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Memoria J. Carvajal C MECHANISMS UNDERLYING UTERINE QUIESCENCE DURING PREGNANCY PONTIFICIA UNIVERSIDAD CATOLICA DE CHILE FACULTAD DE MEDICINA PROGRAMA DE DOCTORADO EN CIENCIAS MEDICAS TESIS DOCTORAL M ECHANISMS UNDERLYING UTERINE QUIESCENCE DURING PREGNANCY Dr. Jorge A. Carvajal Cabrera Alumno Programa Doctorado en Ciencias Médicas Dr. Carl P. Weiner Profesor Guía Professor of Obstetrics, Gynecology and Reproductive Sciences Professor of Physiology University of Maryland School of Medicine Noviembre 2000 DR. JORGE A.CARVAJAL CABRERA 1 2 MECHANISMS UNDERLYING UTERINE QUIESCENCE DURING PREGNANCY Manuscrito final DR. JORGE A.CARVAJAL CABRERA 3 4 MECHANISMS UNDERLYING UTERINE QUIESCENCE DURING PREGNANCY DR. JORGE A.CARVAJAL CABRERA 5 6 MECHANISMS UNDERLYING UTERINE QUIESCENCE DURING PREGNANCY D edicate to Pamela, Diego and Cristóbal… this work would have not been possible without their support DR. JORGE A.CARVAJAL CABRERA 7 8 MECHANISMS UNDERLYING UTERINE QUIESCENCE DURING PREGNANCY INDEX PREFACE ............................................................................................................................. 11 ACKNOWLEDGMENTS........................................................................................................ 13 ABSTRACT ........................................................................................................................... 15 INTRODUCTION ................................................................................................................... 17 Hypothesis ............................................................................................................................ 19 Objectives ............................................................................................................................. 19 General Objectives ........................................................................................................ 19 Specific Objectives......................................................................................................... 19 MATERIAL AND METHODS ................................................................................................. 20 Animal Model and Tissue Preparation .................................................................................. 20 Human Tissues ..................................................................................................................... 20 Isometric Tension Studies ..................................................................................................... 21 cGMP Measurement by Radio Immuno-Assay (RIA)............................................................ 21 Reverse Transcription -Polymerase Chain Reaction (RT-PCR)............................................ 22 Ribonuclease Protection Assay (RPA) .................................................................................. 23 Immunohistochemistry (IHC) ................................................................................................. 24 Experimental Protocols ......................................................................................................... 25 a. Effect of Fetal Membranes on Oxytocin-Stimulated Contractility ................................... 25 b. Effect of Fetal Membranes on Spontaneous Contractility .............................................. 26 c. Effect of Chorion-Conditioned Medium on Oxytocin-Stimulated Contractility ................ 26 d. Effect of Human Chorion on Oxytocin-Stimulated Contractility ...................................... 27 e. Evaluation of the Mechanism of Action of Chorion-Induced Relaxation ........................ 27 f. Effect of Natriuretic Peptides on Oxytocin-Stimulated Contractility ............................... 29 g. Evaluation of the Mechanism of Natriuretic Peptide-Induced Relaxation ...................... 29 h. Effect of Natriuretic Peptides on Myometrial cGMP ....................................................... 30 i. Evaluation of BNP expression on Human Gestational Tissues ..................................... 31 j. Effect of 8-Br-cGMP on Oxytocin-Stimulated Myometrial Contractility .......................... 31 k. Effect of Fetal Membranes on Myometrial cGMP Content ............................................. 31 l. Evaluation of the Mechanism of Chorion-Induced cGMP Increase ............................... 32 m. Evaluation of the source of cGMP in gestational tissues ............................................... 33 Drugs and Solutions .............................................................................................................. 34 Statistical Analysis................................................................................................................. 34 DR. JORGE A.CARVAJAL CABRERA 9 RESULTS .............................................................................................................................. 35 Guinea Pig Myometrium as a Model for Isometric Tension Studies ...................................... 35 Effect of Chorion and Amnion on Myometrial Contractile Activity ......................................... 36 Effect of Chorion Conditioned Medium on Myometrial Contractile Activity ........................... 38 Effect of Human Chorion on Myometrial Contractile Activity ................................................. 38 Effect of Blocking Myometrial cGMP Pathway on Chorion-Induced Relaxation ................... 39 Effect of Inhibition of Putative Relaxing Agonist Synthesis in the Chorion ............................ 40 Effect of Blocking Myometrial K+ Channels on Chorion-Induced Relaxation ....................... 41 Effect of Natriuretic Peptides on Oxytocin-Stimulated Contractility ....................................... 41 Temporal Course of Natriuretic Peptide-Induced Relaxation ................................................ 41 Effect of Anantin on Natriuretic Peptide-Induced Relaxation ................................................ 42 Effect of Rp-8-Br-cGMP on BNP-induced relaxation ............................................................ 43 Effect of cANP on Oxytocin Induced Contractility ................................................................. 43 Effect of PTX and TEA on BNP-induced relaxation .............................................................. 43 Natriuretic Peptide-Induced Myometrial cGMP Generation .................................................. 44 Effect of Anantin on Natriuretic Peptide-Induced cGMP Generation..................................... 45 BNP Expression in Human Gestational Tissues ................................................................... 45 Effect of 8-Br-cGMP on Oxytocin-Stimulated Myometrial Contractility ................................. 46 Effect of Fetal Membranes on Myometrial cGMP Content .................................................... 47 Effect of Guanylate Cyclase Blockers on Chorion-Induced cGMP Increase ......................... 47 cGMP Production by the Chorion.......................................................................................... 48 Effect of Myometrial Incubation with cGMP .......................................................................... 49 Tissue Distribution of cGMP .................................................................................................. 49 DISCUSSION ........................................................................................................................ 52 Chorion Releases A Substance that Inhibits Oxytocin-Stimulated Myometrial Contractility . 52 Mechanism of the Chorion-Induced Relaxation .................................................................... 55 Natriuretic Peptide-Induced Relaxation is not Mediated by Guanylate Cyclase Activation ... 59 Chorion Produced BNP may mediate Chorion Induced Relaxation ...................................... 62 Role and Tissue Distribution of cGMP During Pregnancy..................................................... 63 REFERENCES...................................................................................................................... 65 APPENDICES ....................................................................................................................... 73 Glossary of Abbreviations ..................................................................................................... 73 Pharmacological Tools Used ................................................................................................. 74 10 MECHANISMS UNDERLYING UTERINE QUIESCENCE DURING PREGNANCY PREFACE he Medical Sciences Ph.D. program at the Pontificia T Universidad Católica de Chile is a three years program. After completing my first year in Chile, I was fortunate to receive funding from the Fogarty International Center, a division of the National Institute of Health (NIH) of United States. Coupled with support from our School of Medicine, I was able to perform my Thesis work at the University of Maryland. With the approval of my proposal by the Thesis Committee, I started research work in the Department of Obstetrics, Gynecology and Reproductive Sciences at the University of Maryland Baltimore in September 1998. This text is the result of a two years work in the laboratory of Perinatal Research of Dr. Carl P. Weiner M.D. at the University of Maryland Baltimore. The Laboratory is located in the Bressler Research Building in the University Neighborhood in Downtown Baltimore, State of Maryland. DR. JORGE A.CARVAJAL CABRERA 11 12 MECHANISMS UNDERLYING UTERINE QUIESCENCE DURING PREGNANCY
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