Ion Flux in Pulmonary Vascular Control NATO ASI Series Advanced Science Institutes Series A series presenting the results of activities sponsored by the NATO Science Committee, which aims at the dissemination of advanced scientific and technological knowledge, with a view to strengthening links between scientific communities. The series is published by an international board of publishers in conjunction with the NATO Scientific Affairs Division A Life Sciences Plenum Publishing Corporation B Physics New York and London C Mathematical and Physical Sciences Kluwer Academic Publishers D Behavioral and Social Sciences Dordrecht, Boston, and London E Applied Sciences F Computer and Systems Sciences Springer-Verlag G Ecological Sciences Berlin, Heidelberg, New York, London, H Cell Biology Paris, Tokyo, Hong Kong, and Barcelona I Global Environmental Change Recent Volumes in this Series Volume 246 —New Developments in Lipid-Protein Interactions and Receptor Function edited by K. W. A. Wirtz, L. Packer, J. A. Gustafsson, A. E. Evangelopoulos, and J. P. Changeux Volume 247—Bone Circulation and Vascularization in Normal and Pathological Conditions edited by A. Schoutens, J. Arlet, J. W. M. Gardeniers, and S. P. F. Hughes Volume 248 —Genetic Conservation of Salmonid Fishes edited by Joseph G. Cloud and Gary H. Thorgaard Volume 249 —Progress in Electrodermal Research edited by Jean-Claude Roy, Wolfram Boucsein, Don C. Fowles, and John H. Gruzelier Volume 250 —Use of Biomarkers in Assessing Health and Environmental Impacts of Chemical Pollutants edited by Curtis C. Travis Volume 251 —Ion Flux in Pulmonary Vascular Control edited by E. Kenneth Weir, Joseph R. Hume, and John T. Reeves Volume 252 —Advances in Bacterial Paracrystalline Surface Layers edited by Terry J. Beveridge and Susan F. Koval Series A: Life Sciences Ion Flux in Pulmonary Vascular Control Edited by E. Kenneth Weir Veterans Administration Medical Center Minneapolis, Minnesota Joseph R. Hume University of Nevada Reno, Nevada and John T. Reeves University of Colorado Denver, Colorado Springer Science+Business Media, LLC Proceedings of a NATO Advanced Research Workshop: The Sixth Grover Conference on the Pulmonary Circulation, held October 15-18, 1992, in Sedalia, Colorado NATO-PCO-DATA BASE The electronic index to the NATO ASI Series provides full bibliographical references (with keywords and/or abstracts) to more than 30,000 contributions from international scientists published in all sections of the NATO ASI Series. Access to the NATO-PCO-DATA BASE is possible in two ways: —via online FILE 128 (NATO-PCO-DATA BASE) hosted by ESRIN, Via Galileo Galilei, I-00044 Frascati, Italy —via CD-ROM "NATO Science and Technology Disk" with user-friendly retrieval software in English, French, and German (©WTV GmbH and DATAWARE Technologies, Inc. 1989). The CD-ROM also contains the AGARD Aerospace Database. The CD-ROM can be ordered through any member of the Board of Publishers or through NATO-PCO, Overijse, Belgium. Library of Congress Catalog1ng-1n-Pub1icatIo n Data Ion flu x i n pulmonary vascula r contro l / edite d by E. Kenneth Weir, Joseph R. Hume, and John T. Reeves. p. cm . — (NATO ASI series . Serie s A. Lif e science s v. ; 251) "Proceedings of a NATO advanced researc h workshop, the Sixth Grover Conference on the Pulmonary Circulation , held October 15-18 , 1992, i n Sedalia, Colorado"—T.p . verso . "Published i n cooperation wit h NATO Scientifi c Affair s Division. " Includes bibliographica l reference s an d index . ISBN 978-1-4613-6016-2 1. Pulmonary circulation—Regulation—Congresses . 2 . Pulmonary endothelium—Congresses. 3 . Ion channels—Congresses. 4 . Vascular smooth muscle—Congresses. 5 . Vascular endothelium—Congresses . 6. Pulmonary hypertension—Congresses . I . Weir, E. Kenneth. II. Hume, Joseph Randy, 1947- . III . Reeves. John T. IV . North Atlanti c Treat y Organization . Scientifi c Affair s Division . V. Grover Conference on the Pulmonary Circulatio n (6t h : 1992 : Sedalia. Colo. ) VI . Series. [DNLM: 1. Ion Channels—congresses. 2 . Pulmonary Clrculation - -physiology—congresses . 