Protection by Cyclosporin A of Ischemia/Reperfusion-Induced Damage in Isolated Rat Hearts

Griffiths, Elinor J.; Halestrap, Andrew P.

doi:10.1006/jmcc.1993.1162

Cited by 533 publications

(343 citation statements)

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“…Although this phenomenon, called mitochondrial permeability transition (MPT), has been intensively studied with isolated mitochondria, its physiological relevance remains uncertain. Accumulating data show that MTP might be an important consequence of intracellular Caz+ redistribution in different in vivo processes such as hormonal [33] and cytokine [34] stimulation, apoptosis [35] and ischemia-reperfusion injury [36,371. The potential importance of the MPT for cellular function suggests that this process has to be regulated [lo-121.…”

Section: Discussionmentioning

confidence: 99%

“…The fact that NO can alter the sensitivity of mitochondria to MPT inducers might be important for some physiological and pathophysiological processes where the mitochondrial permeability transition is implicated. Thus, NO production might influence the development of such pathologies as drug hepatotoxicities [47], glutamate-mediated neuronal injury [48], ischaemidreperfusion [36,37,491, and reperfusion injury after limb revascularization [50] by modulating the amount of mitochondria under MPT state. For example, several studies have shown that NO production can protect the heart against ischaemiaheperfusion injury [51,52].…”

Section: Discussionmentioning

confidence: 99%

“…For example, several studies have shown that NO production can protect the heart against ischaemiaheperfusion injury [51,52]. On the other hand, it has been suggested that the MPT is likely to be involved in reperfusion injury [36,37,491. In the present report it was shown that increase of NO production resulted in the decrease of number of mitochondria undergoing a rapid permeability transition.…”

Section: Discussionmentioning

confidence: 99%

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Modulation of the Mitochondrial Permeability Transition by Nitric Oxide

Balakirev

Khramtsov

Zimmer

1997

European Journal of Biochemistry

105

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The influence of nitric oxide on mitochondrial permeability transition (MPT) phenomenon was studied. NO was generated by photolysis of S-nitroso-N-acetylcysteine, AcCys(NO), with green light (2 = 550 nm). Two distinct effects of nitric oxide on rat liver mitochondria were identified. First, NO accelerated an onset of swelling in Caz'-loaded mitochondria in a cyclosporin-A-sensitive manner acting as an inducer of permeability transition. This was, apparently, a result of irreversible alteration of mitochondrial function accompanying the inhibition of respiratory chain in the presence of calcium. Formation of ESR-visible iron-sulfur dinitrosyl complexes (g = 2.041) could also contribute to the irreversible changes resulting in MPT induction. Second, NO changed significantly the response of mitochondria to Ca'+/phosphate-induced MPT, acting as a regulator of permeability transition. In this case the action of nitric oxide led to division of the mitochondria into two subpopulations: one which underwent the rapid permeability transition and another in which the MPT was inhibited. The effect of NO on Ca2+/Pi-induced MPT was transient and resulted from reversible inhibition of cytochrome oxidase followed by the changes in transmembrane potential and Ca2+ distribution. The characteristic time of duration of these NO modulated effects depended on nitric oxide as well as on oxygen concentrations. With increasing NO at fixed oxygen concentrations, this time levelled off to reach a maximum value which was inversely related to the oxygen concentration. It is concluded that under physiological condition the duration of reversible NO effects on mitochondrial function could be determined by oxygen concentration.Keywords: nitric oxide ; mitochondrial permeability transition.Nitric oxide (NO) plays multiple roles in diverse physiological processes, including relaxation of smooth muscle, neurotransmission, inhibition of platelet aggregation and killing of pathogens [l]. At the present time a large body of evidence has accumulated suggesting an important role of NO and peroxynitrite (the product of NO interaction with superoxide) in modulation of mitochondrial function. It has been shown that nitric oxide can reversibly inhibit mitochondrial respiration by competing with oxygen at cytochrome oxidase [2, 31. On the other hand, the fonnation of peroxynitrite from NO and mitochondria-derived superoxide can cause the irreversible inhibition of complexes 1-111 leading to mitochondrial dysfunction [4, 51. It has been proposed that NO exerts some of its main physiological and pathological effects by shifting ATP/ADP due to inhibition of respiratory chain [6]. It has also been shown that nitric oxide influences the mitochondrial Caz+ metabolism. Thus both NO and peroxynitrite are able to induce mitochondrial Ca*+ efflux by distinct and apparently specific pathways 17, 81. Calcium efflux induced by nitric oxide could contribute significantly to cellular damage during NO overproduction [9].It is now generally believed that mitochondrial C...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Modulation of the Mitochondrial Permeability Transition by Nitric Oxide

Balakirev

Khramtsov

Zimmer

1997

European Journal of Biochemistry

105

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“…Mitochondrial Ca 2+ overload, oxidative stress, adenine nucleotide depletion and mitochondrial depolarization contribute to the pore opening. Inhibition of prolonged mPTP opening (high-conductance) during reperfusion with cyclosporine-A (CsA) or sanglifehrin-A (SfA) can reduce cardiomyocyte injury [73][74][75]. Conversely, evidence suggests that the transient (lowconductance) opening of mPTP during ischemic PC plays a role in cell survival [54].…”

