Kluwer Academic Publishers

Hypertension Exercise Program

High Blood Pressure Causes and Treatments

Get Instant Access

NEW YORK, BOSTON, DORDRECHT, LONDON, MOSCOW

eBook ISBN: 1-4020-7858-7 Print ISBN: 1-4020-7857-9

©2004 Kluwer Academic Publishers

New York, Boston, Dordrecht, London, Moscow

Print ©2004 Kluwer Academic Publishers Boston

All rights reserved

No part of this eBook may be reproduced or transmitted in any form or by any means, electronic, mechanical, recording, or otherwise, without written consent from the Publisher

Created in the United States of America

Visit Kluwer Online at: and Kluwer's eBookstore at:

http://kluweronline.com http://ebooks.kluweronline.com

TABLE OF CONTENTS

List of Contributors ix

I. PHYSIOLOGY AND PATHOPHYSIOLOGY OF HYPOXIC PULMONARY

VASOCONSTRICTION

1. Physiological Function of Hypoxic Pulmonary Vasoconstriction

Charles A. Hales 3

2. Hypoxic Pulmonary Vasoconstriction: Heterogeneity

3. The Physics of Hypoxic Pulmonary Hypertension and Its Connection with Gene Actions

Yuan-Cheng Fung and Wei Huang 35

II. ROLE OF INTRACELLULAR Ca2+ AND Ca2+ SENSITIVITY IN HYPOXIC PULMONARY VASOCONSTRICTION

4. Ca2+ Sparks in Pulmonary Artery Smooth Muscle Cells: Implications for Hypoxic Pulmonary Vasoconstriction

Wei-Min Zhang, Carmelle V. Remillard, and James S.K. Sham 53

5. Hypoxia-mediated Regulation on Transients in Pulmonary Artery Smooth Muscle Cells

Jean-Pierre Savineau, Sébastien Bonnet,

6. Calcium Mobilization by Hypoxia in Pulmonary Artery Smooth Muscle

A. Mark Evans and Michelle Dipp 81

7. Critical Role of Ca2+ Sensitization in Acute Hypoxic Pulmonary Vasoconstriction

Tom P. Robertson and Ivan F. McMurtry 103

III. ROLE OF ION CHANNELS IN HYPOXIC PULMONARY VASOCONSTRICTION

8. Regulation of Ion Channels in Pulmonary Artery Smooth Muscle Cells

9. Regulation of 02-sensitive K+ Channels by a Mitochondrial Redox Sensor: Implications for Hypoxic Pulmonary Vasoconstriction

Rohit Moudgil, Evangelos D. Michelakis, and Stephen L. Archer 135

10. Hypoxic Regulation of K+ Channel Expression and Function in Pulmonary Artery Smooth Muscle Cells Hemal Patel, Carmelle V. Remillard, and Jason X.-J. Yuan 165

