The effect of androgenic anabolic steroids on the susceptibility of the rat heart to ischaemia and reperfusion injury

Rossouw, Ellen (2002-12)

Thesis (MSc)--University of Stellenbosch, 2002.

Thesis

ENGLISH ABSTRACT: Background: Athletes use androgenic anabolic steroids (AAS) to enhance their physical performance. The abuse of AAS is however associated with a host of side effects including sudden death due to cardiac arrest. The use of AAS leads to myocardial hypertrophy, which possibly makes the heart more prone to ischaemia/reperfusion injury, since it often develops in the absence of proper vasculature development. Chronic AAS use also disrupts myocardial p-adrenoreceptor function and possibly cAMP, signalling in the heart. Drugs increasing cAMP and decreasing cGMP levels in the ischaemic myocardium exacerbate myocardial ischaemia/reperfusion injury. We also know that AAS causes coronary artery disease secondary to the deleterious alteration of lipid profiles by increasing the LOL cholesterol and decreasing the HOLcholesterol levels. AAS treatment may increase systemic TNFa levels by stimulating lymphocyte TNFa secretion that has been implicated in the depression of myocardial function, myocardial hypertrophy and the worsening of ischaemia/reperfsuion injury. Aims: To determine whether chronic AAS treatment in trained and untrained rats influences: 1) heart function and susceptibility to ischaemia/reperfusion injury, 2) myocardial cyclic nucleotide levels (cAMP and cGMP) and 3) myocardial TNFa levels. Material and methods: Male Sprague-Dawley rats (n=100) were divided into 4 groups: sedentary vehicle (placebo) treated group, sedentary AAS treated group, exercise vehicle (placebo) treated group, and exercise AAS treated group. Steroid treated animals received an intramuscular injection of nandrolone laureate (0.375 mg/kg) once a week, for six weeks. Training consisted of swim sessions 6 days a week for 6 weeks. Swim time was incrementally increased up to a maximum of 50 minutes a day. For biometric parameters heart weight and body weight were documented. Hearts were mounted on a l.anqendorff perfusion apparatus and left ventricular developed pressure (LVDP), heart rate (HR) and coronary flow (CF) was monitored. The hearts were subjected to a period of 20 minutes of global ischaemia, followed by 30 minutes of reperfusion. Functional parameters was again monitored and documented. For biochemical analysis, blood was collected for the determination of serum lipid levels and myocardial tissue samples were collected before, during and after ischaemia for the determination of myocardial TNFa, cGMP and cAMP levels and p38 activity. Conclusions: Results obtained would suggest that AAS exacerbate exercise induced myocardial hypertrophy. It also prevents the exercise-induced improvement in cardiac function. AAS use reduces reperfusion function in treated hearts, which may suggest that AAS exacerbates ischaemie and reperfusion injury. Furthermore it was seen that AAS elevates basal (preischaemie) cyclic nucleotide levels and basal (pre-ischaemic) as well as reperfusion TNFa levels. This may also contribute to the exacerbation of ischaemic and reperfusion injury.

AFRIKAANSE OPSOMMING: Agtergrond: Androgeniese anaboliese steroïede (AAS) word dikwels deur atlete gebruik om sportprestasie te verbeter. Die misbruik van AAS het egter talle newe effekte, insluitende skielike dood wat gewoonlik toegeskryf word aan hartaanvalle. Die gebruik van AAS lei onder andere tot miokardiale hipertrofie wat opsigself, as gevolg van ontoereikende vaskulêre ontwikkeling tydens die ontwikkeling van hipertrofie, die hart nog meer vatbaar vir isgemie/herperfusie skade maak. Kroniese AAS toediening versteur miokardiale beta-adtenoresepter funksie en moontlik die tweede boodskapper, sAMP, seintransduksie in die hart. Ons weet ook dat AAS koronêre hartvatsiektes veroorsaak. Laasgenoemde is sekondêr tot die nadelige lipiedprofiel verandering, wat 'n verhoging in LDL-C en 'n verlaging in HDL-C insluit. Middels wat miokardiale sAMP vlakke verhoog en sGMP vlakke in die isgemiese miokardium verlaag, vererger miokardiale isgemie/herperfusie skade. AAS behandeling kan moontlik ook sistemiese TNFa vlakke verhoog deur limfosiet TNFa sekresie te stimuleer. Die verhoogde TNFa vlakke word verbind aan die onderdrukking van miokardiale funksie, miokardiale hipertrofie en die verergering van isgemie/herperfusie skade. Doelwitte: Die doelwitte van die studie was om te bepaal of kroniese AAS toediening in geoefende en ongeoefende rotte 1) hartfunksie en die hart se vatbaarheid vir isgemie/herperfusie skade beïnvloed, 2) miokardiale sikliese nukleotiedvlakke (sAMP en sGMP) beïnvloed en 3) miokardiale TNFa-vlakke beïnvloed. Materiale en metodes: Manlike Sprague-Dawley rotte (n=100) is gebruik en in 4 groepe verdeel: 'n ongeoefende placebo groep (kontrole); 'n ongeoefende steroïedbehandelde groep; 'n geoefende placebo groep (kontrole) en 'n geoefende steroïedbehandelde groep. Steroïed behandelde diere het 'n intramuskulêre nandroloon lauraat inspuiting (0.375 mg/kg) een keer per week vir ses weke ontvang. Die oefenprogram het bestaan uit ses swemsessies 'n week vir ses weke. Die swemtyd is geleidelik weekliks verhoog tot by 'n maksimum tyd 50 min. Die waterbadtemperatuur is tussen 30 - 32 oe gehandhaaf. Vir biometriese parameters is hartgewig en liggaamsgewig genoteer. Harte is op 'n Langendorff perfusie apparaat gemonteer en linker ventrikulêre ontwikkelde druk (LVOD), koronêre vloei (KV) en harttempo (HT) is genoteer. Die harte is vervolgens blootgestel aan 20 minute van globale isgemie gevolg deur 'n 30 minute herperfusieperiode. LVOD, KV en HT is weer eens noteer. Vir biochemiese doeleindes is bloed voor perfusie versamelom serum lipied vlakke te bepaal. Miokardiale weefsel is versamel voor, tydens en na isgemie vir die bepaling van TNFa, cGMP en AMP vlakke asook p38 aktiwiteit. Gevolgtrekkings: Na aanleiding van resultate verkry wil dit voorkom asof die gebruik van steroïde oefeningsgeïnduseerde miokardiale hipertrofie vererger. Dit verhoed ook oefeningsgeïnduseerde verbetering in miokardiale funksie. AAS lei tot 'n verlaagde herperfusiefunksie in behandelde harte, wat dalk mag dui op MS verergering van isgemie en herperfusie skade. Verder was daar ook waargeneem dat MS basale (pre-isgemiese) sikliese nukleotiedvlakke en basale TNFa-vlakke sowel as herperfusie TNFa vlakke verhoog. Die verhoging in TNF-a vlakke mag dus moontlik ook bydra tot die verergering van isgemie- en herperfusieskade.

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