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ROLE of BRAIN SOLUBLE EPOXIDE HYDROLASE in CARDIOVASCULAR FUNCTION by KATHLEEN WALWORTH SELLERS a DISSERTATION PRESENTED TO

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ROLE of BRAIN SOLUBLE EPOXIDE HYDROLASE in CARDIOVASCULAR FUNCTION by KATHLEEN WALWORTH SELLERS a DISSERTATION PRESENTED TO ROLE OF BRAIN SOLUBLE EPOXIDE HYDROLASE IN CARDIOVASCULAR FUNCTION By KATHLEEN WALWORTH SELLERS A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2004 Copyright 2004 by Kathleen Walworth Sellers This work is dedicated to my family, who has taught me to embrace life with love, perseverance, and grace. ACKNOWLEDGMENTS I could not have completed this work without the assistance from many colleagues and friends. First and foremost, I would like to thank my mentor, Dr. Mohan Raizada, who has consistently supported and encouraged me these last several years. It was by chance that I worked in his research group before starting my graduate program, and I could not have found a better group with which to work. Dr. Raizada’s excitement and fervor for new ideas have helped shape my appreciation for scientific research and the pursuit of knowledge. I also want to acknowledge all of the members of the Raizada research group, past and present. I am fortunate to work in such a friendly and intellectually-stimulating environment. Specifically, I want to thank Drs. Beverly Falcon and Matthew Huentelman, the two graduate students in our research group who both helped me tremendously. In addition, I would like to thank Drs. Carlos Diez, Cheng-wen Sun, Jorge Vazquez, Shereeni Veerasingham and Hong Yang for all of their intellectual guidance. I greatly acknowledge the members of my committee, Drs. Michael Katovich, Gerard Shaw, Colin Sumners and Charles Wood. Each has provided me with unique experience and expertise to further my research and career. In addition, I want to thank all of my teachers throughout my education. Without a solid learning base, I would not have reached this goal. iv Finally, I want to thank all my family and friends who have supported me over the years. It is they who lift my spirits and keep my sights set high. Each of my loved ones has a purpose in my life for which I am eternally grateful. v TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................................................................................. iv LIST OF FIGURES .............................................................................................................x ABSTRACT...................................................................................................................... xii CHAPTER 1 INTRODUCTION ........................................................................................................1 Central Regulation of Hypertension .............................................................................1 Brainstem...............................................................................................................2 Hypothalamus........................................................................................................4 Baroreceptor Reflex...............................................................................................4 Mechanisms Underlying SNA...............................................................................5 Renin-angiotensin system ..............................................................................5 Reactive oxygen species.................................................................................7 Implications .........................................................................................................10 Soluble Epoxide Hydrolase ........................................................................................11 History .................................................................................................................11 Epoxyeicosatrenoic Acids ...................................................................................12 Vasodilatory properties ................................................................................12 EETs in the brain..........................................................................................14 Alternate actions of EETs ............................................................................14 Dihydroxyeicosatrenoic Acids .....................................................................15 Cytochrome P-450...............................................................................................16 Epoxygenases in the brain............................................................................16 20-HETE ......................................................................................................17 sEH and Hypertension.........................................................................................17 sEH Polymorphisms ............................................................................................19 Rodent ..........................................................................................................19 Human ..........................................................................................................20 sEH polymorphisms in cardiovascular disease ............................................21 sEH polymorphisms in other disorders ........................................................21 Phosphatase Studies.............................................................................................22 Summary.....................................................................................................................23 vi 2 INCREASED SEH EXPRESSION IN SHR VS. WKY RAT BRAIN: IN VITRO AND IN VIVO ANALYSIS........................................................................................31 Introduction.................................................................................................................31 Materials and Methods ...............................................................................................33 Animals................................................................................................................33 Immunohistochemistry........................................................................................33 Real-Time RT-PCR.............................................................................................34 Western Blot Analysis.........................................................................................34 Neuronal Cells in Primary Culture......................................................................35 Losartan Treatment of SHRs to Normalize Blood Pressure................................35 Statistical Analysis ..............................................................................................36 Results.........................................................................................................................36 Cellular Localization of sEH...............................................................................36 sEH Expression in the SHR.................................................................................37 In vitro Validation with Neuronal Cells in Primary Culture ...............................37 sEH Expression Following Blood Pressure Normalization.................................38 Discussion...................................................................................................................39 3 CENTRAL SEH INHIBITION INCREASES BLOOD PRESSURE AND HEART RATE IN THE SHR ...................................................................................................49 Introduction.................................................................................................................49 Materials and Methods ...............................................................................................51 Animals................................................................................................................51 Statistical Analysis ..............................................................................................51 ICV Cannulation..................................................................................................51 Abdominal Aorta Cannulation ............................................................................51 Blood Pressure and Heart Rate Recordings.........................................................52 In vivo Drug Delivery..........................................................................................52 Results.........................................................................................................................53 Effect of sEH Inhibitor DCU on Blood Pressure and Heart Rate .......................53 WKY rat .......................................................................................................53 SHR ..............................................................................................................53 Effect of sEH Inhibitor AUDA on Blood Pressure and Heart Rate ....................54 Dose response...............................................................................................54 WKY rat ..............................................................................................................55 SHR .....................................................................................................................55 Discussion...................................................................................................................55 4 ROLE OF ROS IN ANG II-INDUCED REGULATION OF BLOOD PRESSURE.63 Introduction.................................................................................................................63
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