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Life Sci. 2009 Feb 13;84(7-8):250-6. doi: 10.1016/j.lfs.2008.12.007. Epub 2008 Dec 14.

Mechanisms of alpha1-adrenoceptor mediated QT prolongation in the diabetic rat heart.

Author information

1
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

Abstract

AIMS:

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.

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 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.

SIGNIFICANCE:

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.

PMID:
19133277
DOI:
10.1016/j.lfs.2008.12.007
[Indexed for MEDLINE]

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