Anti-ischemic properties of a new spiro-cyclic benzopyran activator of the cardiac mito-KATP channel

Many activators of K-ATP channels exhibit cardioprotective effects, mainly mediated by channels expressed on mitochondria (mito-K-ATP) Previous results showed anti-ischemic effects of the spiro-cyclic derivative A, oil isolated rat hearts In this work this molecule was more extensively studied and diazoxide Was used as reference mito-K-ATP, opener The Studies were performed oil ail in vivo rat model of myocardial infarct and on heart-derived H9c2 cells exposed to ail anoxic: environment The mechanism of action was further investigated oil isolated rat heart mitochondria In the model of myocardial infarct Compound A and diazoxide produced significant cardioprotective effects, antagonised by the selective mito-K-ATP blocker 5-hydroxydecanoic acid (5-HD). Compound A, like diazoxide, produced modest and non-significant hypotensive responses. while the hyperglycacmic effects of diazoxide were not observed for the new compound Protective effects of compound A and diazoxide were also recorded in H9c2 cells and again were inhibited by 5-HD Compound A and diazoxide Caused swelling of cardiac mitochondria, in agreement with the profile of mito-K-ATP Openers Both compounds evoked concentration-dependent Ca2+-release from Ca2+-preloaded mitochondria, prevented mitochondrial Ca2+-uptake and caused mitochondrial membrane depolarisation These effects were antagonised by ATP, the endogenous K-ATP inhibitor. In conclusion, compound A exhibits a promising profile of an anti-ischemic agent, with a mechanism likely to be linked to the activation of mito-K-ATP channels, and, because of its chemical characteristics such as structural rigidity and chirality due to the spiro-cyclic moiety, represents an interesting template for development of analogues further improved in activity and selectivity (C) 2009 Elsevier Inc All rights reserved