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Ovine Maternal and Fetal Cardiovascular Effects of The Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 1990 Ovine maternal and fetal cardiovascular effects of the serotonergic agonist R(- )-2,5-dimethoxy-4-methyl-amphetamine and characterization of serotonergic receptors in the ovine uterine and umbilical vessels Lubo Zhang Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Pharmacology Commons Recommended Citation Zhang, Lubo, "Ovine maternal and fetal cardiovascular effects of the serotonergic agonist R(-)-2,5-dimethoxy-4-methyl-amphetamine and characterization of serotonergic receptors in the ovine uterine and umbilical vessels " (1990). Retrospective Theses and Dissertations. 11236. https://lib.dr.iastate.edu/rtd/11236 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. INFORMATION TO USERS The most advanced technology has been used to photograph and reproduce this manuscript from the microfihn master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. University Microlilms International A Bell & Howell Information Company 300 North Zeeb Road. Ann Arbor. Ml 48106-1346 USA 313/761-4700 800/521-0600 Order Number 9035131 Ovine maternal and fetal cardiovascular effects of the serotonergic agonist R(—)-2,5-dimethoxy-4-methyl-amphetamine and characterization of serotonergic receptors in the ovine uterine and umbilical vessels Zhang, Lubo, Ph.D. Iowa State University, 1990 UMI 300N.ZeebRd. Ann Arbor, MI 48106 Ovine maternal and fetal cardiovascular effects of the serotonergic agonist R(-)-2,5-dimethoxy-4-methyl-amphetamine and characterization of serotonergic receptors in the ovine uterine and umbilical vessels by Lubo Zhang A Dissertation Submitted to the Graduate Faculty in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Department: Veterinary Physiology and Pharmacology Major: Physiology (Pharmacology) Approved: Members of the Committee: Signature was redacted for privacy. â""Charg^of Mai or Work Signature was redacted for privacy. Signature was redacted for privacy. ?or the Major Department Signature was redacted for privacy. For the Graduate College Iowa State University Ames, Iowa 1990 ii TABLE OF CONTENTS Page GENERAL INTRODUCTION 1 Explanation of Dissertation Format 1 Research Objective 1 Background and Literature Review 2 Rationale 48 SECTION I. CARDIOVASCULAR ACTION OF R(-) 2,5-DIMETH0XY-4-METHYL- AMPHETAMINE (DOM) IN THE PREGNANT EWE AND FETAL LAMB 50 Abstract 50 Introduction 51 Methods 52 Results 59 Discussion 80 Acknowledgements 88 References 88 SECTION II. CHARACTERIZATION OF 5-HYDROXYTRYPTAMINE (5-HT) RECEPTORS ON ISOLATED OVINE UTERINE ARTERY IN LATE PREGNANCY 93 Abstract 93 Introduction 94 Methods 96 Results 102 Discussion 127 Acknowledgements 136 References 136 iii SECTION III. 5-HT2 RECEPTOR-STIMULATED CALCIUM INFLUX IN THE OVINE UTERINE ARTERY IN LATE PREGNANCY 141 Abstract 141 Introduction 142 Methods 143 Results 147 Discussion 159 Acknowledgements 167 References 167 SECTION IV. CHARACTERIZATION OF SEROTONERGIC RECEPTORS MEDIATING CONTRACTION OF THE OVINE UMBILICAL ARTERY 173 Abstract 173 Introduction 174 Methods 175 Results 181 Discussion 198 Acknowledgement 210 References 210 SECTION V. RECEPTOR MECHANISMS FOR 5-HYDROXYTRYPTAMINE (5-HT) IN THE ISOLATED OVINE UMBILICAL VEIN 215 Abstract 215 Introduction 216 Methods 217 Results 223 Discussion 241 Acknowledgement 252 iv References 252 DISCUSSION 256 SUMMARY 265 REFERENCES 271 ACKNOWLEDGEMENTS 293 1 GENERAL INTRODUCTION Explanation of Dissertation Format This dissertation is written in an alternate thesis format as permitted by the Graduate College. It includes a research objective, a background and literature review, a rationale, an experimental part, a discussion, a summary, a list of references cited in the background and literature review and in the discussion. The experimental part has five sections which correspond to the manuscripts submitted for publication. This dissertation contains the experimental results obtained by the