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First published on October 1, 2004; DOI: 10.1124/mol.104.004168

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Received for publication June 24, 2004.
Revised September 27, 2004.
Accepted for publication September 27, 2004.

Dynamics of Ca2+-dependent Cl- Channel Modulation by Niflumic Acid in Rabbit Coronary Arterial Myocytes

Jonathan Ledoux 1, Iain A. Greenwood 2, Normand Leblanc 3*

1 University of Montreal 2 St. George's Hospital Medical School 3 University of Nevada School of Medicine

* Address correspondence to: E-mail: nleblanc{at}med.unr.edu

Abstract

Calcium-activated chloride channels (ClCa) are crucial regulators of vascular tone by promoting a depolarizing influence on the resting membrane potential of vascular smooth muscle cells. Niflumic acid (NFA), a potent blocker of ClCa in vascular myocytes, was shown recently to cause inhibition and paradoxical stimulation of sustained ICl(Ca) in rabbit pulmonary artery myocytes. The aims of the present study were to investigate whether NFA produced a similar dual effect in coronary artery smooth muscle cells, and to determine the concentration-dependence and dynamics of such a phenomenon. Sustained ICl(Ca) evoked by intracellular Ca2+ clamped at 500 nM were dose-dependently inhibited by NFA (IC50 = 159 µM), and transiently augmented in a concentration-independent manner (10 µM to 1 mM) ~ 2-fold after NFA removal. However, the time to peak and duration of NFA-enhanced ICl(Ca) increased in a concentration-dependent fashion. Moreover, the rate of recovery was reduced by membrane depolarization, suggesting the involvement of a voltage-dependent step in the interaction of NFA leading to stimulation of ICl(Ca). Computer simulations based on a kinetic model involving low (Ki = 1.25 mM) and high (Ki < 30 µM) affinity sites could fairly well reproduce the properties of the NFA-modulated ICl(Ca).


Key words: Ion channel regulation, Ion transporters (SERCA, Na/K ATPase, CFTR), Molecular dynamics, Func. analysis receptor/ion channel mutants


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