Browsing by Author "Moreno, AJ"
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- Carvedilol improves energy production during acute global myocardial ischaemiaPublication . Monteiro, P; Duarte, AI; Moreno, AJ; Gonçalves, L; Providência, LACardiac mitochondria may become dysfunctional during ischaemia, thus compromising cardiomyocyte function. Carvedilol is an alpha(1)/beta-adrenoceptor antagonist with antioxidant, neuroprotective, cardioprotective and vascularprotective properties, and is used to treat hypertension, myocardial ischaemia and congestive heart failure. However, its impact on mitochondrial function during acute prolonged ischaemia is unknown. We aimed to study the effect of carvedilol on cardiac mitochondrial function during acute ischaemia, using Wistar rat hearts perfused with a Langendorff system, and then submitted to ischaemia in the presence and absence of carvedilol. We determined the electrical potential of the mitochondrial membrane, O(2) consumption by the respiratory chain, energy charge and the activity of the mitochondrial respiratory chain complexes. In our model, carvedilol had a preferential action on phosphorylation, increasing the mitochondrial energy charge (0.76+/-0.03 vs. 0.65+/-0.01 arbitrary units; P<0.05) and decreasing the phosphorylation lag phase (28.64+/-4.23 vs. 62.4+/-11.63 s; P<0.05) during ischaemia. The larger amount of energy available allowed the preservation of the electrical potential (201.2+/-2.45 vs. 186.66+/-3.36 mV;P<0.05), thus improving mitochondrial function during acute prolonged ischaemia
- Carvedilol: Relação Entre A Actividade Antioxidante e Inibição da Transição de Permeabilidade MitocondrialPublication . Oliveira, PJ; Esteves, T; Rolo, AP; Monteiro, P; Gonçalves, L; Palmeira, CM; Moreno, AJOBJECTIVES: 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.
- Familial camptodactylyPublication . Brites, MM; Moreno, AJ; Salgado, M; Poiares-Baptista, ACamptodactyly is a permanent flexion deformity at the interphalangeal joints, usually at the proximal, interphalangeal joints. It is by far most commonly encountered in the little finger, but it can occur in any of the others, and may be associated with a deformity in the little finger or not. It is usually bilateral. It can also appear in the toes, the second toe being the most frequently affected. This deformity can appear in two different situations: it can occur in isolation, or can be a part of a malformative syndrome. It can also be sporadic or be transmitted as an autosomal dominant trait [1, 5, 7, 8]. We report a case of familial camptodactyly not associated with any other disorders: the differential diagnoses included scleroderma and Dupuytren's contracture.
- Histological changes and impairment of liver mitochondrial bioenergetics after long-term treatment with alpha-naphthyl-isothiocyanate (ANIT)Publication . Palmeira, CM; Ferreira, FM; Rolo, AP; Oliveira, PJ; Santos, MS; Moreno, AJ; Cipriano, MA; Martins, MI; Seiça, RThis study was designed to evaluate the effects of long-term treatment with alpha-naphthyl-isothiocyanate (ANIT) on liver histology and at the mitochondrial bioenergetic level. Since, ANIT has been used as a cholestatic agent and it has been pointed out that an impairment of mitochondrial function is a cause of hepatocyte dysfunction leading to cholestatic liver injury, serum markers of liver injury were measured and liver sections were analyzed in ANIT-treated rats (i.p. 80 mg/kg/week x 16 weeks). Mitochondrial parameters such as transmembrane potential, respiration, calcium capacity, alterations in permeability transition susceptibility and ATPase activity were monitored. Histologically, the most important features were the marked ductular proliferation, proliferation of mast cells and the presence of iron deposits in ANIT-treated liver. Mitochondria isolated from ANIT-treated rats showed no alterations in state 4 respiration, respiratory control ratio and ADP/O ratio, while state 3 respiration was significantly decreased. No changes were observed on transmembrane potential, but the repolarization rate was decreased in treated rats. Consistently with these data, there was a significant decrease in the ATPase activity of treated mitochondria. Associated with these parameters, mitochondria from treated animals exhibited increased susceptibility to mitochondrial permeability transition pore opening (lower calcium capacity). Since, human cholestatic liver disease progress slowly overtime, these data provide further insight into the role of mitochondrial dysfunction in the process.
- Impacto do Carvedilol Sobre O Dano Mitocondrial Induzido Por Hipoxantina/xantina Oxidase: Que Papel Na Isquemia e Reperfusão do Miocárdio?Publication . Oliveira, PJ; Rolo, AP; Monteiro, P; Gonçalves, L; Palmeira, CM; Moreno, AJOBJECTIVES: 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.
