Dynamics of Ca2+-dependent Cl- channel modulation by niflumic acid in rabbit coronary arterial myocytes.
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 Ca(2+) clamped at 500 nM were dose-dependently inhibited by NFA (IC(50) = 159 microM) and transiently augmented in a concentration-independent manner (10 microM to 1 mM) approximately 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 microM) affinity sites could reproduce the properties of the NFA-modulated I(Cl(Ca)) fairly well.
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, USA.
Jonathan
J
Ledoux
Iain A
IA
Greenwood
Normand
N
Leblanc
D000818:Animals; D002463:Cell Membrane Permeability; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D017629:Gap Junctions / Q000502:physiology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000502:physiology; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology*; D009544:Niflumic Acid / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011817:Rabbits
D018118:Chloride Channels; D009544:Niflumic Acid