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The Combined Cardiac Effect of the Anabolic Steroid, Nandrolone And

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The Combined Cardiac Effect of the Anabolic Steroid, Nandrolone And ù1. v -¿. rlc) 77.- *n*hi.rnool oowol,ù*o ffi"/fu -lo *rn*(o fii'o fio¿o¿¿, /v&"ùún lonno **al cooaiæe';¿vfl"- oã. Benjamin D. Phillis, B.Sc. (Hons) Phatmacology Depattment of Clinical & Experimental Pharmacology Ftome Rd. , Medical School Noth Adelaide Univetsity ADEIAIDE SA 5OOO û.)r.'-*hr/7enveltîù Foremost, I would like to thank my two supervisors for the direction that they have given this ptojecr. To Rod, for his unfailing troubleshooting abiJity and to Jenny fot her advice and ability to add scientific rigour' Many thanks to Michael Adams for his technical assistance and especially fot performing the surgery for the ischaemia-reperfusion projects and for his willingness to work late nights and public holidays. Lastly I would like to thank my v¡ife for her extreme patience during the tumult of the last 5 years. Her love, suppoït, patience and undetstanding have been invaluable in this endeavout. Beniamin D. Phillis Octobet,2005 ADE,I-AIDE ii T*(¿t of Ao,t",tù DECI.ARATION I ACKNOWLEDGEMENTS il TABLE OF CONTENTS UI ABBREVIATIONS x ABSTRACT )ilr CÉIAPTER t-l Inttoduction 1-1 1.1 Background 1,-1, 1.2What ate anabolic stetoids? 7-1 1,3 General pharmacology of Anabolic steroids t-2 '1,-2 1.3.1 Genomic effects of anabolic steroids 1.3.2 Non-genomic effects of anabolic steroids 1-3 1.4 Clinical use of AS 1.-4 1.5 Patterns of AS abuse 1.-4 1.5.1 Steroid abuse by athletes 1.-+ 1.5.2 Stetoid abuse by sedentary teenagers r-6 1.5.3 Prevalence of abuse 1-6 1.5.4 Abuse ptevalence in Australia 1.-9 1.6 Cardiotoxicity of anabolic steroids r-9 1.6.1 Reduced cotonary flow 1.-1.1, 1,.6.2 Dtect myocatdial eff ects 1-1 5 1.6.3 Hypertension 1-21 1.7 Difficulties associated with anabolic steroid research 1.-24 1-25 1.8 The polydrug abuse Phenomenon 1.9 The pharmacology of cocaine 1-26 1.10 Pteparations 1-28 1-29 1.11 Metabolism lll 1-30 1. .7 2 Pharmacokin etic s 1,-31 1. 1 3 Cocaine CardiotoxicitY 1.13.1 Reduced coronary flow 1.-34 1.-40 1,.13.2 Carðtac arrhYthmias 1-43 1.13.3 DirecT cardiac effects 1-47 1.14 Conclusion 1.15,\ims 1-48 1.-49 1.16 Hlpotheses 1-50 1.17 Refetences CHAPTER 2 2-l General Methods 2'l 2-1 2.1 Animals _ 2-I 2.2Radtotelemetry recording 2.3 Generalanaesthesia 2-2 a') 2.4 StxgScal irnplantation of radiotelemetry devices 2.4.l.Eccimplants 2-2 2.4.2PioodPressure ImPlants 2-3 2-4 2.4.3 P ost- operative Management 2-4 2.5 Analysis of tadiotelem erry data 2-4 2. 6 Sttg¡cú, procedure for is chaemia-rep erfu sion s tu dies 2-6 2.7 Con¡1nuous recording of cardiac patâmeters during ischaemia-teperfusion. - 2-6 2.8 Induction of ischaemia and reperfusion 2-7 2.9 Analysis of ischaemia-reperfusion data heatts' 2.10 DeterminatLon of the extra-neuronal uptake of noradrenaline in isolated perfused 2-1,1, 2-1,1, 2.1,0.1. P re- tteatment 2.10.2 Protocol 2-1,1, 2.70.3 Calculation of results 2-1.2 2-1.3 2.11 Dtugs 2-15 2.12 References CTIAPTER 3 3-l The effect of rat sttain on the catdiovasculat tesponse to cocaine 3-1 3-1 3.1. Introduction 3-1 3.1.1 Is the cardiovascular tesponse to intraperitoneal cocaine strain dependent? 3-4 3.2. Aim. lv 3-4 3.3. Hypothesis 3-5 3.4. Methods 3.4.1Animals 3-5 3.4.2Protocol 3-5 3.4.3Data Analysis 3-5 3-6 3.5. Results 3.5.1 Time course of the cocaine response 3-6 3.5.2 Between sttain changes in the HR, SI-4, DP and SP fesponse to cocaine - 3-6 3-9 3.6. Discussion 3.7. Conclusion 3-11, 3.8 Refetences 3-r2 CHAPTER 4 4.I The acute effect of nandrolone and cocaine on heaft late 4-l 4.1 Introduction 4-1, 4-2 4.2 Nm 4-2 4.3 Hypothesis 4-3 4.4 Methodology 4.4.1Ânimals 4-3 4-3 4.4.2 4.4.3 4-3 4-4 4. 