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

Vincenzo Calderone , Lara Testai , Alma Martelli , Simona Rapposelli , Maria Digiacomo , Aldo Balsamo , Maria C. Breschi

Many activators of K channels exhibit cardioprotective effects, mainly mediated by channels expressed on mitochondria (mito-K). Previous results showed anti-ischemic effects of the spiro-cyclic derivative on isolated rat hearts. In this work this molecule was more extensively studied and diazoxide was used as reference mito-K opener. The studies were performed on an rat model of myocardial infarct and on heart-derived H9c2 cells exposed to an anoxic environment. The mechanism of action was further investigated on isolated rat heart mitochondria. In the model of myocardial infarct compound and diazoxide produced significant cardioprotective effects, antagonised by the selective mito-K blocker 5-hydroxydecanoic acid (5-HD). Compound , like diazoxide, produced modest and non-significant hypotensive responses, while the hyperglycaemic effects of diazoxide were not observed for the new compound. Protective effects of compound and diazoxide were also recorded in H9c2 cells and again were inhibited by 5-HD. Compound and diazoxide caused swelling of cardiac mitochondria, in agreement with the profile of mito-K openers. Both compounds evoked concentration-dependent Ca- release from Ca pre-loaded mitochondria, prevented mitochondrial Ca- uptake and caused mitochondrial membrane depolarisation. These effects were antagonised by ATP, the endogenous K inhibitor. In conclusion, compound exhibits a promising profile of an anti-ischemic agent, with a mechanism likely to be linked to the activation of mito-K 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.

Mots clés: myocardial ischemia/reperfusion; anti-ischemic drugs; mitochondrial K channel; benzopyran K activators; spirocyclic derivatives

Vincenzo Calderone, Lara Testai, Alma Martelli, Simona Rapposelli, Maria Digiacomo, et al.. Anti-ischemic properties of a new spiro-cyclic benzopyran activator of the cardiac mitoK channel. Biochemical Pharmacology, 2009, 79 (1), pp.39. ⟨10.1016/j.bcp.2009.07.017⟩. ⟨hal-00529098⟩