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Glucose versus acetate as substrate during subtotal ischaemia

Segadavan, Arisha (1999-12)

Thesis (M.Sc.) -- University of Stellenbosch, 1999.

Thesis

ENGLISH ABSTRACT: Background: The provision of glucose (Glu) is beneficial during ischaemia (Opie, 1970). Part of Glu protection may be due to Glu oxidation, specifically the Krebs Cycle and oxidative phosphorylation (Lopaschuk, 1998). Therefore, 30 mM acetate (Ac) may hypothetically provide protection similar to 10 mM Glu providing that there is residual oxygen available to allow functioning of the Krebs Cycle and oxidative phosphorylation. Aim: The aim of this study was to establish an optimal Ac concentration at which the consequences of ischaemia were minimal, to determine whether the protective effects of Glu and. Ac is oxygen dependent, and to investigate whether equi-carbon concentrations of Ac and Giu would offer similar protection during low flow ischaemia. Materials and Methods: Isolated rat hearts (n = 6-8) were perfused (Langendorff, 95% 02, 5% CO2) with 5 mM Ac for 30 minutes, followed by 2 ml/min low flow ischaemia with 1 mM or 5 mM or 10 mM or 30 mM Ac or 10 mM Glu. Additional hearts were subjected to anoxia during the same period. All hearts were reperfused for 30 minutes under the preischaemic conditions. We measured the time to the onset of ischaemic contracture (TOIC), the percentage recovery of left ventricular developed pressure (L VDP), and tissue ATP, creatine phosphate, lactate, glycogen and cAMP content. Results: 5 mM and 10 mM Ac perfused hearts yielded optimal yet similar protection against the consequences of ischaemia. In addition, Ac (5 mM) and Glu (10 mM) treated hearts performed equally poorly in the absence of oxygen. This implies that the beneficial effects conferred by Glu is oxygen dependent, due possibly to the activity of the Krebs Cycle and oxidative phosphorylation. An equi-carbon concentration of Ac (30 mM) could not offer protection analogous to 10 mM Glu during oxygenated, low flow ischaemic conditions. Instead, 10 mM Glu provided optimal protection against ischaemia while 30 mM Ac was associated with accelerated TOIC, reduced ATP and glycogen levels, elevated lactate and· cAMP levels, and weakened function upon reperfusion. Conclusion: Glu provided maximal protection against the consequences of low flow ischaemia. However, this protection was dependent on the availability of oxygen, suggesting that oxidative phosphorylation and Krebs Cycle activity may contribute more to the protective effects of a particular substrate than previously anticipated.

AFRIKAANSE OPSOMMING: Agtergrond: Voorsiening van glukose (GIu) gedurende iskemie is voordelig (Opie, 1970). Giu beskerming mag gedeeitelik te danke wees aan Giu oksidasie, spesifiek oksidatiewe fosforilering en die Krebs siklus (Lopaschuk, 1998). Dus mag 30 mM asetaat (Ac) beskerming soortgeIyk aan die van 10 mM Giu verleen, indien claar genoeg suurstofbeskikbaar is om funksionering van die Krebs Siklus en oksidatiewe fosforilering toe te laat. Doel: Die doel van hierdie studie was om 'n optimale Ac konsentrasie vas te stel waar die gevolge van iskemie minimaal is, om te bepaal of die beskermingseffekte van Glu en Ac suurstof athanklik is, en om te ondersoek of ewe-kooistotkonsentrasies van Giu en Ac soortgelyke beskerming gedurende lae vioei iskemie sal bied. Metodes: Geisoleerde rotharte (n = 6-8) is vir 30 minute met 5 mM Ac geperfuseer (Langendorff, 95 % O2, 5 % CO2), gevoig deur 2 ml/min lae vloei iskemie met of 1mM, 5 mM, 10 mM, of 30 mM Ac, of 10 mM Glu. Addisionele harte is tydens dieselfde periode aan anoksie blootgestel. Alle harte is vir 30 minute geherperfuseer onder die pre-iskemiese toestande. Ons het die tydsduur tot die begin van iskemiese kontraksie (TOIC), die persentasie wat die linkerventrikulere ontwikkeide druk herstel (LVDP), en die weefsel ATP, kreatienfosfaat, laktaat, glikogeen en cAMP inhoud gemeet. Resultate: 5 mM en 10 mM Ac het optimale, maar soortgelyke beskerming teen die gevolge van iskemie gebied. Ac (5 mM) en Glu (10 mM) behandelde harte het, in die afwesigheid van suurstof, ewe swak resultate getoon. Dit impliseer dat -die voordelige effekte verleen deur Glu suurstof afhanklik is en moontlik te danke is aan die aktiwiteit van die Krebs sikius en oksidatiewe fosforilering. Ewe-kooistotko08entrasies van Ac (30 mM) kon me soortgelyke beskerming as 10 mM Glu gedurende lae vloei iskemie bied me. Terwyl Giu optimale beskerming teen iskemie gebied het, is Ac geassosieer met vervroegde TOIC, verlaagde ATP- en glikogeenvlakke, verhoogde laktaat- en cAMP-vlakke en swak: herstel van funksie tydens herperfusie. Gevolgtrekking: Glu het maksimale beskerming teen die gevolge van lae vloei iskemie gebied. Die beskerming is egter suurstof afhanklik wat aandui dat oxidatiewe fosforilasie en die Krebs Siklus 'n groter bydra het tot die beskennende efiekte van 'n spesifieke substraat as wat voorheen verwag is.

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