11. Transient Receptor Potential Channels and Capacitative Ca2+ Entry in Hypoxic Pulmonary Vasoconstriction

Alison M. Gurney and Lih-Chyuan Ng 199

IV. ROLE OF ENDOTHELIUM IN HYPOXIC PULMONARY VASOCONSTRICTION

12. Endothelium-dependent Hypoxic Pulmonary Vasoconstriction

Jeremy P.T. Ward and Philip I. Aaronson 217

V. MECHANISMS OF OXYGEN SENSING IN THE PULMONARY

VASCULATURE

13. Chemistry of Oxygen and Its Derivatives in the Lung

14. Interaction of Oxidants with Pulmonary Vascular Signaling Systems

Sachin A. Gupte and Michael S. Wolin 247

15. Mitochondrial Oxygen Sensing in Hypoxic Pulmonary Vasoconstriction

Navdeep S. Chandel 263

16. Redox Oxygen Sensing in Hypoxic Pulmonary Vasoconstriction

Andrea Olschewski and E. Kenneth Weir 277

17. Mitochondrial Diversity in the Vasculature: Implications for Vascular Oxygen Sensing

Sean McMurtry and Evangelos D. Michelakis 293

18. Hypoxia, Cell Metabolism, and cADPR Accumulation

VI. OXYGEN-SENSING MECHANISMS IN OTHER ORGANS AND TISSUES

19. Involvement of Intracellular Reactive Oxygen Species In the Control of Gene Expression by Oxygen

Agnes Görlach, Helmut Acker, and Thomas Kietzmann 341

20. Oxygen Sensing, Oxygen-sensitive Ion Channels and Mitochondrial Function in Arterial Chemoreceptors

José López-Barneo, Patricia Ortega-Sáenz,

Maria García-Fernández, and Ricardo Pardal 361

21. Oxygen Sensing by Adrenomedullary Chromaffin Cells

Roger J. Thompson and Colin A. Nurse 375

22. Oxygen-sensitive Ion Channels in Pheochromocytoma (PC12) Cells

Laura Conforti and David E. Millhorn 389

VII. PATHOLOGY AND MECHANISMS OF HYPOXIA-INDUCED PULMONARY HYPERTENSION

23. Pulmonary Vascular Remodeling in Hypoxic Pulmonary Hypertension

Marlene Rabinovitch 403

24. Rho/Rho-kinase Signaling in Hypoxic Pulmonary Hypertension

Ivan F. McMurtry, Natalie R. Bauer, Sarah A. Gebb, Karen A. Fagan, Tetsutaro Nagaoka, Masahiko Oka, and Tom P. Robertson 419

25. Hypoxia-sensitive Transcription Factors and Growth Factors

25. Hypoxia-sensitive Transcription Factors and Growth Factors

Ari L. Zaiman and Rubin M. Tuder 437

26. Heterogeneity in Hypoxia-induced Pulmonary Artery Smooth Muscle Cell Proliferation

Maria G. Frid, Neil J. Davie, and Kurt R. Stenmark 449

27. Persistent Pulmonary Hypertension of the Newborn: Pathophysiology and Treatment

Steven H. Abman and Robin H. Steinhorn 471

28. Roles for Vasoconstriction and Gene Expression in Hypoxia-induced Pulmonary Vascular Remodeling

Bernadette Raffestin, Serge Adnot, and Saadia Eddahibi 497

29. Polyamine Regulation in Hypoxic Pulmonary Arterial Cells

Mark N. Gillespie, Kathryn A. Ziel, Mykhaylo Ruchko,

Pavel Babal, and Jack W. Olson 511

30. Strain Differences of Hypoxia-Induced Pulmonary Hypertension

Mallik R. Karamsetty, James C. Leiter, Lo Chang Ou,

Ioana R. Preston, and Nicholas S. Hill 523

VIII. EXPERIMENTAL MODELS FOR THE STUDY OF HYPOXIC PULMONARY VASOCONSTRICTION

31. Animal and In Vitro Models for Studying Hypoxic Pulmonary Vasoconstriction

Jane A. Madden and John B. Gordon 545

32. Transgenic and Gene-Targeted Mouse Models in Hypoxic Pulmonary Hypertension Research

Yadong Huang 559

33. Measurement of Ionic Currents and Intracellular Using Patch Clamp and Fluorescence Microscopy Techniques

Carmelle V. Remillard and Jason X.-J. Yuan 569

List of Contributors

Philip I. Aaronson, Ph.D., Reader, Department of Asthma, Allergy and Respiratory Science, King's College London, London, U.K. (Chapter 12)

Steven H. Abman, M.D., Professor, The Children's Hospital, Pediatric Heart-Lung Center, University of Colorado, Denver, Colorado (Chapter 27)

Helmut Acker, M.D., Professor, Facharzt für Physiologie, Max-Planck-Institut für Molekulare Physiologie, Dortmund, Germany (Chapter 19)

Serge Adnot, Ph.D., Professor, INSERM U492, Département de Physiologie, Hôpital Henri Mondor, Créteil, France (Chapter 28)

Stephen L. Archer, M.D., Professor and Director, Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada (Chapter 9)

Pavel Babal, M.D., Associate Professor, Department of Pathology, Comenius University, Bratislava, Slovak Republic (Chapter 29)

Natalie R. Bauer, Ph.D., Fellow, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado (Chapter 24)