4.4 Statistical Analysis 4-5 4.5 Results 4.5.1 Plasma levels of nandtolone 4-5 4-5 4.5.2 P re-tteatment response 4.5.3 Cocatne resPonse 4-5 4-5 4.5.4 E ffect of nandrolone pre-treatment on the tesponse to cocaine 4-8 4.6 Discussion 4.7 Conclusion 4-9 4-1.0 4.8 References CHAPTER 5 5'1 The effect of inttavenous nandlolone in tats subiected to catdiac ischaemia and teperfusion 5-1 5-1 5.1 Inttoduction 5-3 5.2 Aim v 5.3 Hypothesis 5-3 5.4 Methodology 5-4 5.4.1Änimals 5-4 5.4.2 Protocol 5-4 5.4.3Data analysis 5-5 5.4.4 Drugs 5-5 5.5 Results 5-7 5.5.1 Plasma level of nandrolone 5-7 5.5.2 Atea at risk of ischaemia 5-7 5.5.3 Cardiovascular response to pre-ischaemia nandrolone infusions 5-7 5.5.4 Catdiovascular tesponse to ischaernia and reperfusion 5-1 5-8 5.5.5 Suwival - 5.5.6 Arhythmia 5-9 5.6 Discussion 5-19 5.6.1 Potential mechanisms for an acute nandrolone effect during catdiac ischaemia 5-21, 5.7 Conclusion 5-22 5.8 References 5-23 CTIAPTER 6 6-l The effect of intravenous cocaine in tats subiected to catdiac ischaemia and tepelfusion 6-1 6.1 Introduction 6-1, 6-2 6.2 Aims 6-2 6.3 Hypotheses 6.4 Methodology 6-3 6-3 6.4.1 '\nimals 6.4.2Protocol 6-3 6-3 6.4.3 Data Ânalysis 6.5 Results 6-5 6-5 6.5.1 ,A,rea at dsk of ischaemia 6-5 6.5.2 C añtovas cular tesp orìs e to pre- tteatment 6-6 6.5.3 Cardiovascular resPonses to ischaemia and reperfusion 6.5.4 Survival 6-l 6-8 6.5.5 Arrhythmia 8 6.6 Discussion 6-1 vr 6.6.1 Btood pressure effects of cocaine 6-1 8 6. 6.2 E,ff ect o f cocain e and is chaemia/ tep erfusion 6-18 6.6.3 Effect of the nandrolone-cocaine combination on arth¡hmia and 6-20 6.6.4Effect of pre-tteatment orì reperfusion atthythmias 6-22 6.7 Conclusion 6-23 6.8 Refetences 6-2+ CHAPTER 7 7-l Effects of chtonic nandlolone administtation 7-l 7.1 Introduction 7 -1, 7.2 7-2 'A.ims 7.3 Hlpothesis 7-2 7.4 Methodology t--) 7.4.1Animals t-J 7.4.2Protocol 7-3 7.4.3Data Analysis 7-+ 7.5 Results 7-7 7.5.1 Change in body weþht 7-7 7.5.2 Change in otgan weights t-7 7.5.3 Histopathology 7-8 7.5.4 Cholestetol, tdglycetides, LDL and HDL profìles' 7-8 7.5.5 Setology 7-8 7.5.6 Plasma level of nandrolone 7-8 7.5.7 Cardtovasculat response to chronic nandrolone treatment 7-9 7.5.8 Cardiovascular response to cocaine administration t-9 7.5.9 Cardtovascular response to ischaemia and reperfusion 7 -1.0 7.5.1.0 Zote at risk of infarctron 7-10 7.5.11 Survival 7 -1.1, 7.5.12 Arth¡hmia 7-1,1, 7.6 Discussion 7-26 7.6.1 Bodyweigh 7-26 7.6.2 Changes in organ weight 7-28 7.6.3 Changes in cholesterol 7-30 7.6.4 Serological Changes 7-32 7.6.5 Plasma nandrolone level 7-32 vrl 7 .6.6 E ffect of treatment on BP and HR 7-32 7.6.7 CaÁtovascular effect of cocaine infusion / -J3 7.6.8 Affect of pre-treatment on the frequency and duration of arhythmia and on 7-34 7.7 Conclusion 1-36 7.8 Refetences 7-37 CHAPTER 8 8-1 3H]-notadtenaline The effect of nandtolone on extraneuronal [ leuptake in lat heatt 8-1 8.1 Introduction 8-1 8.1.1 Summary 8-1 8.1. .2 Bxtraneutonal uPtake 8-1 9.2,\im 8-5 8.3 Hypothesis 8-5 8.4 Method 8-6 8.5 Results 8-7 8.6 Discussion 8-8 8.7 Conclusion 8-9 8.8 References 8-10 CI{APTER 9 9-t Discussion 9-1 9.1 Rat sttain 9-1, g.2Effects of nandtolone alone 9-1 9.2.7 Cardtovasculat effects of nandtolone in non-ischaemic rats 9-1, 9.2.2 CaÅtovascular effects of nandrolone in tats subjected to catdiac ischaemia and reperfusion 9-2 9.3 Effects of cocaine alone 9-4 9.4 Cocat¡e effects in combination with chtonic nandrolone 9-5 9.5 Cocaine effects in combination with acute nandtolone 9-6 9. 6 Experimental Lirnitations 9-6 9-7 9.6.L SoeciesI- 9.6.2Statn 9-7 9.6.3 Gender 9-7 9.6.4 Exercise 9-8 vrrl 9.6.5 Sttess 9-8 9.6.6 Route of drug administtation 9-9 9.6.7 CaÅtac ischaemia 9-10 9.7 Future studies 9-1.1, 9.8 Conclusion 9-1 5 9.9 References 9-11 APPENDIXA.
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