Inhibition of the calcium-activated chloride current in cardiac ventricular myocytes by N-(p-amylcinnamoyl)anthranilic acid (ACA) |
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Authors: | Gwanyanya Asfree Macianskiene Regina Bito Virginie Sipido Karin R Vereecke Johan Mubagwa Kanigula |
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Institution: | a Division of Experimental Cardiac Surgery, Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium b Laboratory of Membrane Biophysics, Institute of Cardiology, Kaunas University of Medicine, Kaunas, Lithuania c Laboratory of Experimental Cardiology, Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium d Laboratory of Physiology, Department of Cellular and Molecular Biology, University of Leuven, Leuven, Belgium |
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Abstract: | N-(p-amylcinnamoyl)anthranilic acid (ACA), a phospholipase A2 (PLA2) inhibitor, is structurally-related to non-steroidal anti-inflammatory drugs (NSAIDs) of the fenamate group and may also modulate various ion channels. We used the whole-cell, patch-clamp technique at room temperature to investigate the effects of ACA on the Ca2+-activated chloride current (ICl(Ca)) and other chloride currents in isolated pig cardiac ventricular myocytes. ACA reversibly inhibited ICl(Ca) in a concentration-dependent manner (IC50 = 4.2 μM, nHill = 1.1), without affecting the L-type Ca2+ current. Unlike ACA, the non-selective PLA2 inhibitor bromophenacyl bromide (BPB; 50 μM) had no effect on ICl(Ca). In addition, the analgesic NSAID structurally-related to ACA, diclofenac (50 μM) also had no effect on ICl(Ca), whereas the current in the same cells could be suppressed by chloride channel blockers flufenamic acid (FFA; 100 μM) or 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS;100 μM). Besides ICl(Ca), ACA (50 μM) also suppressed the cAMP-activated chloride current, but to a lesser extent. It is proposed that the inhibitory effects of ACA on ICl(Ca) are PLA2-independent and that the drug may serve as a useful tool in understanding the nature and function of cardiac anion channels. |
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Keywords: | ACA N-(p-amylcinnamoyl)anthranilic acid DIDS 4 4&prime -diisothiocyanostilbene-2 2&prime -disulfonic acid ICl(Ca) calcium-activated chloride current ICl(cAMP) cyclic AMP-activated chloride current Ito transient outward current NPPB 5-nitro-2-(3-phenylpropylamino)benzoic acid NSAID non-steroidal anti-inflammatory drug PLA2 phospholipase A2 TRP transient receptor potential |
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