Sébastien Bonnet, Ph.D., Laboratoire de Physiologie Cellulaire Respiratoire, Université Victor Ségalen Bordeaux2, Bordeaux, France (Chapter 5)

Navdeep S. Chandel, Ph.D., Assistant Professor, Department of Medicine, Northwestern University, Chicago, Illinois (Chapter 15)

Laura Conforti, Ph.D., Assistant Professor, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio (Chapter 22)

Neil J. Davie, Ph.D., Fellow, Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado (Chapter 26)

Christopher A. Dawson, Ph.D., Professor, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin (Chapter 2)

Michelle Dipp, Ph.D., Student, Worcester College, University of Oxford, Oxford, U.K. (Chapter 6)

Saadia Eddahibi, Ph.D., INSERM U492, Faculté de Médecine de Créteil,

Créteil, France (Chapter 28)

A. Mark Evans, Ph.D., Lecturer, School of Biology, University of St. Andrews, Fife, U.K. (Chapters 6 and 18)

Karen A. Fagan, M.D., Assistant Professor, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado (Chapter 24)

Maria G. Frid, Ph.D., Instructor, Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado (Chapter 26)

Yuan-Cheng Fung, Ph.D., Professor Emeritus, Department of Bioengineering, University of California, San Diego, La Jolla, California (Chapter 3)

Maria García-Fernández, B.Sc., Student, Laboratorio de Investigaciones Biomédicas Edificio de Laboratorios, Hospital Universitario Virgen del Rocio, Sevilla, Spain (Chapter 20)

Sarah A. Gebb, Ph.D., Instructor, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado (Chapter 24)

Mark N. Gillespie, Ph.D., Professor and Chairman, Department of Pharmacology and Center for Lung Biology, University of South Alabama, Mobile, Alabama (Chapter 29)

John B. Gordon, M.D., Associate Professor, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin (Chapter 31)

Agnes Görlach, M.D., Department Leader, Abt. Experimentelle Kinderkardiologie, Deutsches Herzzentrum Muenchen, Muenchen, Germany (Chapter 19)

Sachin A. Gupte, M.D., Ph.D., Fellow, Department of Physiology, New York Medical College, Valhalla, New York (Chapter 14)

Alison M. Gurney, Ph.D., Professor, Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, U.K. (Chapter 11)

Charles A. Hales, M.D., Professor and Chief, Pulmonary and Critical Care Medicine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (Chapter 1)

Nicholas S. Hill, M.D., Professor, Tufts University School of Medicine-New

England Medical Center, Boston, Massachusetts (Chapter 30)

Wei Huang, Ph.D., Associate Project Scientist, Department of Bioengineering, University of California, San Diego, La Jolla, California (Chapter 3)

Yadong Huang, M.D., Ph.D., Assistant Professor, Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California

(Chapter 32)

Mallik R. Karamsetty, Ph.D., Assistant Professor, Department of Medicine, Brown University, Providence, Rhode Island (Chapter 30)

Thomas Kietzmann, M.D., Assistant Professor, Institut fuer Biochemie und Molekulare, Goettingen, Germany (Chapter 19)

James C. Leiter, M.D., Professor, Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire (Chapter 30)

José Lopez-Barneo, M.D., Ph.D., Professor, Laboratorio de Investigaciones Biomédicas Edificio de Laboratorios, Hospital Universitario Virgen del Rocio, Sevilla, Spain (Chapter 20)

Jane A. Madden, Ph.D., Professor, Department of Neurology, Medical College of Wisconsin, Milwaukee, Wisconsin (Chapter 31)

Roger Marthan, M.D., Ph.D., Professor, Laboratoire de Physiologie Cellulaire Respiratoire, INSERM 256, Université Victor Ségalen Bordeaux2, Bordeaux, France (Chapter 5)

Sean McMurtry, M.D., Fellow, Department of Medicine (Cardiology), University of Alberta, Edmonton, Alberta, Canada (Chapter 17)

Ivan F. McMurtry, Ph.D., Professor, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado (Chapters 7 and 24)

