Inhibitory effect of carvedilol in the high-conductance state of the mitochondrial permeability transition pore

Abstract

The mitochondrial permeability transition is a widely studied, but poorly understood, phenomenon in mitochondrial bioenergetics. It has been recognised that this phenomenon is related to the opening of a protein pore in the inner mitochondrial membrane, and that opening of this pore is the cause of some forms of mitochondrial dysfunction. In this work, we propose that carvedilol, a multi-role cardioprotective compound, may act as an inhibitor of the high-conductance state of the mitochondrial permeability transition pore, a conclusion supported by the finding that carvedilol provides differential protection against mitochondrial swelling in sucrose and KCl-based media, and that it is unable to protect against calcium-induced depolarisation of the mitochondrial membrane. We also show that carvedilol inhibits the oxidation of mitochondrial thiol groups and that, beyond causing a slight depression of the membrane potential, it has no inhibitory effect on mitochondrial calcium uptake.A decrease in the number of oxidised protein thiol groups may be the main mechanism responsible for this selective inhibition of the permeability transition pore in heart mitochondria. These effects may be important for the role of carvedilol in some cardiac pathologies. q

Mitochondrial Permeability Transition Pore Opening as an Endpoint to Initiate Cell Death and as a Putative Target for Cardioprotection

“…The authors attributed the cardioprotection to inhibition of pore opening by carvedilol acting as an antioxidant, as opposed to its β-adrenergic antagonist properties. This conclusion was supported by the demonstration that carvedilol decreased the number of oxidized protein thiol groups in heart mitochondria [169].…”

Mitochondrial Involvement in Cardiac Apoptosis During Ischemia and Reperfusion: Can We Close the Box?

“…Oliveira et al has shown that carvedilol can prevent the MPT in rat heart by inhibiting the formation of high-conductance pores. The underlying mechanism appears to be the prevention of oxidation of membrane thiol groups, which are important in the formation of the MPTP [94,98,99]. Besides the cardioprotective properties described, members of our research team have reported that carvedilol inhibits the exogenous NADH dehydrogenase in rat heart mitochondria [100], which is described to play a key role in the cardiotoxicity of doxorubicin [101].…”

High Copper Levels Promotes Broiler Hepatocyte Mitochondrial Permeability Transition In Vivo and In Vitro

“…Mitochondrial swelling was measured by monitoring the decrease in absorbance at 540 nm [16]. The decrease in absorbance was measured by incubating 9 mg of mitochondrial protein in 3 mL of basic medium D (70 mM sucrose, 213 mM mannitol, 3 mM HEPES, 1 mM EGTA, 10 mM succinate, and 1 μM rotenone); the medium D was adjusted to pH 7.3 with Tris.…”