Beneficial Effect of Ursodeoxycholic Acid on High Glucose-Induced Long QT Interval Arrhythmia in Isolated Rat Heart

The aim of the present study was to investigate whether ursodeoxycholic acid (UDCA) could prevent the high glucose-induced long QT interval arrhythmia in isolated perfused rat heart Moreover, we studied whether UDCA could affect the cardiac expression of two arrhythmias-related miRNAs, miR-1 and miR-133 together with monitoring of caspase-3, caspase-9, ubiquitin-protesome system, Mn-SOD levels and NO bioavailability. Rat hearts perfused with standard Krebs solution containing 11.1 mmol D-glucose showed a cardiac QT interval of 107±11 ms and a coronary perfusion pressure (CPP) of 72±5 mmHg. These were increased by a Krebs containing 33.3 mmol D-glucose (e.g +98% QT interval; +79% CPP). The pretreatment of the rats with UDCA (150 mg/kg in drinking water for 12 weeks) prior to the heart excision while not affecting the QT interval and CPP in rats perfused with 11.1 mmol D-glucose it significantly reduced these parameters of -46% and -43% in rat perfused with D-glucose 33.3 mmol. The beneficial effect of UDCA on the cardiac instability caused by high glucose was also observed in an in vivo setting of rats made diabetics with streptozotocin (65 mg/kg i.p.). In these rats the basal cardiac parameters R-R interval, P-R interval and QT interval were not affected by UDCA. In both the in vitro and in vivo settings the reduction of QT interval operated by UDCA was associated to a reduction of the expression of miR-1 and miR-133, a reduction of the expression of the ubiquitin, proteasome, caspase-3, and caspase-9 into the hearts and by an increase of the expression of eNOS and nitrate/nitrite levels.