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

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.

Inhibition of aldose-reductase-2 by a benzofuroxane derivative bf-5m increases the expression of kcne1, kcnq1 in high glucose cultured H9c2 cardiac cells and sudden cardiac death

“…We have previously shown that the selective ALR2 inhibitor 5(6)-(benzo[𝑑]thiazol-2-ylmethoxy) benzofuroxane (BF-5m), a novel nonhydantoin noncarboxylic acid benzofuroxane derivative [ 18 , 19 ], reduced QT interval in isolated rat heart perfused with Krebs solution containing high glucose concentrations [ 11 ]. In order to gain insights into the molecular targets of BF-5m we translated the previous above observation on cultured embryonic rat heart ventricle H9c2 cells under high glucose stimulus and show here that the ALR2 inhibitor BF-5m is able to increase cell viability, by reducing the cytotoxic effects induced by hyperglycemia.…”

“…On this base the initial inhibition of the endogenous ALR2 with a benzofuroxane derivative BF-5m [ 11 ] represented a new and important strategy to indirectly approach high glucose-induced QT interval prolongation. Insights acquired here show for the first time that the blockade of the ALR2 with BF-5m causes changes of the expression of H9c2 KCNQ1/KCNE1 potassium channels subunits at the plasma membrane level and not at the level of the mitochondria after high glucose exposure.…”

“…Further findings obtained on isolated rat hearts perfused with high-glucose Krebs solution (33 mM) showed that the new ALR2 inhibitor benzofuroxane derivative 5(6)-(benzo[ d ]thiazol-2-ylmethoxy) benzofuroxane (BF-5m) supplies cardioprotection from QT prolongation induced by the presence of a high glucose concentration into the medium [ 11 ], probably due to an interference with the potassium ion channels at the level of cardiac myocytes.…”

Untitled

“…We have previously shown that the selective ALR2 inhibitor 5(6)-(benzo[ ]thiazol-2-ylmethoxy) www.oncotarget.com benzofuroxane (BF-5m), a novel nonhydantoin noncarboxylic acid benzofuroxane derivative [18,19], reduced QT interval in isolated rat heart perfused with Krebs solution containing high glucose concentrations [11]. In order to gain insights into the molecular targets of BF-5m we translated the previous above observation on cultured embryonic rat heart ventricle H9c2 cells under high glucose stimulus and show here that the ALR2 inhibitor BF-5m is able to increase cell viability, by reducing the cytotoxic effects induced by hyperglycemia.…”

“…On this base the initial inhibition of the endogenous ALR2 with a benzofuroxane derivative BF-5m [11] represented a new and important strategy to indirectly approach high glucose-induced QT interval prolongation. Insights acquired here show for the first time that the blockade of the ALR2 with BF-5m causes changes of the expression of H9c2 KCNQ1/KCNE1 potassium channels subunits at the plasma membrane level and not at the Merged images did not demonstrate a significant colocalization of KCNE1 with the mitochondria in H9c2 exposed to normal or high glucose medium and receiving DMSO 0.1 µM or BF-5m 0.01-0.025-0.05 µM pretreatment.…”