have opposing effects. AngII is a potent vasoconstrictor that also causes aldosterone release and Na+ retention via activation of the AT1 receptor; bradykinin is a vasodilator that stimulates Na+ excretion by activating the B2 receptor. ACE generates active AngII and, at the same time, inactivates bradykinin and kallidin; thus, its effects are prohypertensive, and ACE inhibitors are effective antihypertensive agents. The B2 receptor mediates most of bradykinin's effects under normal circumstances, whereas synthesis of the B1 receptor is induced by inflammatory mediators in inflammatory conditions. Both B1 and B2 receptors couple through Gq to activate PLC and increase intracellular Ca2+; the physiological response depends on receptor distribution on particular cell types and occupancy by agonist peptides. For instance, on endothelial cells, activation of B2 receptors results in Ca2+–calmodulin–dependent activation of eNOS and generation of NO, which causes cyclic GMP accumulation and relaxation in neighboring smooth muscle cells. However, in endothelial cells under inflammatory conditions, B1 receptor stimulation results in prolonged NO production via Gi and MAP kinase-dependent activation of iNOS expression. On smooth muscle cells, activation of kinin receptors coupling through Gq results in an increased [Ca2+]i and contraction. B1 and B2 receptors also can couple through Gi to activate PLA2, causing the release of arachidonic acid and the local generation of prostanoids (PGs) and other metabolites such as endothelium-derived hyperpolarizing factor (EDHF). Kallikrein also plays a role in the intrinsic blood coagulation pathway (see Chapter 30). Source: Histamine, Bradykinin, and Their Antagonists, Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e Citation: Brunton LL, Chabner BA, Knollmann BC. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e; 2011 Available at: https://accesspharmacy.mhmedical.com/DownloadImage.aspx?image=/data/Books/1613/bru12_ch32_f004.png&sec=102160962&BookID=1613&ChapterSecID=102160870&imagename= Accessed: October 03, 2017 Copyright © 2017 McGraw-Hill Education. All rights reserved