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Effects of dapoxetine on cloned Kv1.5 channels expressed in CHO cells

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Abstract

The effects of dapoxetine were examined on cloned Kv1.5 channels stably expressed in Chinese hamster ovary cells using the whole-cell patch clamp technique. Dapoxetine decreased the peak amplitude of Kv1.5 currents and accelerated the decay rate of current inactivation in a concentration-dependent manner with an IC 50 of 11.6 μM. Kinetic analysis of the time-dependent effects of dapoxetine on Kv1.5 current decay yielded the apparent association (k +1 ) and dissociation (k −1 ) rate constants of 2.8 μM−1 s−1 and 34.2 s−1, respectively. The theoretical K D value, derived by k −1 /k +1 , yielded 12.3 μM, which was reasonably similar to the IC 50 value obtained from the concentration–response curve. Dapoxetine decreased the tail current amplitude and slowed the deactivation process of Kv1.5, which resulted in a tail crossover phenomenon. The block by dapoxetine is voltage-dependent and steeply increased at potentials between −10 and +10 mV, which correspond to the voltage range of channel activation. At more depolarized potentials, a weaker voltage dependence was observed (δ = 0.31). Dapoxetine had no effect on the steady-state activation of Kv1.5 but shifted the steady-state inactivation curves in a hyperpolarizing direction. Dapoxetine produced a use-dependent block of Kv1.5 at frequencies of 1 and 2 Hz and slowed the time course for recovery of inactivation. These effects were reversible after washout of the drug. Our results indicate that dapoxetine blocks Kv1.5 currents by interacting with the channel in both the open and inactivated states of the channel.

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Acknowledgment

We thank Dr. Kaczmarek (Yale University School of Medicine, USA) for the Kv1.5-transfected CHO cells. This work was supported by a grant from the Medical Research Center, Korea Science and Engineering Foundation, Republic of Korea (R13-2002-005-01002-0).

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No conflicts of interest, financial or otherwise, are declared by the authors.

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Authors and Affiliations

  1. Department of Physiology, Medical Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul, 137-701, South Korea

    Imju Jeong, Shin Hee Yoon & Sang June Hahn

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  1. Imju Jeong
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  2. Shin Hee Yoon
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Correspondence to Sang June Hahn.

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Jeong, I., Yoon, S.H. & Hahn, S.J. Effects of dapoxetine on cloned Kv1.5 channels expressed in CHO cells. Naunyn-Schmiedeberg's Arch Pharmacol 385, 707–716 (2012). https://doi.org/10.1007/s00210-012-0754-y

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