Sandouka, A.; (2006) Carbon monoxide-releasing molecules (CO-RMs): effects on physiology and ischaemia-reperfusion injury in the kidney. Doctoral thesis , University of London.

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Abstract

Background: Although high concentrations of carbon monoxide (CO) are unquestionably toxic, emerging evidence reveals that CO at low concentrations plays a significant role in vasorelaxation, blockade of apoptotic pathways, suppression of inflammation and protection against ischaemia-reperfusion (I-R) injury. Our group has recently identified a series of compounds (CO-releasing molecules or CO-RMs) which exert important pharmacological activities by carrying and delivering CO to biological systems.;Aims: The present study was designed to evaluate the influence of CO released from CO-RMs on mitochondrial respiration and its consequences on renal haemodynamic, biochemical, and physiological parameters as well as to examine the possible beneficial effects of CO-RMs against I-R injury.;Methods: Parallel experiments were conducted using: 1) the isolated renal cortical rat mitochondria for evaluation of oxygen consumption, hydrogen peroxide production, and lipid peroxidation. 2) the ex vivo isolated perfused rabbit kidney (IPRK) model to measure the physiological and biochemical parameters and mitochondrial respiration for freshly harvested kidneys and kidneys exposed to ischaemic injury, and 3) an in vitro model of renal proximal tubular epithelial (LLC-PKi) cells to assess membrane integrity and metabolic activity.;Results: The major findings of this study indicate that CO modulates mitochondrial respiratory activity in isolated rat mitochondria. In IPRK model, CO reduces tubular reabsorption and increases urine and perfusion flow rate and glomerular filtration rate of freshly isolated kidneys. However, in IPRK model, kidneys flushed with a cold preservation solution supplemented with CO-RMs and stored at 4 C for 24 or 48 hr displayed at reperfusion a significant protective vasodilatory effect, improved renal function and mitochondrial respiration compared to control kidneys flushed with cold solution alone. Additionally, CO released from CO-RMs protects against preservation injury using the in vitro model of LLC-PKi cells. In contrast, in a warm I-R model using the IPRK circuit, CO was only beneficial by increasing the perfusate flow rate at reperfusion.;Conclusion: the results emphasize that CO liberated from CO-RMs has a protective vasodilatory effect, improves renal function and increases mitochondrial respiration after cold ischaemia and reperfusion. These findings suggest that CO-RMs could be used therapeutically in preservation solutions as an efficacious strategy to prevent the injury sustained by organs during cold storage prior to transplantation.

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