Abstract
Vesnarinone, a phosphodiesterase inhibitor, prolongs cardiac action potential duration by inhibiting the delayed rectifier K+current, IK. We examined the effect of this agent on human ether-a-go-go related gene (HERG) and KvLQT1/minK K+ channels heterologously expressed in human embryonic kidney 293T cells with the whole-cell patch-clamp technique. HERG channel current was inhibited by vesnarinone in a concentration-dependent manner, whereas KvLQT1/minK current was hardly affected by the drug. The inhibition of HERG current by vesnarinone became more prominent and faster as the membrane potential was more depolarized. The properties of inhibition could be described by a first order reaction between the drug and the channel that was apparently independent of HERG channel gating. Although the unbinding rate constant of the drug was constant, the apparent binding rate constant increased as the membrane was more depolarized and the drug concentration was raised. This model also could explain the fast recovery from the drug's effect at hyperpolarized potentials and its rate-dependent inhibition of HERG. Therefore, the effect of vesnarinone on the HERG-K+ current could be adequately described by a simple kinetic model of drug-channel interaction.
Footnotes
-
Send reprint requests to: Dr. Yoshihisa Kurachi, Department of Pharmacology II, Faculty of Medicine & Graduate School of Medicine, A7, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail:ykurachi{at}pharma2.med.osaka-u.ac.jp
- Abbreviations:
- PDE
- phosphodiesterase
- IK
- cardiac delayed rectifier K+current
- IKr
- rapidly activating component of cardiac delayed rectifier K+ current
- IKs
- slowly activating component of cardiac delayed rectifier K+ current
- HERG
- humanether-a-go-go related gene
- MiRP1
- minK-related peptide 1
- I-V
- current-voltage
- Received December 27, 1999.
- Accepted March 16, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|