Effects of the New Aldose Reductase Inhibitor Benzofuroxane Derivative BF-5m on High Glucose Induced Prolongation of Cardiac QT Interval and Increase of Coronary Perfusion Pressure.

C Di Filippo,F Ferraraccio,M D’Amico,R Maisto,N Di Carluccio,C La Motta,B Ferraro,S Sartini,F Rossi,M C Trotta

doi:10.1155/2016/5281267

Abstract

This study investigated the effects of the new aldose reductase inhibitor benzofuroxane derivative 5(6)-(benzo[d]thiazol-2-ylmethoxy)benzofuroxane (BF-5m) on the prolongation of cardiac QT interval and increase of coronary perfusion pressure (CPP) in isolated, high glucose (33.3 mM D-glucose) perfused rat hearts. BF-5m was dissolved in the Krebs solution at a final concentration of 0.01 μM, 0.05 μM, and 0.1 μM. 33.3 mM D-glucose caused a prolongation of the QT interval and increase of CPP up to values of 190 ± 12 ms and 110 ± 8 mmHg with respect to the values of hearts perfused with standard Krebs solution (11.1 mM D-glucose). The QT prolongation was reduced by 10%, 32%, and 41%, respectively, for the concentration of BF-5m 0.01 μM, 0.05 μM, and 0.1 μM. Similarly, the CPP was reduced by 20% for BF-5m 0.05 μM and by 32% for BF-5m 0.1 μM. BF-5m also increased the expression levels of sirtuin 1, MnSOD, eNOS, and FOXO-1, into the heart. The beneficial actions of BF-5m were partly abolished by the pretreatment of the rats with the inhibitor of the sirtuin 1 activity EX527 (10 mg/kg/day/7 days i.p.) prior to perfusion of the hearts with high glucose + BF-5m (0.1 μM). Therefore, BF-5m supplies cardioprotection from the high glucose induced QT prolongation and increase of CPP.

Highlights

Hyperglycemia during the diabetes has detrimental effects on various organs including eye, kidney, central nervous system, and heart [1]
Since the action of ALR2 on glucose metabolism is linked to depletion into the cells of the cofactor nicotinamide adenine dinucleotide (NAD)+ [11] and SIRT1 is a NAD1-dependent protein deacetylase which belongs to a class of proteins that lead to improved energy consumption, limitation of oxidative stress, and reduced DNA damage [12, 13], the second aim of the study was to investigate whether there is an involvement of the sirtuin 1 (SIRT1) in the cardiac effects of benzofuroxane derivative 5(6)-(benzo[d]thiazol-2ylmethoxy)benzofuroxane (BF-5m)
A discrete preservation of the heart structure was seen in rat hearts perfused with high glucose + BF-5m with an almost intact structure of the tissue

Summary

Introduction

Hyperglycemia during the diabetes has detrimental effects on various organs including eye, kidney, central nervous system, and heart [1]. The most dangerous consequence of the hyperglycemia is the prolongation of the cardiac QT interval, which leads diabetic patients to sudden death [2]. Increased interest has gained the discovery of new drugs that may modulate pathways involved in glucose metabolism and hyperglycemia-induced modifications, in order to produce cardiovascular protection. In this context, one pathway that could be targeted is the aldose reductase (ALR2), because it contributes to the deleterious actions of hyperglycemia onto the cardiovascular system by inducing oxidative damage into the heart following diabetes [5,6,7,8,9]

Objectives

Methods

Results

Conclusion