Evangelos D. Michelakis, M.D., Associate Professor, Department ofMedicine, University of Alberta, Edmonton, Alberta, Canada (Chapters 9 and 17)

David E. Millhorn, Ph.D., Professor and Director, Genome Research Institute and Department of Genome Science, University of Cincinnati College of Medicine, Cincinnati, Ohio (Chapter 22)

Rohit Moudgil, M.Sc., Student, Division of Cardiology, University of Alberta

Hospital, Edmonton, Alberta, Canada (Chapter 9)

Tetsutaro Nagaoka, M.D., Fellow, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado (Chapter 24)

Lih-Chyuan Ng, Ph.D., Fellow, Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada (Chapter 11)

Colin A. Nurse, Ph.D., Professor, Department of Biology, McMaster University, Hamilton, Ontario, Canada (Chapter 21)

Masahiko Oka, M.D., Assistant Professor, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado (Chapter 24)

Andrea Olschewski, M.D., Staff Anesthesiologist, Department of Anesthesiology, Justus-Liebig-University Giessen, Giessen, Germany (Chapter 16)

Jack W. Olson, Ph.D., Professor, Department of Pharmacology and Center for Lung Biology, University of South Alabama, Mobile, Alabama (Chapter 29)

Patricia Ortega-Sáenz, Ph.D., Fellow, Laboratorio de Investigaciones Biomédicas Edificio de Laboratorios, Hospital Universitario Virgen del Rocio, Sevilla, Spain (Chapter 20)

Lo Chang Ou, Ph.D., Professor, Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire (Chapter 30)

Lisa A. Palmer, Ph.D., Associate Professor, Department of Pediatrics, University of Virginia Health System, Charlottesville, Virginia (Chapter 13)

Ricardo Pardal, Ph.D., Fellow, Laboratorio de Investigaciones Biomédicas Edificio de Laboratorios, Hospital Universitario Virgen del Rocio, Sevilla, Spain (Chapter 20)

Hemal Patel, Ph.D., Fellow, Department of Pharmacology, University of California, San Diego, La Jolla, California (Chapter 10)

Ioana R. Preston, M.D., Assistant Professor, Tufts University School of Medicine-New England Medical Center, Boston, Massachusetts (Chapter 30)

Marlene Rabinovitch, M.D., Professor, The Wall Center for Pulmonary Vascular Diseases, Stanford University School of Medicine, Stanford, California

(Chapter 23)

Bernadette Raffestin, M.D., Ph.D., INSERM U492, Département de Physiologie, Hôpital Ambroise Paré, Boulogne, France (Chapter 28)

Carmelle V. Remillard, Ph.D., Fellow, Department of Medicine, University of California, San Diego, California (Chapters 4, 10 and 33)

Thomas P. Robertson, Ph.D., Assistant Professor, Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia (Chapters 7 and 24)

Mykhaylo Ruchko, Ph.D., Instructor, Department of Pharmacology, University of South Alabama, Mobile, Alabama (Chapter 29)

Jean-Pierre Savineau, Ph.D., Professor, Laboratoire de Physiologie Cellulaire Respiratoire, INSERM 356, Université Victor Ségalen Bordeaux2, Bordeaux, France (Chapter 5)

James S.K. Sham, Ph.D., Associate Professor, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland (Chapter 4)

Sergey V. Smirnov, Ph.D., Lecturer, Department of Pharmacy and Pharmacology, University of Bath, U.K. (Chapter 8)

Robin H. Steinhorn, M.D., Professor, Department of Pediatrics, Northwestern University, Chicago, Illinois (Chapter 27)

Kurt R. Stenmark, M.D., Professor, Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado (Chapter 26)

Roger J. Thompson, Ph.D., Fellow, Department of Cellular and Structural Biology, University of Colorado Health Sciences Center, Denver, Colorado (Chapter 21)

Rubin M. Tuder, M.D., Associate Professor, Departments of Pathology and Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

(Chapter 25)

Jeremy P.T. Ward, Ph.D., Professor, Department of Asthma, Allergy and Respiratory Science, King's College London, London, U.K. (Chapter 12)

