title: Mechanisms of alpha1-adrenoceptor mediated QT prolongation in the diabetic rat heart.
abstract: 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.
authors.affiliation: 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
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.forename: Linlin
authors.initials: L
authors.lastname: Wang
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Guangxia
authors.initials: G
authors.lastname: Ni
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.forename: Bin
authors.initials: B
authors.lastname: Han
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Yu
authors.forename: Kelin
authors.initials: K
authors.lastname: Wang
authors.forename: Yueyang
authors.initials: Y
authors.lastname: Lai
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Zhou
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhu
mesh_terms: 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
chemical_list: D015221:Potassium Channels; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D013311:Streptozocin