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Pergolide block of the cloned Kv1.5 potassium channels

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Abstract

Pergolide mesylate, an ergot-derivative dopamine receptor agonist, is prescribed for the management of patients with Parkinson’s disease. Pergolide caused vasoconstriction in a pulmonary artery. Kv1.5 channel is highly expressed in pulmonary arterial smooth muscle cells, where it plays an important role as a determinant of vascular tone. In the present study, we investigated the effects of pergolide on Kv1.5 stably expressed in Chinese hamster ovary cells using the whole-cell patch-clamp technique. The Kv1.5 block by pergolide was concentration-, time-, voltage-, and use-dependent. Pergolide blocked Kv1.5 currents in a concentration-dependent manner, with an IC50 value of 15.4 μM and a Hill coefficient of 1.7. The activation and inactivation of Kv1.5 were significantly accelerated by pergolide in a concentration-dependent manner. The apparent association and dissociation rate constants were 0.43 μM−1 s−1 and 8.34 s−1, respectively, with a K D value of 19.1 μM. Pergolide slowed deactivation kinetics of Kv1.5, resulting in a tail crossover phenomenon. The block of Kv1.5 by pergolide was voltage-dependent, increasing significantly at test potentials from −10 to +10 mV, whereas the current was reduced slightly with a shallower voltage dependence in the range between +20 and +50 mV (δ = 0.34). There was a significant hyperpolarizing shift in the voltage dependence of steady-state inactivation of Kv1.5. Pergolide produced a use-dependent Kv1.5 block at 1 and 2 Hz, and also slowed the time course for recovery from inactivation. These results suggest that pergolide has an affinity for the open and inactivated states of Kv1.5 channels.

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Acknowledgments

We thank Dr. Leonard K. Kaczmarek (Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA) for the Kv1.5 cDNA. 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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Authors and Affiliations

  1. Department of Physiology, Cell Death and Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, 137-701, South Korea

    Imju Jeong & Sang June Hahn

  2. Department of Pharmacology, Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Jeonbuk, 561-180, South Korea

    Bok Hee Choi

  3. Department of Physiology, College of Medicine, The Catholic University of Korea, 224 Banpo-daero, Seocho-gu, Seoul, 137-701, South Korea

    Sang June Hahn

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  1. Imju Jeong
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Correspondence to Sang June Hahn.

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Jeong, I., Choi, B.H. & Hahn, S.J. Pergolide block of the cloned Kv1.5 potassium channels. Naunyn-Schmiedeberg's Arch Pharmacol 386, 125–133 (2013). https://doi.org/10.1007/s00210-012-0776-5

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