E. Kenneth Weir, M.D., Professor, Department of Medicine, University of Minnesota, Minneapolis, Minnesota (Chapter 16)

Michael S. Wolin, Ph.D., Professor, Department of Physiology, New York Medical College, Valhalla, New York (Chapter 14)

Jason X.-J. Yuan, M.D., Ph.D., Professor, Department of Medicine, University of California, San Diego, California (Chapters 10 and 33)

Ari L. Zaiman, M.D., Ph.D., Fellow, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland (Chapter 25)

Wei-Min Zhang, M.D., Ph.D., Fellow, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

(Chapter 4)

Kathryn A. Ziel, Ph.D., Instructor, Department of Pharmacology and Center for Lung Biology, University of South Alabama, Mobile, Alabama (Chapter 29)

Preface

Hypoxic pulmonary vasoconstriction (HPV) serves a regulatory function by matching perfusion to ventilation and shunting blood flow away from the poorly oxygenated regions of the lung. HPV is a critical physiological mechanism of the lung to ensure maximal oxygenation of the venous blood in the pulmonary artery. Persistent alveolar hypoxia, however, causes pulmonary hypertension which is characterized by sustained pulmonary vasoconstriction and pulmonary vascular remodeling. The hypoxia-mediated pulmonary hypertension causes right heart failure in patients with a variety of cardio-pulmonary diseases, including chronic obstructive pulmonary disease, congenital heart disease, and mountain sickness. Over the last decade, considerable progress has been made in understanding the cellular and molecular mechanisms involved in HPV and hypoxia-induced pulmonary vascular remodeling. These significant findings provide an essential basis to specify the precise sequences of events of HPV, to identify the etiology ofhypoxia-mediated pulmonary hypertension, and to develop new therapeutic approaches for patients with pulmonary hypertension.

The major objective of this book is to provide a timely and long lasting guide for investigators in the fields of cardiovascular physiology and pathophysiology, pulmonary vascular disease, and high-altitude physiology and medicine. This will establish a solid scientific foundation for subsequent applications in clinical practice. The book is divided into eight sections: I. Physiology and pathophysiology of HPV; II. Role of intracellular Ca2+ and Ca2+ sensitivity in HPV; III. Role of ion channels in HPV; IV. Role of the endothelium in HPV; V. Mechanisms of oxygen sensing in the pulmonary vasculature; VI. Oxygen-sensing mechanisms in other organs and tissues; VII. Pathology and mechanisms of hypoxia-induced pulmonary hypertension; and VIII. Experimental models for the study of HPV.

Subsections in each of the main sections address critical aspects related to hypoxia-induced pulmonary vasoconstriction and pulmonary hypertension. Section I highlights the physiological function (Chapter 1) and heterogeneity (Chapter 2) of HPV, as well as the physical principles of pulmonary circulation, gas exchange, and HPV and their correlation with gene actions (Chapter 3). Intracellular Ca2+ is not only a major trigger for smooth muscle contraction, but also an important signal transduction element that mediates gene expression, protein synthesis, cell migration, and cell proliferation. Section II discusses how intracellular Ca2+ signals are regulated by hypoxia to induce HPV and pulmonary vascular smooth muscle cell proliferation. Four chapters are devoted to aspects of recent findings on the roles of Ca2+sparks (Chapter 4), agonist-mediated Ca2+ transients (Chapter 5), Ca2+ mobilization from the sarcoplasmic reticulum (Chapter 6), and Ca2+ sensitization (Chapter 7) in the development of HPV. How acute hypoxia regulates cytoplasmic, nuclear, and intracellularly-stored Ca2+

concentration in pulmonary artery smooth muscle cells is also discussed in this section. Section III is designed to explore the role of ion channels in HPV. Chapter 8 discusses the functionally expressed ion channels along with their regulation in the pulmonary vasculature. Two chapters focus on the regulation of K+ channel activity by a mitochondrial redox sensor (Chapter 9) and by acute exposure to hypoxia (Chapter 10). The functional role ofK+ channels (especially voltage-gated K+ channels) in regulating membrane potential and cytoplasmic Ca2+ concentration (via altering activity of voltage-gated Ca2+ channels) in pulmonary artery smooth muscle cells, the transcriptional regulation of K+ channel genes by chronic hypoxia, and the role of dysfunctional K+ channels in the development ofhypoxia-induced pulmonary hypertension are also discussed extensively in Chapters 9 and 10. Furthermore, the contribution of transient receptor potential channels and capacitative Ca2+ entry to the development of HPV is reviewed in Chapter 11. Section IV includes an elegant discussion on the role of endothelium in HPV.

