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Objectives: A growing number of reports in the literature have been correlating cardiovascular alterations with the presence of chronic liver disease, such as cirrhosis and cholestasis. The objective of this work was to compare mitochondrial bioenergetics and calcium loading capacity in the hearts of rats injected with alpha-naphthylisothiocyanate (ANIT), a compound used to induce cholestasis in animal models., Methods: Female Wistar rats (n = 12) were randomly divided into two groups. One of the groups was injected with six weekly doses of ANIT. Each group was evaluated in terms of mitochondrial bioenergetic capacity and susceptibility to the mitochondrial permeability transition (MPT), a deleterious phenomenon associated with oxidative stress and excessive mitochondrial calcium accumulation., Results: Our data showed unequivocally that cardiac mitochondria of rats chronically injected with ANIT lost their ability to accumulate calcium, in a cyclosporin A sensitive manner. This was reflected in a higher calcium-dependent swelling rate and amplitude (p < 0.01). The RCI value, an index of mitochondrial integrity, was also lower in the ANIT-treated group (p < 0.05)., Conclusions: This suggests that during cholestasis development, cardiac mitochondria lose their normal ability to control cytosolic calcium due to increased susceptibility to the MPT. Our results may suggest an explanation for the occurrence of cardiomyopathies associated with cholestatic disease, which may persist even in the absence of serum markers for liver disease.

Objectives: The mitochondrial permeability transition (MPT) is an event related to severe oxidative stress (for example, during myocardial ischemia and reperfusion) and excessive mitochondrial calcium accumulation, also being implicated in cell death. In this study, we compared the effect of carvedilol on the cardiac MPT induced by calcium and phosphate (Ca/Pi) and calcium/carboxyatractyloside (Ca/Catr). Oxidative stress plays a major role in MPT induction by Ca/Pi, leading to the oxidation of protein thiol groups, in contrast with Ca/Catr, where such oxidation is secondary to MPT induction and is not caused by oxidative stress., Materials and Methods: Mitochondria were isolated from rat hearts and parameters related to MPT induction were evaluated (n = 5 for each inducer): mitochondrial swelling and oxidation of protein thiol groups (both measured by spectrophotometry)., Results: Using Ca/Pi, carvedilol protected mitochondria from MPT induction, particularly in its high conductance form. Its effect was demonstrated by analyzing the decrease in mitochondrial swelling amplitude. Simultaneously, we observed inhibition of protein thiol group oxidation (p < 0.001). By contrast, carvedilol did not show any protective effect with Ca/Catr., Conclusions: Carvedilol was only effective against the MPT when the oxidation of protein thiol groups was the cause and not the consequence of the MPT phenomenon. The results clearly show that during myocardial aggressions (ischemia and reperfusion, for example), the protective effect of carvedilol is primarily due to an antioxidant mechanism, inhibiting the production and effects of reactive oxygen species.

Objectives: The cardioprotective effects of carvedilol (CV) may be explained in part by interactions with heart mitochondria. The objective of this work was to study the protection afforded by CV against oxidative stress induced in isolated heart mitochondria by hypoxanthine and xanthine oxidase (HX/XO), a well-known source of reactive oxygen species (ROS) in the cardiovascular system., Methods: Mitochondria were isolated from Wistar rat hearts (n = 8) and incubated with HX/XO in the presence and in the absence of calcium. Several methods were used to assess the protection afforded by CV: evaluation of mitochondrial volume changes (by measuring changes in the optical density of the mitochondrial suspension), calcium uptake and release (with a fluorescent probe, Calcium Green 5-N) and mitochondrial respiration (with a Clark-type oxygen electrode)., Results: CV decreased mitochondrial damage associated with ROS production by HX and XO, as verified by the reduction of mitochondrial swelling and increase in mitochondrial calcium uptake. In the presence of HX and XO, CV also ameliorated mitochondrial respiration in the active phosphorylation state and prevented decrease in the respiratory control ratio (p < 0.05) and in mitochondrial phosphorylative efficiency (p < 0.001)., Conclusions: The data indicate that CV partly protected heart mitochondria from oxidative damage induced by HX and XO, which may be useful during myocardial ischemia and reperfusion. It is also suggested that mitochondria may be a priority target for the protective action of some compounds.

Diabetes is one of the most common metabolic diseases of our times. Specific cardiovascular alterations are often associated with the progression of this disease. Considerable controversy exists in the literature concerning the greater or lesser susceptibility of the diabetic heart to ischemia and reperfusion. Cardiac mitochondria may be fundamental to the differential susceptibility of the cardiomyocyte to pathologic phenomena, particularly those due to the induction of the degenerative process known as the mitochondrial permeability transition (MPT), which is triggered by excessive mitochondrial calcium accumulation. The MPT has been associated with cellular dysfunction resulting from ischemia and reperfusion. The objective of this work was to examine the susceptibility of mitochondria isolated from diabetic rats to the MPT, in comparison to healthy control rats of the same age. Cardiac mitochondria from the diabetic rats had higher calcium loading capacity before the development of the MPT, with a decreased incidence of MPTP-associated features. This was associated with a greater capacity to sustain multiple pulses of externally added calcium, simultaneously with maintenance of the transmembrane electrical potential and reduced swelling amplitude. This could mean that cardiomyocytes from diabetic hearts may indeed be less prone to dysfunctions resulting from ischemia and reperfusion, at least in milder diabetic conditions, thus explaining many reports in the literature.