author during his graduate study under the supervision of his major professor. Dr. Donald C. Dyer. A portion of the results included in Section I were obtained in collaboration with Dr. Miguel Isla. Research Objective The purpose of this research was to study the effects of the serotonergic agonists acting on the uterine and umbilical circulation in the near-term pregnant ewe/fetus. Maternal and fetal heart rate and blood pressure, uterine artery blood flow, and fetal umbilical artery blood flow were monitored following maternal administration of the serotonergic agonist and antagonist in the chronically instrumented ewe/fetus model. In addition, isolated uterine artery and umbilical vessels were used to explore in more detail agonist-antagonist receptor mechanisms. The significance of this research is that it documents 2 under in vivo conditions the ability of the serotonergic agonists to alter fetal hemodynamics, their dose-response relationship and, through the use of in vitro techniques, the receptor mechanisms involved. Background and Literature Review The uterine and umbilical vasculature are the potential sites at which drugs could affect the fetus by producing vasoconstriction. Serotonin causes contraction of most isolated large arteries (Cohen et al., 1981; Cohen et al., 1983; Van Nueten et al., 1982; Van Nueten et al., 1981; Van Nueten et al., 1984) including uterine and umbilical vessels (Altura et al., 1972; Dyer, 1970a; Dyer and Gough, 1971; Nair and Dyer, 1973). In this section the uterine and fetal circulation and serotonin receptors and vascular responses are briefly reviewed. Uteroplacental and fetal circulation Uterine circulatory anatomy The uterine artery is a continuation of the umbilical artery which originates from the internal iliac artery. In humans, the abdominal aorta divides into iliac arteries which subdivides into external and internal iliac arteries. In sheep the caudal end of the abdominal aorta trifurcate into two external iliac arteries and a common internal iliac artery. The common internal iliac artery subdivides into two internal iliac arteries that branch into the main uterine and sacral arteries. The main uterine artery is further subdivided into middle and dorsal uterine arteries (Fig. 1). The uterus receives its blood supply from both the uterine and Fig. 1. Arterial supply to the ewe uterus (From Fuller et al., 1978) Ovarian a Aorta— Common internal iliac a. Moir» uterine o. ^5 Sacral a Middle uterine a. Dorsal uterine a. Extra-uterine cervical arts 5 ovarian arteries. The functional importance of these two vessels varies among different species and within the same species during pregnancy. In guinea pigs, the ovarian artery is the major contributor to the total blood flow of the ovary-oviduct-uterus complex in the nonpregnant state and becomes the lesser contributor at day 11 of pregnancy (Chaichareon et al., 1976). In sheep, the uterus receives its blood supply predominantly from the uterine artery. Using electro-magnetic flow probes and microspheres, Rosenfeld et al. (1974) estimated that in sheep the uterine arteries contributes approximately 80% of the uterine blood flow. Adjustment of the uterine circulation to pregnancy Vascular adjustment to pregnancy The diameter of the uterine arteries enlarges several fold during pregnancy. In sheep, the external diameter increases from about 1 mm in the nonpregnant state to 8 or 9 mm in the near-term pregnant state (Assail and Brinkman, 1972). The diameter reverts to the nonpregnant size within one week post partum. The mechanisms by which these reversible changes take place are not quite clear. Moll and Gotz (1985) suggested that the increased diameter of arteries supplying uterine tissue during pregnancy in the guinea pig were due to changes in the nonmuscular elements of the arterial wall and that estrogen may mediate these effects. Guenther et al. (1988) demonstrated that a decrease in the collagen to elastin ratio in the uterine
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