Mechanisms of α 1-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.