The Combined Cardiac Effect Of The Anabolic Steroid, Nandrolone And Cocaine In The Tat

283 Pages·2015·15.14 MB·English

by  Benjamin Phillis

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Benjamin D. Phillis, B.Sc. (Hons) Phatmacology
Depattment of Clinical & Experimental Pharmacology
Noth
Ftome Rd. , Medical School
Adelaide Univetsity
ADEIAIDE SA 5OOO

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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
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DECI.ARATION
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ACKNOWLEDGEMENTS
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TABLE OF CONTENTS
x
ABBREVIATIONS
)ilr
ABSTRACT
t-l
CÉIAPTER
Inttoduction 1-1
1.1 Background 1,-1,
1.2What ate anabolic stetoids? 7-1
t-2
1,3 General pharmacology of Anabolic steroids
1.3.1 Genomic effects of anabolic steroids '1,-2
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.-+
r-6
1.5.2 Stetoid abuse by sedentary teenagers
1.5.3 Prevalence of abuse 1-6
1.5.4 Abuse ptevalence in Australia 1.-9
r-9
1.6 Cardiotoxicity of anabolic steroids
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
1-28
1.10 Pteparations
1-29
1.11 Metabolism
lll
1-30
1. .7 2 Pharmacokin etic s
1. 1 3 Cocaine CardiotoxicitY 1,-31
1.13.1 Reduced coronary flow 1.-34
1,.13.2 Carðtac arrhYthmias 1.-40
1.13.3 DirecT cardiac effects 1-43
1-47
1.14 Conclusion
1-48
1.15,\ims
1.16 Hlpotheses 1.-49
1-50
1.17 Refetences
2-l
CHAPTER 2
2'l
Methods
General
_ 2-1
2.1 Animals
recording 2-I
2.2Radtotelemetry
Generalanaesthesia 2-2
2.3
a')
2.4 StxgScal irnplantation of radiotelemetry devices
2.4.l.Eccimplants 2-2
ImPlants 2-3
2.4.2PioodPressure
2.4.3 P ost- operative Management 2-4
data 2-4
2.5 Analysis of tadiotelem erry
2. 6 Sttg¡cú, procedure for is chaemia-rep erfu sion s tu dies 2-4
2.7 Con¡1nuous recording of cardiac patâmeters during ischaemia-teperfusion. 2-6
-
2.8 Induction of ischaemia and reperfusion 2-6
data 2-7
2.9 Analysis of ischaemia-reperfusion
2.10 DeterminatLon of the extra-neuronal uptake of noradrenaline in isolated perfused heatts'
2-1,1,
2.1,0.1. P re- tteatment 2-1,1,
2.10.2 Protocol 2-1,1,
2.70.3 Calculation of results 2-1.2
2.11 Dtugs 2-1.3
References 2-15
2.12
3-l
CTIAPTER 3
The effect of rat sttain on the catdiovasculat tesponse to cocaine 3-1
3-1
3.1. Introduction
3.1.1 Is the cardiovascular tesponse to intraperitoneal cocaine strain dependent? 3-1
3-4
3.2. Aim.
lv
3-4
3.3. Hypothesis
3-5
3.4. Methods
3-5
3.4.1Animals
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-r2
3.8 Refetences
4 4.I
CHAPTER
4-l
The acute effect of nandrolone and cocaine on heaft late
4.1 Introduction 4-1,
Nm 4-2
4.2
4-2
4.3 Hypothesis
4-3
4.4 Methodology
4-3
4.4.1Ânimals
4-3
4.4.2
4-3
4.4.3
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
4.5.3 Cocatne resPonse
4.5.4 E ffect of nandrolone pre-treatment on the tesponse to cocaine 4-5
4-8
4.6 Discussion
4-9
4.7 Conclusion
4-1.0
4.8 References
5 5'1
CHAPTER
The effect of inttavenous nandlolone in tats subiected to catdiac ischaemia and
5-1
teperfusion
Inttoduction 5-1
5.1
5-3
5.2 Aim
v
5-3
5.3 Hypothesis
5-4
5.4 Methodology
5-4
5.4.1Änimals
5.4.2 Protocol 5-4
5.4.3Data analysis 5-5
5.4.4 Drugs 5-5
5-7
5.5 Results
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
Suwival 5-8
5.5.5 -
5.5.6 Arhythmia 5-9
5-19
5.6 Discussion
5.6.1 Potential mechanisms for an acute nandrolone effect during catdiac
ischaemia 5-21,
5-22
5.7 Conclusion
5-23
5.8 References
6-l
CTIAPTER 6
The effect of intravenous cocaine in tats subiected to catdiac ischaemia and
6-1
tepelfusion
6.1 Introduction 6-1,
6-2
6.2 Aims
6-2
6.3 Hypotheses
6-3
6.4 Methodology
6-3
6.4.1
'\nimals
6-3
6.4.2Protocol
6-3
6.4.3 Data Ânalysis
6-5
6.5 Results
6.5.1 ,A,rea at dsk of ischaemia 6-5
6.5.2 C añtovas cular tesp orìs e to pre- tteatment 6-5
6.5.3 Cardiovascular resPonses to ischaemia and reperfusion 6-6
6-l
6.5.4 Survival
6-8
6.5.5 Arrhythmia
6.6 Discussion 6-1 8
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+
7-l
CHAPTER 7
7-l
Effects of chtonic nandlolone administtation
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
The effect of nandtolone on extraneuronal [ 3H]-notadtenaline 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
8-10
8.8 References
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
9.6.L Soecies 9-7
I-
9.6.2Statn 9-7
9.6.3 Gender 9-7
9.6.4 Exercise 9-8
vrrl
9-8
9.6.5 Sttess
9.6.6 Route of drug administtation 9-9
9-10
9.6.7 CaÅtac ischaemia
9.7 Future studies 9-1.1,
9.8 Conclusion 9-1 5
9-11
9.9 References
APPENDIXA. A-1
Reported fatal and.non-fatal catdiovasculat outcomes tesulting ftom
A-1
anabolic stetoid use
B-1
APPENDIX B.
Reported histological changes in laboratory animals administered anabolic
1
stetoids
c-1
APPENDIX C
Pilot study: chtonic effect of nandtolone in telemeteted mts c-1
I
APPENDIX D.
slices D-l
Pilot study: extfaneulonal notadrenaline feuptake in tat heatt
APPENDIX E. E-1
Effect of anabolic steroids in the CNS E-1
APPENDIX F. F-1
Effect of nandtolone on Plasma ET-l F'-1
APPENDIX G. G-1
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