Section V is designed to describe the putative and potential mechanisms of oxygen sensing in the pulmonary vasculature. It is focused on oxygen radicals (Chapters 13 and 14), mitochondrial oxidative phosphorylation chain (Chapters 15 and 17), cellular redox status (Chapter 16), and cADPR accumulation (Chapter 18). In addition to the pulmonary vasculature, there are many tissues and cells whose function is regulated by oxygen. Section VI is focused on the cellular mechanisms involved in oxygen-sensitive gene expression (Chapter 19), as well as the oxygen sensing mechanisms and oxygen-sensitive ion channels in arterial chemoreceptor (Chapter 20), chromaffin cells (Chapter 21), and pheochromocytoma cells (Chapter 22). Section VII discusses current knowledge on the etiology and pathological characterization ofhypoxia-induced pulmonary hypertension and right heart failure. It is focused on the hypoxia-sensitive agonists, mitogens, and transcription factors found in animal and human lung tissues (Chapters 25, 28, and 29); the role of the heterogeneity in hypoxia-induced pulmonary vascular smooth muscle cells proliferation (Chapter 26); the potential mechanisms involved in pulmonary vascular remodeling and hypoxic pulmonary hypertension (Chapters 23, 24, and 28); the pathophysiology and treatment of persistent pulmonary hypertension in the newborn (Chapter 27); and the strain difference of hypoxia-induced pulmonary hypertension (Chapter 30). Section VIII includes three chapters on how to use animal and in vivo models (Chapter 31) and transgenic animal models (Chapter 32) for studying HPV and hypoxia-mediated pulmonary hypertension. A chapter on patch clamp and fluorescence microscopy techniques (Chapter 33) for measuring ion channel currents and intracellular is included.

In summary, this book not only covers the current state-of-the-art findings relevant to cellular and molecular processes of hypoxic pulmonary vasoconstriction but also provides the underlying conceptual basis and knowledge regarding etiological mechanisms and experimental therapeutics for hypoxia-mediated pulmonary hypertension. I hope this book will be something of use not only to those who are experienced basic science investigators in the research fields ofhypoxic cardiopulmonary physiology and pathophysiology and pulmonary vascular diseases, but also to a large community of clinicians or physician scientists whose primary subspecialty is in pulmonary and critical care medicine, cardiology, cardiothoracic surgery, environmental medicine, and sports medicine.

Acknowledgment:

The book is dedicated to Dr. Ayako Makino for continuously supporting me in pursuing an academic career and for her selfless love during the editing of the book, to my parents and grandparents who taught me how to overcome hurdles and difficulties, and to my mentors who guided me into the research field and taught me what HPV was. I would like to take this opportunity to thank all contributors for the excellent chapters and Ms. M. Ramondetta for her instruction in preparing and editing the text. I am indebted to Dr. C.V. Remillard for her diligence in preparing and editing the figures, to Dr. I.F. McMurtry for his suggestions in compiling this book, and to my colleagues and students at the University of California, San Diego for their dedication to sharing their knowledge with others. Finally, I would like to thank Drs. M.P. Blaustein and L.J. Rubin for their guidance and support throughout my career.

Jason X.-J. Yuan San Diego, California October, 200S

This page intentionally left blank

I. PHYSIOLOGY AND PATHOPHYSIOLOGY

HYPOXIC PULMONARY VASOCONSTRICTION

This page intentionally left blank

Was this article helpful?

0 0
Allergy Relief

Allergy Relief

Have you ever wondered how to fight allergies? Here are some useful information on allergies and how to relief its effects. This is the most comprehensive report on allergy relief you will ever read.

Get My Free Ebook


Post a comment