Metabolic therapy: cardioprotective effects of orotic acid and its derivatives

Metabolic therapy involves the administration of a substance normally found in the human body to enhance cellular reactions involved in the pathogenesis of disease. Myocardial ischaemia/reperfusion injury represents a leading cause of morbidity and mortality, also in cardiovascular disease. Therapeutic strategies aimed at limiting cardiomyocyte death during the postischaemic reperfusion and in the perioperative settings are nowadays extensively studied. Conceived originally as a dietary constituent (known as vitamin B13) only, it is now apparent that most orotic acid is synthesized in the human body where it arises as an intermediate in the biosynthetic pathway of pyrimidine nucleotides. Previous investigations in the heart suggest that orotate and its derivatives could be of significant clinical benefit in the treatment of heart disease. The present brief review is concerned with the current knowledge of the major effects of these compounds in both experimental and clinical cardiology. The potential mechanisms and biochemical pathways responsible for cardioprotection are highlighted.Biomedical Reviews 2010; 21: 47-55

Modulation of mitochondrial respiratory function and ROS production by novel benzopyran analogues

A substantial body of evidence indicates that pharmacological activation of mitochondrial ATP-sensitive potassium channels (mKATP) in the heart is protective in conditions associated with ischemia/reperfusion injury. Several mechanisms have been postulated to be responsible for cardioprotection, including the modulation of mitochondrial respiratory function. The aim of the present study was to characterize the dose-dependent effects of novel synthetic benzopyran analogues, derived from a BMS-191095, a selective mKATP opener, on mitochondrial respiration and reactive oxygen species (ROS) production in isolated rat heart mitochondria. Mitochondrial respiratory function was assessed by high-resolution respirometry, and H2O2 production was measured by the Amplex Red fluorescence assay. Four compounds, namely KL-1487, KL-1492, KL-1495, and KL-1507, applied in increasing concentrations (50, 75, 100, and 150 �mol/L, respectively) were investigated. When added in the last two concentrations, all compounds significantly increased State 2 and 4 respiratory rates, an effect that was not abolished by 5-hydroxydecanoate (5-HD, 100 �mol/L), the classic mKATP inhibitor. The highest concentration also elicited an important decrease of the oxidative phosphorylation in a K+ independent manner. Both concentrations of 100 and 150 �mol/L for KL-1487, KL-1492, and KL-1495, and the concentration of 150 �mol/L for KL-1507, respectively, mitigated the mitochondrial H2O2 release. In isolated rat heart mitochondria, the novel benzopyran analogues act as protonophoric uncouplers of oxidative phosphorylation and decrease the generation of reactive oxygen species in a dose-dependent manner