Section: Mitochondrial Permeability Transition Porementioning

confidence: 99%

Role of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injury

Seubert¹,

Zeldin²,

Nithipatikom³

et al. 2007

Prostaglandins & Other Lipid Mediators

133

131

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Cardiomyocyte injury following ischemia-reperfusion can lead to cell death and result in cardiac dysfunction. A wide range of cardioprotective factors have been studied to date, but only recently has the cardioprotective role of fatty acids, specifically arachidonic acid (AA), been investigated. This fatty acid can be found in the membranes of cells in an inactive state and can be released by phospholipases in response to several stimuli, such as ischemia. The metabolism of AA involves the cycloxygenase (COX) and lipoxygenase (LOX) pathways, as well as the less well characterized cytochrome P450 (CYP) monooxygenase pathway. Current research suggests important differences with respect to the cardiovascular actions of specific CYP mediated arachidonic acid metabolites. For example, CYP mediated hydroxylation of AA produces 20-hydroxyeicosatetraenoic acid (20-HETE) which has detrimental effects in the heart during ischemia, pro-inflammatory effects during reperfusion and potent vasoconstrictor effects in the coronary circulation. Conversely, epoxidation of AA by CYP enzymes generates 5,6-, 8,9-, 11,12-and 14,15-epoxyeicosatrienoic acids (EETs) that have been shown to reduce ischemia-reperfusion injury, have potent anti-inflammatory effects within the vasculature, and are potent vasodilators in the coronary circulation. This review aims to provide an overview of current data on the role of these CYP pathways in the heart with an emphasis on their involvement as mediators of ischemia-reperfusion injury. A better understanding of these relationships will facilitate identification of novel targets for the prevention and/or treatment of ischemic heart disease, a major worldwide public health problem.

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“…Ce phénomène, dû à l'ouverture irréversible d'un pore non sélectif localisé dans la membrane interne de la mitochondrie, constitue probablement un événement majeur dans les deux types de mort cellulaire que sont la nécrose et l'apoptose [18,19]. Expérimentalement, on observe une ouverture du pore de transition après ischémie-reperfusion chez le rat, ainsi que l'atténua-tion des lésions cellulaires après administration de ciclosporine A, un bloqueur spécifique de ce «mégacanal» [20,21]. Des travaux récents, dont les nôtres, suggèrent que le préconditionne-ment pourrait moduler la transition de perméabilité mitochondriale au cours de l'ischémie-reperfusion [22,23].…”

Section: Du Mécanisme Au Traitementunclassified

Comment utiliser le paradigme de préconditionnement ischémique pour protéger le myocarde ?

Argaud

Ovize

2004

Med Sci (Paris)

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Le concept de préconditionnement est né en 1985 dans le laboratoire nord-américain dirigé par R.B. Jennings [1]. Les chercheurs ont montré que des occlusions coronariennes brèves (trop courtes pour provoquer une nécrose myocytaire) réalisées avant une occlusion prolongée (de durée suffisante pour provoquer un infarctus myocardique) peuvent réduire de façon très importante (50% à 75%) la taille finale de l'infarctus. Le fait de rendre le myocarde brièvement ischémique induit une protection endogène qui s'exprime lors d'une ischémie prolongée consécutive. Ce phénomène a été nommé preconditioning (préconditionnement). Tout se passe comme si le myocarde, «prévenu» par une première agression (ici de nature ischémique), mettait en jeu des mécanismes endogènes de défense le rendant capable de mieux tolérer une nouvelle agression à venir: il s'agit là d'un phénomène d'adaptation au stress. Des résultats prometteurs chez l'animal…Le préconditionnement constitue donc un traitement préventif de la lésion myocardique, l'intervention protectrice (épisode bref d'ischémie-reperfusion) précé-dant le développement de la lésion. La cardioprotection est nettement plus importante que celle obtenue avec les traitements connus à ce jour. Par ailleurs, elle s'étend au-delà de la limitation de la nécrose tissulaire: le précondition-nement limite égale-ment l'apoptose myocardique induite par l'épisode d'ischémie-reperfusion [2,3]. Il améliore la récupéra-tion contractile postischémique en raison de la limitation de la taille de la nécrose, et non pas du fait d'un effet protecteur propre sur l'appareil contractile [4,5]. Son effet sur les arythmies ventriculaires reste quant à lui débattu [6,7]. L'ischémie n'est pas le seul stimulus capable d'induire cette cardioprotection. L'hypoxie, le stress thermique, la stimulation par pacing, l'étirement myocardique sont susceptibles d'activer ces mécanismes de défense [8]. De nombreux agonistes (ou substances cardioactives) peuvent mimer ce phénomène dans certains modèles expérimentaux: agonistes A1/A3 de l'adénosine, bradykinine, opioïdes, angiotensine II, noradrénaline ou endothéline [9,10]. Il est bien évident que ces résul-tats expérimentaux laissent entrevoir la possibilité d'une manipulation pharmacologique de ce phénomène et, par conséquent, le développement de nouveaux agents anti-ischémiques. Le phénomène de préconditionnement a cependant des limites temporelles. D'une part, la protection qui se met en place dans les quelques minutes qui suivent la stimulation inductrice n'est efficace que si le myocarde, > Le préconditionnement ischémique est un concept né il y a une quinzaine d'années. Dans cet article, nous présentons les généralités sur la protection anti-ischémique qui en découle ainsi que la part du mécanisme qui a pu être éclaircie à ce jour. Nous discutons l'application clinique de ce phénomène et envisageons comment l'évo-lution récente du concept ainsi que les derniers travaux laissent entrevoir d'importants dévelop-pements dans un avenir proche. <

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Protection by Cyclosporin A of Ischemia/Reperfusion-Induced Damage in Isolated Rat Hearts

Cited by 533 publications

References 0 publications

Modulation of the Mitochondrial Permeability Transition by Nitric Oxide

Modulation of the Mitochondrial Permeability Transition by Nitric Oxide

Role of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injury

Comment utiliser le paradigme de préconditionnement ischémique pour protéger le myocarde ?

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