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Sildenafil citrate concentrations not affecting oxidative phosphorylation depress H(2)O (2) generation by rat heart mitochondria.

Fernandes MA, Marques RJ, Vicente JA, Santos MS, Monteiro P, Moreno AJ, Custódio JB

Departamento de Zoologia, Faculdade de Ciências e Tecnologia, Universidade de Coimbra, 3004-517, Coimbra, Portugal, mfer@ci.uc.pt.

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 (mitoK(ATP)). 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, Ca(2+)-induced mitochondrial permeability transition, and hydrogen peroxide (H(2)O(2)) 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 muM 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 (DeltaPsi), the phosphorylation rate, and the membrane permeability to H(+), K(+) and Ca(2+) were not affected either. However, sildenafil citrate decreased H(2)O(2) generation by mitochondria respiring glutamate/malate, and also decreased the formation of superoxide radical (O (2) (*-) ) generated in a hypoxantine/xantine oxidase system. It was concluded that sildenafil citrate concentrations of up to 50 muM do not affect either rat heart mitochondrial bioenergetics or Ca(2+)-induced mitochondrial permeability transition, but it depresses H(2)O(2) generation by acting as a superoxide dismutase (SOD)-mimetic. By preventing reactive oxygen species (ROS) generation, sildenafil citrate may preserve heart mitochondrial function.

Published 24 January 2008 in Mol Cell Biochem, 309(1): 77-85.
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