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

Department of Physiology, University of Montréal (J.L.), and Research Centre, Montréal Heart Institute (J.L.), Montréal, Québec, Canada; Department of Basic Medical Sciences, Pharmacology & Clinical Pharmacology, St. George's Hospital Medical School, London, United Kingdom (I.A.G.); and Department of Pharmacology, Centre of Biomedical Research Excellence, University of Nevada School of Medicine Reno, Nevada (N.L.)

Calcium-activated chloride channels (Cl_Ca) 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 Cl_Ca in vascular myocytes, was shown recently to cause inhibition and paradoxical stimulation of sustained calcium-activated chloride currents [I_Cl(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 I_Cl(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 I_Cl(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 I_Cl(Ca). Computer simulations derived from a kinetic model involving low (K_i = 1.25 mM) and high (K_i < 30 µM) affinity sites could reproduce the properties of the NFA-modulated I_Cl(Ca) fairly well.

Address correspondence to: Dr. Normand Leblanc, Department of Pharmacology/Mail Stop 318, Center of Biomedical Research Excellence, Savitt Medical Sciences Building, Room 50, University of Nevada School of Medicine, Reno, NV 89557-0270. E-mail: NLeblanc{at}med.unr.edu

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