Mechanisms of α1-adrenoceptor mediated QT prolongation in the diabetic rat heart

Abstract Aims Diabetes mellitus is associated with changes of α 1 -adrenoceptor (α 1 -AR) on heart electrical function and expression. In this study, we investigated the ionic basis underlying abnormal α 1 -AR mediated QT prolongation in the diabetic rat hearts. Main methods Electrophysiological and biochemical techniques were used in Streptozotocin (STZ)-induced diabetic and control rat hearts. Key findings In both control and diabetic rats, the α 1 -AR agonist, phenylephrine (PE, 10–100 µM) prolonged the rate-corrected QT intervals (QTc) and action potential durations at 30% (APD 30 ) and 90% (APD 90 ) repolarization levels with the increased QTc and APD 90 significantly greater in diabetic rats. PE significantly decreased the transient outward K + current ( I to ) and the steady-state K + current ( I ss ) in both control and diabetic rats but had no effects on the delayed rectifier K + current ( I k ). However, PE induced a greater reduction mainly in the I ss , but not I to , in diabetic rats. Furthermore, using RT–PCR and Western blot analyses, we found that α 1A -ARs were over-expressed in the left ventricular tissues of the diabetic rat hearts at both the mRNA and the protein levels. Significance These data suggested that in diabetic hearts, a greater sensitivity of the α 1A -AR mediated the larger suppression of I ss and resulted in a more prolonged APD 90 and QTc. Thus, higher α 1A -AR expression levels in diabetic heart may underlie this type of diabetic cardiomyopathy and suggests that α 1A -AR may serve as a therapeutic target.