Impact of captopril on cardiac mitochondrial function in an in-vivo animal model of atherosclerosis

Abstract

Recently, we have demonstrated that a twelve-week treatment with hypercholesterolemic atherogenic diet induced profound alterations in mitochondrial energy metabolism and oxidative capacity of isolated cardiac muscle’s mitochondria. The aim of the present study was to investigate the effects of treatment with an ACE inhibitor (captopril) on energy metabolism and oxidative capacity in cardiac muscle’s mitochondria using an in-vivo animal model of experimental atherosclerosis. Mitochondrial oxidative capacity was followed-up during the course of twelve weeks of atherogenic hypercholesterolic diet. Fifty five male Chinchilla rabbits, were randomized to one of four groups: a control group (A, n=17) received physiological saline orally; experimental group (B, n=18) received atherogenic 2% hypercholesterolemic diet; group C (n=10) received the atherogenic diet and two hours later on the aqueous solution of captopril (10 mg/kg/day); group D (n=10) received the aqueous solution of captopril, only. Isolation of mitochondrial fraction of the heart was performed by the method of Tyler. The oxygen consumption rate was studied at different respiration phases: as basal, unstimulated (V4) and as ADP-stimulated (V3), and expressed as indices of respiratory control ratio (RCR) and ADP/O. Hypercholesterolemic atherogenic diet induced profound alterations in mitochondrial energy metabolism and oxidative capacity. Basal oxygen consumption rate without ADP (V4) and the maximal ADP-stimulated respiration rate (V3) showed a marked reduction (quantitative changes i.e. dramatic decrease in oxidative capacities). The sensibility of mitochondria to ADP (ADP/O) was also reduced (qualitative change) in rabbits treated with the atherogenic diet (group B) compared to controls (group A). Respiratory control ratio was not significantly different among the studied groups. These results indicate that hypercholesterolemic atherogenic diet impairs mitochondrial oxidative capacity without affecting coupling of oxidation and phosphorilation. Captopril treatment had only limited effects on alterations of oxidative capacity in hypercholesterolemic rabbits. The main characteristic of oxidative capacity, i.e. the maximal respiration rate (V3), was not improved by captopril.