3 . Endothelium, Vascular—physiology - -congresses. W F 600 164 1992] QP107.156 199 3 612.2—dc20 DNLM/DCL for Librar y of Congress 93-562 8 CIP ISBN 978-1-4613-6016-2 ISBN 978-1-4615-2397-0 (eBook) DOI 10.1007/978-1-4615-2397-0 ©1993 Springer Science+Business Media New York Originally published by Plenum Press.New York in 1993 Softcover reprint of the hardcover 1st edition 1993 All rights reserved No part of this book may be reproduced, stored in retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher PREFACE Ions can pass through a single membrane channel at a rate of 106 ions/second. Over the last decade the ability to measure ion flux so precisely and to document the opening and closing of individual ion channels has provided a powerful tool to those working on smooth muscle physiology and vascular reactivity. The use of potassium channel blockers by Tom Lloyd in the 1960s and calcium channel blockers by Ivan McMurtry in the 1970s indicated the importance of ion flux in regulating pulmonary vascular tone. Recent advances in technology. principally the patch-clamp technique and fluorescent ion-sensitive dyes. now permit a more detailed description of physiologic mechanisms. This volume arises from the Sixth Grover Conference on the Pulmonary Circulation. a NATO Advanced Research Workshop. held in Colorado in October 1992. A group of international sCientists who are leaders in the field of ion flux focused their attention on the problems of the pulmonary vasculature. The chapters in this book describe the present state of knowledge of the movement and storage of ions in vascular endothelial and smooth muscle cells. Those who are not familiar with the techniques of patch clamping and calcium imaging will find an introduction to these methods in the chapters by Leblanc and Wan and Archer et al. The role of potassium channels in oxygen sensing illustrates the rapid progress which the study of ion currents has made possible. Several chapters describe the concept that hypoxic inhibition of one or more potassium channels may lead to membrane depolarization and signal a fall in oxygen tension. The possibility that oxygen tension alters gating of the potaSSium channels through changes in redox status is discussed by Post et al. The endothelium modulates pulmonary and systemic vascular reactivity and permeability. Five chapters examine the function of ion channels and ion flux in endothelial cells. Measurement of intracellular calCium and patch-clamp techniques have provided new insights into endothelial control mechanisms. such as the action of endothelium dependent vasodilators. These dilators increase cytosolic calcium by inducing both calcium entry through receptor-operated channels and calcium release from intracellular stores. Calcium-dependent potassium channels are then activated. leading to hyperpolarization which generates the electrochemical gradient for further calCium entry. Differences in the handling of ions between cultured and freshly dispersed endothelial cells remain to be resolved. This NATO workshop provided the opportunity for the interchange of an immense amount of information. The book is the distillation of that information. written immediately after the conference. with the advantage v of that intense period of discussion. The organizing committee is grateful to the sponsors of the meeting. especially the Scientific Affairs Division of NATO. the National Heart. Lung and Blood Institute of the National Institutes of Health. Axon Instruments. Inc .. Burroughs Wellcome Company. Marion Merrell Dow Inc .. Merck Sharp & Dohme. Pfizer Laboratories. the Upjohn Company. and the Pulmonary Circulation Foundation. E. Kenneth Weir Joseph R. Hume John T. Reeves vi CONTENTS Introduction Pulmonary Hypertension: From Phenomenology to a Molecular. . . . . . 1 Understanding of Disease Mechanisms N.F. Voelkel The Electrophysiology of Smooth Muscle Cells and Techniques for. . . 15 Studying Ion Channels N. Leblanc and X. Wan CALCIUM CONTROL IN SMOOTH MUSCLE CalCium Channels in Arterial Smooth Muscle Cells. . . . . . . . . . . . . . . 41 J .M. Quayle and M. T. Nelson Interactions of Intracellular Ca2+ Pools in Vascular Smooth Muscle. . 49 C. van Breemen and Q. Chen Na-Ca Exchange in Isolated Coronary Myocytes: A Study Combining. . 57 Voltage clamp and Ca2+ Fluorometry G. Isenberg and V. Ganitkevich Role of CalCium ATPases in Pulmonary Vascular Reactivity. . . . . . . . . 67 I.S. Farrukh and J.R. Michael Fast Na+ Current and Ca2+ Currents in Smooth Muscles. . . . . . . . . . 77 N. Sperelakis, Z. Xiong, Y. Inoue, Y. Ohya, K. Shimamura, D. Bielefeld and J. Lorenz Influence of Physical and Environmental Factors on Ion Channels. . .. 