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

AimsDiabetes mellitus is associated with changes of α1-adrenoceptor (α1-AR) on heart electrical function and expression. In this study, we investigated the ionic basis underlying abnormal α1-AR mediated QT prolongation in the diabetic rat hearts.Main methodsElectrophysiological and biochemical techniques were used in Streptozotocin (STZ)-induced diabetic and control rat hearts.Key findingsIn both control and diabetic rats, the α1-AR agonist, phenylephrine (PE, 10–100 µM) prolonged the rate-corrected QT intervals (QTc) and action potential durations at 30% (APD30) and 90% (APD90) repolarization levels with the increased QTc and APD90 significantly greater in diabetic rats. PE significantly decreased the transient outward K+ current (Ito) and the steady-state K+ current (Iss) in both control and diabetic rats but had no effects on the delayed rectifier K+ current (Ik). However, PE induced a greater reduction mainly in the Iss, but not Ito, in diabetic rats. Furthermore, using RT–PCR and Western blot analyses, we found that α1A-ARs were over-expressed in the left ventricular tissues of the diabetic rat hearts at both the mRNA and the protein levels.SignificanceThese data suggested that in diabetic hearts, a greater sensitivity of the α1A-AR mediated the larger suppression of Iss and resulted in a more prolonged APD90 and QTc. Thus, higher α1A-AR expression levels in diabetic heart may underlie this type of diabetic cardiomyopathy and suggests that α1A-AR may serve as a therapeutic target.