- Linfangioma circunscrito neviformePublication . Guiote, MV; Moreno, AJ; Vieira, R; Tellechea, O; Naranjo, R; Figueiredo, A
- O Piruvato Melhora A Energética Mitocondrial Num Modelo Animal Ex-vivo de Isquemia Miocárdica GlobalPublication . Monteiro, P; Duarte, AI; Moreno, AJ; Gonçalves, L; Providência, LAPyruvate is an energy substrate with known cardioprotective activity. We know now that this is due not only to its antioxidant activity, but also to its reduction of intracellular acidosis, modulation of intracytosolic calcium and improvement of cardiomyocyte contractility. However, the role of cardiac mitochondria in such positive effects has only recently begun to be understood and the exact mechanisms of the effect of pyruvate on mitochondria are still largely unknown. Aiming to study the effect of pyruvate on cardiac mitochondrial function during acute ischemia, we used an ex-vivo animal model, perfused in a Langendorff system and then subjected to ischemia in the presence and absence of pyruvate. We evaluated the mitochondrial membrane electrical potential, the respiratory chain O2 consumption (and respiratory control ratio) and the energy charges generated with different energy substrates. We conclude that pyruvate has some effect on the mitochondrial oxidative system (by non-significantly improving the respiratory control ratio), but its main action is on the phosphorylation system, significantly decreasing the time taken to complete a phosphorylation cycle (lag phase) and improving ATP production (increase in energy charge), thus allowing better maintenance of mitochondrial membrane structure, with consequent improvement of the electrical potential after a phosphorylation cycle. These findings have enabled better understanding of the mechanisms behind pyruvate cytoprotection in ischemic cardiomyopathy, clearly highlighting the essential role of cardiac mitochondria in this process.
- Protective effect of trimetazidine on myocardial mitochondrial function in an ex-vivo model of global myocardial ischemiaPublication . Monteiro, P; Duarte, AI; Gonçalves, L; Moreno, AJ; Providência, LATrimetazidine is an anti-ischemic drug whose cytoprotective mechanisms are not yet fully understood (but until now mainly related to the trimetazidine-induced "metabolic shift" from lipid beta-oxidation to glucose aerobic oxidation). We studied the effect of trimetazidine on the mitochondrial function of ischemic Wistar rat hearts perfused with glucose, using a model of ex-vivo perfusion (Langendorff system). We measured the electrical potential of the mitochondrial membrane, O2 consumption by the respiratory chain, energy charges generated and the enzyme activities of the respiratory chain complexes. In this model, trimetazidine had a preferential action on the oxidative system (mainly on complex I), increasing its enzyme activity and decreasing O2 consumption after phosphorylation; this could decrease oxygen free radical production and increase mitochondrial integrity, thus allowing the maintenance of the electrical potential. These results allow us to better understand the cytoprotective effects of trimetazidine in coronary artery disease.
- Vantagens Na Utilização do Carvedilol Em Relação Ao Propranolol Na Protecção da Função Mitocondrial CardíacaPublication . Oliveira, PJ; Rolo, AP; Sardão, VA; Monteiro, P; Gonçalves, L; Providência, LA; Palmeira, CM; Moreno, AJBACKGROUND: Carvedilol is a neurohormonal antagonist of multiple action which is used in clinical practice for the treatment of congestive heart failure, mild to moderate hypertension and myocardial infarction. Previous results from our group have demonstrated that one of the main targets for the protective effect of carvedilol is the cardiac mitochondrial network. In-this work, we compare the effect of carvedilol with propranolol in different models of mitochondrial dysfunction and in the generation of transmembrane electric potential (EP). We further tested if carvedilol was able to inhibit the mitochondrial permeability transition (MPT) induced by doxorubicin and calcium-dependent cytochrome c release, a phenomenon frequently associated with apoptotic cell death. METHODS: Cardiac mitochondria were isolated by differential centrifugation. Oxygen consumption and mitochondrial EP were determined using an oxygen electrode and a tetraphenylphosphonium-sensitive electrode, respectively. Changes in mitochondrial volume and the release of cytochrome c were measured with spectrophotometric techniques. RESULTS: Propranolol, compared with carvedilol, had only a marginal effect, not only in protection against MPT induction, but also against oxygen consumption linked to the oxidation of external NADH, a process that is considered by several authors as key in the cardiotoxicity of doxorubicin. Regarding EP generation, propranolol had no effect, in contrast to carvedilol, which was confirmed to act as a protonophore. For the first time we also show that carvedilol inhibits the MPT induced by doxorubicin and calcium-dependent cytochrome c release. CONCLUSIONS: With this work, we further support the notion that carvedilol is effective in several models of mitochondrial dysfunction, particularly those involving oxidative stress. The results demonstrate that for some pathological conditions, carvedilol and propranolol have different mechanisms of action at the sub-cellular level, as propranolol seems to lack effectiveness in the protection of cardiac mitochondria.