Lee Hyang Mi, Hahn Sang June, Choi Bok Hee
Department of Pharmacology, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54097, Korea.
Department of Physiology, Medical Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
Korean J Physiol Pharmacol. 2022 Mar 1;26(2):135-144. doi: 10.4196/kjpp.2022.26.2.135.
An antidiabetic drug, rosiglitazone is a member of the drug class of thiazolidinedione. Although restrictions on use due to the possibility of heart toxicity have been removed, it is still a drug that is concerned about side effects on the heart. We here examined, using Chinese hamster ovary cells, the action of rosiglitazone on Kv1.5 channels, which is a major determinant of the duration of cardiac action potential. Rosiglitazone rapidly and reversibly inhibited Kv1.5 currents in a concentration-dependent manner (IC = 18.9 μM) and accelerated the decay of Kv1.5 currents without modifying the activation kinetics. In addition, the deactivation of Kv1.5 current, assayed with tail current, was slowed by the drug. All of the results as well as the use-dependence of the rosiglitazone-mediated blockade indicate that rosiglitazone acts on Kv1.5 channels as an open channel blocker. This study suggests that the cardiac side effects of rosiglitazone might be mediated in part by suppression of Kv1.5 channels, and therefore, raises a concern of using the drug for diabetic therapeutics.
抗糖尿病药物罗格列酮是噻唑烷二酮类药物的一员。尽管因心脏毒性可能性而对其使用的限制已被解除，但它仍是一种令人担忧对心脏有副作用的药物。我们在此使用中国仓鼠卵巢细胞研究了罗格列酮对Kv1.5通道的作用，Kv1.5通道是心脏动作电位持续时间的主要决定因素。罗格列酮以浓度依赖性方式迅速且可逆地抑制Kv1.5电流（IC = 18.9 μM），并加速Kv1.5电流的衰减，而不改变激活动力学。此外，用尾电流测定的Kv1.5电流的失活被该药物减慢。所有这些结果以及罗格列酮介导的阻断的使用依赖性表明，罗格列酮作为一种开放通道阻滞剂作用于Kv1.5通道。这项研究表明，罗格列酮的心脏副作用可能部分是由Kv1.5通道的抑制介导的，因此，引发了对将该药物用于糖尿病治疗的担忧。
