Dynamics of Ca2+-dependent Cl- channel modulation by niflumic acid in rabbit coronary arterial myocytes

被引:29
作者
Ledoux, J
Greenwood, IA
Leblanc, N
机构
[1] Univ Nevada, Sch Med, Dept Pharmacol, Ctr Biomed Res Excellence, Reno, NV 89557 USA
[2] Univ Montreal, Dept Physiol, Montreal, PQ H3C 3J7, Canada
[3] Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada
[4] Univ London St Georges Hosp, Sch Med, Dept Basic Med Sci Pharmacol & Clin Pharmacol, London SW17 0RE, England
关键词
D O I
10.1124/mol.104.004168
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 muM) and transiently augmented in a concentration-independent manner (10 muM to 1 mM) similar to2-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 mu M) affinity sites could reproduce the properties of the NFA-modulated I-Cl(Ca) fairly well.
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页码:163 / 173
页数:11
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