Endothelin: A New Cardiovascular Regulatory Peptide AMIR LERMAN, M.D., FREDRIC L. HILDEBRAND, M.D., KENNETH B. MARGULIES, M.D., BRIAN O'MURCHU, M.D., MARK A. PERRELLA, M.D., DENISE M. HEUBLEIN, THOMAS R. SCHWAB, M.D., JOHN C. BURNETT, M.D.  Mayo Clinic Proceedings  Volume 65, Issue 11, Pages 1441-1455 (November 1990) DOI: 10.1016/S0025-6196(12)62168-5 Copyright © 1990 Mayo Foundation for Medical Education and Research Terms and Conditions

Fig. 1 Alignment of amino acid sequences of mammalian “family” of endothelin (ET) peptides ET-1, ET-2, and ET-3 and the structurally similar snake venom sarafotoxin S6b. Residues different from those in ET-1 are highlighted, as are amino (N) and carboxyl (C) terminals. ASP = aspartic acid; CYS = cysteine; GLN = glutamine; GLU = glutamic acid; HIS = histidine; ILE = isoleucine; LEU = leucine; LYS = lysine; MET = methionine; PHE = phenylalanine; SER = serine; THR = threonine; TRP = tryptophan; TYR = tyrosine; VAL = valine. (From Brenner and associates.7 By permission of the American Society for Clinical Investigation, Inc.) Mayo Clinic Proceedings 1990 65, 1441-1455DOI: (10.1016/S0025-6196(12)62168-5) Copyright © 1990 Mayo Foundation for Medical Education and Research Terms and Conditions

Fig. 2 Diagram of possible pathway of endothelin biosynthesis. Preproendothelin undergoes posttranslational modification to yield “big” endothelin, which, in turn, is cleaved to produce endothelin-1. Arg = arginine; C = carboxyl terminal; Lys = lysine; N = amino terminal; Trp = tryptophan; Val = valine. (Modified from Yanagisawa and associates.5 By permission of Macmillan Magazines Ltd.) Mayo Clinic Proceedings 1990 65, 1441-1455DOI: (10.1016/S0025-6196(12)62168-5) Copyright © 1990 Mayo Foundation for Medical Education and Research Terms and Conditions

Fig. 3 Proposed model of endothelium-dependent vascular smooth muscle contraction. Several procontractile factors, including thrombin, epinephrine, calcium ionophore A23187, increased shear stress, endotoxin, and hypoxia, are known to stimulate gene expression and release of endothelin (ET) and possibly other as yet uncharacterized endothelium-dependent contracting factors. Mature ET binds to smooth muscle cell surface receptors and eventually induces the opening of voltage-sensitive plasma membrane calcium channels and activation of phospholipase C (PLC) to liberate inositol triphosphate (IP3) and diacylglycerol (DAG) from plasma membrane inositol phospholipids (IPL). IP3 and DAG, in turn, promote release of Ca2+ from intracellular stores and activation of protein kinase C (PKC), respectively. Calmodulin aids in phosphorylation of myosin light chains, a precondition for smooth muscle cell contraction. (Modified from Brenner and associates.7 By permission of the American Society for Clinical Investigation, Inc.) Mayo Clinic Proceedings 1990 65, 1441-1455DOI: (10.1016/S0025-6196(12)62168-5) Copyright © 1990 Mayo Foundation for Medical Education and Research Terms and Conditions

Fig. 4 Distribution and mean plasma endothelin concentrations in 75 normal humans, as determined by a sensitive radioimmunoassay to endothelin. Mayo Clinic Proceedings 1990 65, 1441-1455DOI: (10.1016/S0025-6196(12)62168-5) Copyright © 1990 Mayo Foundation for Medical Education and Research Terms and Conditions

Fig. 5 Left, Change in membrane potential in canine saphenous veins and mesenteric arteries in response to 10−9 M endothelin. Right, Concentration-dependent effects of endothelin on amplitude of depolarization in canine saphenous veins and mesenteric arteries with endothelium. Data are shown as means ± SEM of 4 to 10 impalements obtained in 4 to 7 different tissues. Asterisks = significant difference between veins and arteries (areas under the curves were compared by one-way analysis of variance; P<0.05). (Modified from Miller and associates.46 By permission of The American Physiological Society.) Mayo Clinic Proceedings 1990 65, 1441-1455DOI: (10.1016/S0025-6196(12)62168-5) Copyright © 1990 Mayo Foundation for Medical Education and Research Terms and Conditions