© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Inhibition of the pentose phosphate pathway decreases ischemia–reperfusion-induced creatine kinase release in the heart
aDepartment of Anaesthesiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
bDepartment of Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
cMetabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
* Corresponding author. Tel.: +31-20-566-5259; fax: +31-20-697-9004. Email address: c.j.zuurbier{at}amc.uva.nl
Objective: The oxidative pentose phosphate pathway (oxPPP) produces NADPH, which can be used to maintain glutathione in its reduced state (anti-oxidant; beneficial effects) or to produce radicals or nitric oxide (NO) through NADPH oxidase/NO synthase (detrimental effects). Changes in cytosolic redox status have been implicated in ischemic preconditioning (PC). This study investigates whether (1) PC affects mitochondrial redox state, (2) the oxPPP plays a protective or detrimental role in ischemia (I)–reperfusion (R) injury in the intact heart and (3) PPP is altered with PC. Methods: Isolated rat hearts were subjected to 40-min global I and 30-min R (CO, control). Ischemia was either preceded by three 5-min I/R periods (PC) and/or oxPPP inhibition by 6-aminonicotinamide (6AN) or NADPH oxidase/NO synthase inhibition by diphenyleneiodonium (DPI). NADH videofluorometry was used to determine mitochondrial redox state. PPP intermediates were determined in CO and PC hearts using tandem mass spectrometry. Results: PC reduced ischemic damage (creatine kinase, CK, release from 337±64 to 147±41 U/R/gdw) and contracture (from 59±5 to 31±3 mm Hg) and increased recovery of contractility (from 48±10% to 88±8%), as compared to CO. PC was without effect on NADH fluorometry. Inhibition of the oxPPP reduced injury (CK release: 91±24 U/R/gdw) to similar levels as PC, without improving contractility. Inhibition of NADPH oxidase/NO synthase mimicked the effects of oxPPP inhibition on injury (CK release: 140±22 U/R/gdw). Although levels of ribose-5P and (ribulose-5P+xylulose-5P) rose several fold during ischemia with minor changes in sedoheptulose-7P, demonstrating an active PPP in the heart, PC did not affect these levels. Conclusions: (1) PC can attenuate cardiac reperfusion injury without alterations in mitochondrial redox state; (2) inhibition of the oxPPP protects the heart against I/R-induced CK release; and (3) PC does not result in altered activity of the PPP.
KEYWORDS Energy metabolism; Ischemia; Necrosis; Preconditioning; Reperfusion
Time for primary review 21 days
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