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 calcium-activated chloride currents [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 derived from a kinetic model involving low (Ki = 1.25 mM) and high (Ki < 30 μM) affinity sites could reproduce the properties of the NFA-modulated ICl(Ca) fairly well.
- Received June 23, 2004.
- Accepted September 27, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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