Mechanisms of alpha1-adrenoceptor mediated QT prolongation in the diabetic rat heart.
OBJECTIVE
Diabetes mellitus is associated with changes of alpha(1)-adrenoceptor (alpha(1)-AR) on heart electrical function and expression. In this study, we investigated the ionic basis underlying abnormal alpha(1)-AR mediated QT prolongation in the diabetic rat hearts.


METHODS
Electrophysiological and biochemical techniques were used in Streptozotocin (STZ)-induced diabetic and control rat hearts.


RESULTS
In both control and diabetic rats, the alpha(1)-AR agonist, phenylephrine (PE, 10-100 microM) 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 alpha(1A)-ARs were over-expressed in the left ventricular tissues of the diabetic rat hearts at both the mRNA and the protein levels.


CONCLUSIONS
These data suggested that in diabetic hearts, a greater sensitivity of the alpha(1A)-AR mediated the larger suppression of I(ss) and resulted in a more prolonged APD(90) and QTc. Thus, higher alpha(1A)-AR expression levels in diabetic heart may underlie this type of diabetic cardiomyopathy and suggests that alpha(1A)-AR may serve as a therapeutic target.
Chen
Long
L
National Standard Laboratory of Pharmacology for Chinese Materia Medica, Research Center of Acupuncture and Pharmacology, Nanjing University of Chinese Medicine, Nanjing 210029, China. longchen@njutcm.edu.cn
Wang
Linlin
L
Xu
Bin
B
Ni
Guangxia
G
Yu
Li
L
Han
Bin
B
Yu
Xiaochun
X
Wang
Kelin
K
Lai
Yueyang
Y
Zhou
Shuyuan
S
Zhu
Quan
Q
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004562:Electrocardiography; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000145:classification / Q000235:genetics / Q000502:physiology*; D013311:Streptozocin
D015221:Potassium Channels; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D013311:Streptozocin