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CARDIOVASCULAR

Stimulation of Ca²⁺-Gated Cl^- Currents by the Calcium-Dependent K⁺ Channel Modulators NS1619 [1,3-Dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one] and Isopimaric Acid

Ion Channels and Cell Signaling Research Centre, Division of Basic Medical Sciences, St. George's, University of London, London, United Kingdom (S.N.S., W.R.S., I.G.); and Department of Pharmacology, Center of Biomedical Research Excellence, University of Nevada School of Medicine, Reno, Nevada (J.E.A., N.L.)

Because chloride (Cl^-) channel blockers such as niflumic acid enhance large-conductance Ca²⁺-activated potassium channels (BK_Ca), the aim of this study was to determine whether there is a reciprocal modification of Ca²⁺-activated chloride Cl^- currents (I_ClCa) by two selective activators of BK_Ca. Single smooth muscle cells were isolated by enzymatic digestion from murine portal vein and rabbit pulmonary artery. The BK_Ca activators NS1619 [1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl-)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one] and isopimaric acid (IpA) augmented macroscopic I_ClCa elicited by pipette solutions containing [Ca²⁺]_i > 100 nM without any alteration in current kinetics. Enhanced currents recorded in the presence of NS1619 or IpA reversed at the theoretical Cl^- equilibrium potential, which was shifted by approximately -40 mV upon replacement of the external anion with the more permeable thiocyanate anion. NS1619 increased the sensitivity of calcium-activated chloride channel (Cl_Ca) to Ca²⁺ (100 nM at +60 mV) and induced a leftward shift in their voltage dependence (80 mV with 1 µMCa²⁺). Single-channel experiments revealed that NS1619 increased the number of open channels times the open probability of small-conductance (1.8–3.1 pS) Cl_Ca without any alteration in their unitary amplitude or number of observable unitary levels of activity. These data, in addition to the established stimulatory effects of niflumic acid on BK_Ca, show that there is similarity in the pharmacology of calcium-activated chloride and potassium channels. Although nonspecific interactions are possible, one alternative hypothesis is that the channel underlying vascular I_ClCa shares some structural similarity to the BK_Ca or that the latter K⁺ channel physically interacts with Cl_Ca.

Address correspondence to: Dr. Iain A. Greenwood, Ion Channels and Cell Signaling Research Centre, Division of Basic Medical Sciences, St. George's, University of London, SW17 0RE London, UK. E-mail: i.greenwood{at}sgul.ac.uk