Uncoupler- and hypoxia-induced damage in the working rat heart and its treatment

Abstract

In the working rat heart we investigated heart function (aortic and coronary flow) during a normoxic, a hypoxic, and a reoxygenation phase after hypoxia. A depressed heart function was obtained by limiting oxygen supply and reducing left ventricular filling pressure (preload). After hypoxic perfusion for about 90 min, reoxygenation resulted in a 50% decrease of aortic flow. Lactate production and release increased immediately after oxygen deprivation and reached a maximum after about 35 min of hypoxia. Following reoxygenation, lactate release decreased. Lactate dehydrogenase became significant after reoxygenation. After stabilization of aortic flow at 50% in the reoxygenation phase different reagents were examined for their influence on heart performance. 1.5 mM of 2-Mercaptopropionylglycine (MPG) significantly increased aortic flow by 40%. The oxidized form of MPG (ox-MPG) at a concentration of 0.6 mM increased aortic flow by 125%. A molecular mechanism is proposed involving reorientation of the ATPase molecules at their membrane sites.

Ex Vivo Cardiotoxicity of Antineoplastic Casiopeinas Is Mediated through Energetic Dysfunction and Triggered Mitochondrial‐Dependent Apoptosis

“…There were no changes in MVO 2 with III-ia, III-Ea, or Doxo treatments; however, a 37%, 56%, and 74% decrease, respectively, in ATP content was observed (Figures 3(b) and 3(c) ). Thus, III-ia, III-Ea, and Doxo act similarly to CCCP (a mitochondrial uncoupler), which stimulates MVO 2 by uncoupling ATP synthesis from the mitochondrial electron transport [ 23 ]. III-ia and Doxo also decreased PCr levels.…”

Cardioprotection and mitochondrial S-nitrosation: Effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia–reperfusion injury

“…In an attempt to overcome such side-effects, the present study focused on enhancing mitochondrial S-nitrosation as a cardioprotective mechanism, using the reagent SNO-MPG. Due to its antioxidant properties, the free thiol MPG has previously been used as a cardioprotective agent in isolated myocytes and perfused hearts, although high doses (0.4-1 mM) were required to elicit protection [33,34,45,[56][57][58][59]. In the current study SNO-MPG (but not MPG) protected myocytes and hearts from IR injury at 10-20 μM, and it is proposed that this protection originated from enhanced delivery of SNO to the mitochondrion.…”

“…The latter is FDA approved for human clinical use [84], and therefore the in-vivo toxicology of SNO-MPG is expected to be similar to that of MPG. We consider it unlikely that the beneficial effects of SNO-MPG are mediated by MPG, since the concentrations of the latter required for cardioprotection are in the mM range [33,34,45,[56][57][58][59]. In addition, mM levels of MPG have been shown to be detrimental to IPC signaling, by scavenging ROS [12,59], but it is unlikely that 10 μM SNO-MPG would release sufficient MPG to elicit such effects.…”

ADP‐ and oligomycin‐sensitive redox behavior of F0 b thiol in ATPsynthase depends on neighbored primary structure: Investigations using 14‐C‐labeled alpha lipoic acid

“…2). Our previous findings [61][62][63][64]20,21,65] using 2-mercapto-propionylglycine (MPG) and the more recent results using alpha lipoic acid [3,11,34,39,47,50,66,68], could, at least in part, become explained by reversible blockade (R-S-MPG; R-S-LA), of reactive sulfhydryl groups at strategic membrane sites including the ATPsynthase with excessive reversible reactivity of the Fo b subunit preserving mobility and structure changes during ATP synthesis.…”