Postischemic recovery and oxidative stress are independent of nitric-oxide synthases modulation in isolated rat heart.
ABSTRACT During myocardial ischemia and reperfusion, nitric oxide ((.)NO) was shown to exert either beneficial or detrimental effects. Uncoupled (.)NO synthases (NOS) can generate superoxide anion under suboptimal concentrations of substrate and cofactors. The aim of our study was to investigate the role of NOS modulation on 1) the evolution of functional parameters and 2) the amount of free radicals released during an ischemia-reperfusion sequence. Isolated perfused rat hearts underwent 30 min of total ischemia, followed by 30 min of reperfusion in the presence of N(G)-nitro-D- or L-arginine methyl ester (NAME, 100 microM) or of D- or L-arginine (3 mM). Functional parameters were recorded and coronary effluents were analyzed with electron spin resonance to identify and quantify the amount of alpha-phenyl-N-tert-butylnitrone spin adducts produced during reperfusion. The antioxidant capacities of the compounds were determined with the oxygen radical absorbance capacity test. L-NAME-treated hearts showed a reduction of coronary flow and contractile performance, although neither L-NAME nor L-arginine improved the recovery of coronary flow, left end diastolic ventricular pressure, rate pressure product, and duration of reperfusion arrhythmia, compared with their D-specific enantiomers. A large and long-lasting release of alkyl/alkoxyl radicals was detected upon reperfusion, but no differences of free radical release were observed between D- and L-NAME or D- and L-arginine treatment. These results may indicate that, in our experimental conditions, cardiac NOS might not be a major factor implicated in the oxidative burst that follows a global myocardial ischemia.
- [Show abstract] [Hide abstract]
ABSTRACT: Calpains are a large family of cytosolic cysteine proteases composed of at least fourteen distinct isoforms. The family can be divided into two groups on the basis of distribution: ubiquitous and tissue-specific. Our current knowledge about calpains properties apply mainly to the ubiquitous isozymes, micro- and milli-calpain (classic calpains). These forms are activated after autolysis. Translocation and subsequent interactions with phospholipids of these enzymes increase their activity. Calpains are able to cleave a subset of substrates, as enzymes, structural and signalling proteins. Cardiac pathologies, such as heart failure, atrial fibrillation or clinical states particularly ischemia reperfusion, are associated with an increase of cytosolic calcium and in this regards, calpain activation has been evoked as one of the mediators leading to myocardial damage. Calpain activities have been shown to be increased in hearts experimentally subjected to ischemia reperfusion or during hypertrophy, but also in atrial tissue harvested from patients suffering from atrial fibrillations. These activities have been related to an increase of the proteolysis of different myocardial components, particularly, troponins, which are major regulators of the contraction of cardiomyocytes. Moreover, recent works have demonstrated that calpains are involved in the development of myocardial cell death by necrosis or apoptosis.Annales de Cardiologie et d Angéiologie 09/2004; 53(5):259-266. · 0.30 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Small amounts of carbon monoxide (CO) are continuously produced in mammals. The intracellular levels of this gaseous molecule can markedly increase under stressful conditions following the induction of heme oxygenases (HO), ubiquitous enzymes responsible for the catabolism of heme. The development of a technology concerning the CO-releasing molecules (CO-RMs) that control the delivery and action of CO under different pathological conditions represents a major step forward in the development of CO-based pharmaceuticals with therapeutic applications. CO is important for the homeostatic control of cardiovascular functions. Abnormal metabolism and function of CO contribute to the pathogenesis and development of hypertension. Another vascular disease in which the role of CO has been evaluated is pulmonary arterial hypertension. Important results have been reported in which CO prevents intimal hyperplasia by arresting hyperproliferative vascular smooth muscle cells as well as increased mobilization and recruitment of bone-marrow-derived progenitor cells. Transplantation has been a field of research, in which most studies have investigated the beneficial properties of CO-RMs. CO gas and CO-RMs have produced promising results in the preservation of organs for transplantation. The anti-inflammatory properties of CO and CO-RMs have been demonstrated in a multitude of animal models of inflammation, suggesting a possible therapeutic application for inflammatory diseases. Despite therapeutic benefit in animal model studies, the efficacy of CO in humans remains unclear. Further studies are expected to better understand the pharmacokinetics as well as long- and short-term effects of CO-RMs.Réanimation 01/2011; 21(2).
- [Show abstract] [Hide abstract]
ABSTRACT: Nitric oxide ((•)NO) is synthetized enzymatically from L-arginine (L-Arg) by three NO synthase isoforms, iNOS, eNOS and nNOS. The synthesis of NO is selectively inhibited by guanidino-substituted analogs of L-Arg or methylarginines such as asymmetric dimethylarginine (ADMA), which results from protein degradation in cells. Many disease states, including cardiovascular diseases and diabetes, are associated with increased plasma levels of ADMA. The N-terminal catalytic domain of these NOS isoforms binds the heme prosthetic group as well as the redox cofactor, tetrahydrobiopterin (BH4) associated with a regulatory protein, calmodulin (CaM). The enzymatic activity of NOS depends on substrate and cofactor availability. The importance of BH4 as a critical regulator of eNOS function suggests that BH4 may be a rational therapeutic target in vascular disease states. BH4 oxidation appears to be a major contributor to vascular dysfunction associated with hypertension, ischemia/reperfusion injury, diabetes and other cardiovascular diseases as it leads to the increased formation of oxygen-derived radicals due to NOS uncoupling rather than NO. Accordingly, abnormalities in vascular NO production and transport result in endothelial dysfunction leading to various cardiovascular disorders. However, some disorders including a wide range of functions in the neuronal, immune and cardiovascular system were associated with the over-production of NO. Inhibition of the enzyme should be a useful approach to treat these pathologies. Therefore, it appears that both a lack and excess of NO production in diseases can have various important pathological implications. In this context, NOS modulators (exogenous and endogenous) and their therapeutic effects are discussed.Pharmacology [?] Therapeutics 07/2013; · 7.75 Impact Factor