Sildenafil citrate concentrations not affecting oxidative phosphorylation depress H2O2 generation by rat heart mitochondria |
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Authors: | Maria A S Fernandes Ricardo J F Marques Joaquim A F Vicente Maria S Santos Pedro Monteiro António J M Moreno José B A Custódio |
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Institution: | Departamento de Zoologia, Faculdade de Ciências e Tecnologia, Universidade de Coimbra, 3004-517 Coimbra, Portugal. mfer@ci.uc.pt |
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Abstract: | Sildenafil citrate (Viagra) is a potent and specific inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase
type 5 (PDE5), which exhibits cardioprotective action against ischemia/reperfusion injury in intact and isolated heart. The
mechanism of its cardioprotective action is not completely understood, but some results suggested that sildenafil exerts cardioprotection
through the opening of mitochondrial ATP-sensitive K+ channels (mitoKATP). However, the impact of sildenafil citrate per se on isolated heart mitochondrial function is unknown. The goal of this
study was to investigate the influence of the compound on mitochondrial function (bioenergetics, Ca2+-induced mitochondrial permeability transition, and hydrogen peroxide (H2O2) generation) in an attempt to correlate its known actions with effects on heart mitochondria. It was observed that sildenafil
citrate concentrations of up to 50 μM did not significantly affect glutamate/malate-supported respiration in states 2, 3,
4, oligomycin-inhibited state 3, and uncoupled respiration. The respiratory control ratio (RCR), the ADP to oxygen ratio (ADP/O),
the transmembrane potential (ΔΨ), the phosphorylation rate, and the membrane permeability to H+, K+ and Ca2+ were not affected either. However, sildenafil citrate decreased H2O2 generation by mitochondria respiring glutamate/malate, and also decreased the formation of superoxide radical (O2•−) generated in a hypoxantine/xantine oxidase system. It was concluded that sildenafil citrate concentrations of up to 50 μM
do not affect either rat heart mitochondrial bioenergetics or Ca2+-induced mitochondrial permeability transition, but it depresses H2O2 generation by acting as a superoxide dismutase (SOD)-mimetic. By preventing reactive oxygen species (ROS) generation, sildenafil
citrate may preserve heart mitochondrial function. |
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Keywords: | Antioxidants Heart Ischemia Mitochondrial bioenergetics Oxidative stress Permeability transition pore Reperfusion Sildenafil citrate Viagra |
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