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Updated: Aug 25, 2026
Model of Ischemia and Reperfusion Injury in Rabbits
Published on: November 3, 2023
Inhibition of the pentose phosphate pathway decreases ischemia-reperfusion-induced creatine kinase release in the
C J Zuurbier1, O Eerbeek, P T Goedhart
1Department of Anaesthesiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. c.j.zuurbier@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.
