| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
Prolongation of QT or QTc is one of the risk factors of sudden cardiac death in patients with diabetic mellitus. In several electrophysiological studies of ventricular cells from diabetic rat hearts, the decreases of outward currents, the transient outward current (Ito)and the steady state outward current (ISS) were noted. In order to clarify the genetic mechanisms of QT prolongation, abundance of mRNA of voltage-gated potassium channels (Kv 1.2, 1.4, 1.5, 2.1, 4.2 and 4.3) in ventricles was compared between rats with diabetes mellitus and age-matched control. Rats rendered diabetic by one shot injection of streptozotocin (65 mg/Kg body wt) were sacrificed after 4 weeks and hearts were removed for RNA analysis. In addition, a strain of WBN/Kob rat that gradually develops hyperglycemia was used as a model of genetic diabetes. At the age of 19 mo, hearts from WBN/Kob rats or age-matched controls were dissected and total RNAs were extracted. Northern blot analyses of Kv 1.2, Kv 1.4, Kv 1.
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5, Kv 2.1, Kv 4.2 and Kv 4.3 were performed using fragments of their cDNAs as probes. In rats injected with STD, the mRNA for Kv 4.2 was significantly decreased. The level of mRNA for Kv 1.2 in STZ-induced diabetic rats was also significantly lower than that in control rats, while the level of mRNA for Kv 1.4 in diabetic rats was significantly higher. There was no significant difference between mRNAs for Kv 1.5, Kv 2.1 and Kv 4.3 In WBN/Kob rats, there were tendencies of decreased Kv 1.2 mRNA and the decrease of Kv 1.4 as compared to control but these changes did not reach the statistical significance (n=10). As the abundances of Kv 4.2 and Kv 4.3 mRNA, that may cord the gene of Ito channel, were not decreased in ventricles of diabetic rats, it is difficult to attribute the decrease in Ito to the decreased transcription of Ito gene. Some unidentified post-transcriptional regulation mechanism(s) may be involved. While, the decreased level of mRNA of Kv 1.2 may contribute, at least in part, to the decreased outward current and the action potential prolongation observed in the ventricular cells from diabetic rats. Less
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