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University Microfilms International 300 North Zeeb Road Ann Arbor, Michigan 48106 USA St INFORMATION TO USERS This material was produced from a microfilm copy of the original document. While the most advanced technological means to photograph and reproduce this document have been used, the quality is heavily dependent upon the quality of the original submitted. The following explanation of techniques is provided to help you understand markings or patterns which may appear on this reproduction. 1.The sign or "target" for pages apparently lacking from the document photographed is "Missing Page(s)". If it was possible to obtain the missing page(s) or section, they are spliced into the film along with adjacent pages. This may have necessitated cutting thru an image and duplicating adjacent pages to insure you complete continuity. 2. When an image on the film is obliterated with a large round black mark, it is an indication that the photographer suspected that the copy may have moved during exposure and thus cause a blurred image. You will finda good image of the page in the adjacent frame. 3. When a map, drawing or chart, etc., was part of the material being photographed the photographer followed a definite method in "sectioning" the material. It is customary to begin photoing at the upper left hand corner of a large sheet and to continue photoing from left to right in equal sections with a small overlap. If necessary, sectioning is continued again — beginning below the first row and continuing on until complete. 4. The majority of users indicate that the textual content is of greatest value, however, a somewhat higher quality reproduction could be made from "photographs" if essential to the understanding of the dissertation. Silver prints of "photographs" may be ordered at additional charge by writing the Order Department, giving the catalog number, title, author and specific pages you wish reproduced. 5. PLEASE NOTE: Some pages may have indistinct print. Filmed as received. University Microfilms International 300 North Zeeb Road Ann Arbor, Michigan 48106 USA St. John's Road, Tyler's Green High Wycombe, Bucks, England HP10 8HR BOUCHER, D.V.M., John Holly, 1930- INOTROPIC AND CHRONOTROPIC EFFECTS OF SOTALOL IN CONSCIOUS DOGS: ASSESSED IN COMBINATION WITH ATROPINE. The Ohio State University, Ph.D., 1977 Veterinary Science Xerox University Microfilms,Ann Arbor, Michigan 48106 INOTROPIC AND CHRONOTROPIC EFFECTS OF SOTALOL IN CONSCIOUS DOGS: ASSESSED IN COMBINATION WITH ATROPINE DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By John Holly Boucher, D.V.M., M.S. * * * * * The Ohio State University 1977 Reading Committee: Approved by Dr. Robert L. Hamlin Dr. Jean Powers Dr. Thomas E. Powers Department of Veterinary Physiology and Pharmacology ACKNOWLEDGMENTS I am grateful for the continuous encouragement and support given me by Professor Robert L. Hamlin. His con­ structive criticisms and patience were of immeasurable help in the completion of this work. To Adelbert L. Stagg, the most skillful, diligent, and devoted technical assistant I have ever known, I give my sincere thanks. I hold in my memory the lessons he taught me about the goodness of service to others. A special word of thanks to Ms. Margie Maxwell for her secretarial assistance in organizing and coordinating my efforts with others at the University. I am indeed appreciative of the support given me by the Department of Veterinary Physiology and Pharmacology. Particularly, the statistical and analytical assistance given me by Dr. Jean Powers was appreciated. Finally, I am grateful to my daughters, Jennifer and Carrie who, at times, not so graciously but, nevertheless, who understandingly and patiently allowed a great deal of neglect in order for me to complete this work. I owe them a debt of love I can never return. VITA December 15, 1930 .... Born: Kansas City, Missouri 195 6................... B.S. and D.V.M. , Missouri University, Columbia, Missouri 195 7................... M.S., Cornell University, Ithaca, New York 1968................... M.S., The Ohio State University, Columbus, Ohio PUBLICATIONS Boucher, J. H., W. H. Zech, and A. L. Stagg. Effective beta-adrenergic receptor blockade with sotalol~~in the absence of myocardial depression. Federation Proceedings 30:228. WTT. Boucher, J. H., D. E. Hilmas, C. T. Liu, W. P. Czajkowski, and R. 0. Spertzel. Myocardial depression during Diplococcus pneumoniae infection in monkeys. Proc. Soc. Exp. Biol. Med. 145:112-116. T 9 7 T : Zech, W. H., J. H. Boucher, D. E. Hilmas, and R. 0. Spertzel. Myocardial contractility in conscious rhesus monkeys: A method for long-term study. Am. J. Vet. Res. 35:83-86. T 5 7 T : FIELDS OF INTEREST Ventricular function in work performance. Clinical veterinary cardiology. TABLE OF CONTENTS Page ACKNOWLEDGMENTS ................................ ii VITA............................................... iii LIST OF T A B L E S ................................ vi LIST OF FIGURES................................... vii INTRODUCTION ................................... 1 LITERATURE REVIEW ............................. 3 MATERIALS AND METHODS .......................... 12 Animals...................................... 12 Drugs......................................... 13 Instrumentation ............................. 16 Indices of LV Function........................ 17 Percent Chronotropic Blockade.................. 21 Experimental Design .......................... 21 Isoproterenol Duration of Response .... 21 Isoproterenol Dose-Response.................. 2 4 Atropine Dose-Response .................... 24 Sotalol Dose-Response........................ 24 Effectiveness of Beta-Adrenergic Blockade . 25 Heart Rate-Contractility Relationship . 25 Sotalol-Atropine Sequences ....... 26 Statistical Analysis.......................... 27 RESULTS......................................... 28 Isoproterenol Duration of Response . 28 Isoproterenol and Atropine Dose-Response . 28 Sotalol Dose-Response........................ 36 Effectiveness of Beta-Adrenergic Blockade . 42 iv Page Heart Rate-Contractility Relationship .... 47 Sotalol-Atropine Sequences............... 47 DISCUSSION ................................... 51 Sotalol Dose-Response ....................... 51 Effectiveness of Beta-Adrenergic Blockade. 54 Heart Rate-Contractility Relationship .... 56 Sotalol-Atropine Sequences............... 57 SUMMARY AND CONCLUSIONS..................... ■ . 61 BIBLIOGRAPHY................................ 64 i v LIST OF TABLES Table Page 1. ANOVA for isoproterenol duration of response................................... 31 2. ANOVA for isoproterenol dose-response . 37 3. ANOVA for atropine dose-response ............ 38 4. ANOVA for sotalol dose-response ............ 41 5. ANOVA for incremental doses of sotalol (combined with atropine) relating graded doses of isoproterenol to percent chrono­ tropic blockade............................. 45 6. Heart rate response to isoproterenol and sotalol + atropine (0.2 mg/kg)............... 46 7. Heart rate and corresponding myocardial contractility indices during graded atropine dosage and atrial pacing..................... 48 8. Chronotropic and inotropic responses following a series of sequential dosings with sotalol and atropine....................... 49 9. ANOVA for sotalol-atropine sequences. 50 i vi LIST OF FIGURES Figure Page 1. Manometer placement and cable modification . 15 2. Estimation of maximal velocity of contractile element shortening (Vmax). 20 3. Definition of percent chronotropic blockade. 23 4. Duration of inotropic and chronotropic responses to an intravenous bolus adminis­ tration of a 0.3 yg/kg dose of isoproterenol . 30 5. Graded dose-response curve for isoproterenol . 33 6. Graded dose-response curve for atropine . 35 7. Families of dose-response curves for sotalol (A: 0.5-4.0 mg/kg; B: 8.0 and 16.0 mg/kg) combined with atropine (0.2 mg/kg) relating the intrinsic heart rate (after autonomic blockade) to t i m e .......................... 40 8. Family of dose-response curves for sotalol (0.5-16.0 mg/kg) combined with atropine (0.2 mg/kg) relating graded isoproterenol dosage to percent chronotropic blockade ............. 44 vii INTRODUCTION The stimulatory effects of beta-adrenergic activity and the inhibitory effects of vagal activity on the ventric­ ular myocradium have been well documented (3). Autonomic reactivity and cardiovascular control mechanisms behave differently in conscious dogs than in those given anes­ thesia (63). The reasons for the differences are not yet understood, but, because differences do exist, traditional physiological mechanisms established under conditions other than consciousness should be re-evaluated in conscious subjects. Sinus arrhythmia is an arrhythmia resulting from waxing and waning of vagal efferent activity (67) , and is one autonomic phenomenon that operates in consciousness as well as during anesthesia. Chemical denervation, to exclude the autonomic endog­ enous neuro-transmitter effects, presents the investigator with an excellent model to identify intrinsic myocardial alterations imposed by an intervention, i.e., responses would reflect a direct effect on the myocardium. Sotalol, a relatively new beta-adrenoceptor blocking drug, has been adequately characterized in anesthetized dogs (8, 19, 48). The purpose of this investigation was to characterize the 1 2 inotropic and chronotropic effects of sotalol in conscious dogs when this beta-adrenoceptor blocking drug was com­ bined with atropine. LITERATURE REVIEW The concepts
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