105 in Arterial Muscle D.R. Harder, D. Gebremedhin and R.J. Roman vii POTASSIUM CHANNELS IN VASCULAR SMOOTH MUSCLE Potassium Channels Activated by Calcium Released from the . . . . . . III Sarcoplasmic Reticulum in Vascular Smooth Muscles K. Kitamura. H. Kuriyama and H. Nabata ATP-Sensitive Potassium Channels in the Pulmonary Vasculature. .. 129 L.H. Clapp and A.M. Gurney Electrophysiological Actions of Extracellular ATP Application. . . . . .. 141 C.D. Benham An ATP-Activated Potassium Channel in Smooth Muscle Cells from. . 149 the Pulmonary Artery S. Albarwani and P. Nye The Effect of Prostacyclin Analogs on Vascular K Channels. . . . . . . . 159 G. Siegel. M. Bostanjoglo. K. Riickborn. F. Schnalke. J. Mironneau and G. Stock POTASSIUM CHANNELS AND OXYGEN SENSING Potassium Channel Modulated by Hypoxia and the Redox Status in. . 177 Glomus Cells of the Carotid Body A.R. Benot. M.D. Ganfornina and J. LOpez-Barneo Redox Regulation of Potassium Channels and Hypoxic Pulmonary. .. 189 Vasoconstriction J.M. Post. E.K. Weir. S.L. Archer and J.R. Hume The Sodium Gradient. Potassium Channels. and Regulation of. . . . .. 205 Calcium in Pulmonary and Mesenteric Arterial Smooth Muscle: Effects of Hypoxia X.-J. Yuan. C.G. Salvaterra. M.L. Tod. M. Juhaszova. W.F. Goldman. L.J. Rubin and M.P. Blaustein ION FLUX IN VASCULAR ENDOTHELIAL CELLS The Importance of Calcium in the Regulation of EDRF Synthesis in .. 223 the Pulmonary Vasculature S.L. Archer. V. Hampl, J. Huang and N. Cowan viii The Role of Ion Channels in Vascular Endothelium. . . . . . . . . . . . . . 247 A Liickhoff Calcium Signalling in Vascular Endothelial Cells: Calcium Entry. . . . 259 and Release D.J. Adams. J. Rusko and G. Van Slooten Mechanosensitive Ion Channels in Vascular Endothelial Cells. . . . .. 277 T.R. Elam and J.B. Lansman Membrane Hyperpolarization as a Mechanism for Endothelium- . . . . 287 Dependent Vasodilation J .E. Brayden The Interaction between Flow-Induced Vasoconstriction and. . . . . .. 297 Vasodilation: A Mechanism for Setting the Level of Vascular Tone J.A Bevan THERAPY OF PULMONARY HYPERTENSION Correlation of Acute Prostacyclin Response in Primary. . . . . . . . . . . 317 (Unexplained) Pulmonary Hypertension with Efficacy of Treatment with Calcium Channel Blockers and Survival B.M. Groves. D.B. Badesch. D. Turkevich. R.V. Ditchey. K. Donnellan. K. Wynne. AD. Robertson. W.A Long. N. Voelkel and J.T. Reeves Role of Endothelium-Derived Nitric Oxide in Perinatal Pulmonary. . . 331 Vasoregulation S.H. Abman. D.N. Cornfield and J.P. Kinsella Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345 ix PULMONARY HYPERTENSION: FROM PHENOMENOLOGY TO A MOLECULAR UNDERSTANDING OF DISEASE MECHANISMS Norbert F. Voelkel Pulmonary and Critical Care Division University of Colorado Health Sciences Center 4200 E. 9th Ave. C-272 Denver, Colorado 80262 Science is the art of shaping questions and identifying the underlying assumptions. Nature has' no secrets. The obstacles to furthering knowledge lie in the formulation of new, probing questions. Artful questions often require new technology from unrelated disciplines. * INTRODUCTION The pulmonary circulation is anatomically defined as the vasculature between the right ventricle and the left atrium; under normal conditions this circulation accommodates the entire cardiac output, yet it is a low pressure, - low resistance system. Leaving the right ventricle, the blood enters the central conduit arteries that have Windkessel - function, then enters rapidly branching muscular arteries, and finally the precapillary resistance vessels. Whereas flow and pressure have been studied with great intensity, cell cell interactions in the lung capillaries are only recently gaining attention (1-3). Flow passive opening of reserve capillaries is a major regulatory factor in the control of the lung circulation and there is the general consensus that the lung circulation does not possess a significant myogenic tone (4). The lung vessels are innervated by both sympathetic and parasympathetic fibers, and it is evident that small changes in the pulmonary venous tone can have devastating effects on capillary fluid filtration - leading to edema formation (5). Large amounts of new information regarding the control of lung vessels under normal Tribute to Robert F. Grover .j< Ion Flux in Pulmonary Vascular Control, Edited by E.K. Weir et al., Plenum Press, New York, 1993