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Activation of large‐conductance Ca 2+ ‐activated K + channels by pinacidil in human umbilical vascular endothelial cells
Author(s) -
Wu ShengNan,
Li HuiFang,
Shen AiYu
Publication year - 1999
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199909)48:1<6::aid-ddr2>3.0.co;2-b
Subject(s) - pinacidil , glibenclamide , chemistry , charybdotoxin , biophysics , potassium channel , membrane potential , pharmacology , biochemistry , endocrinology , biology , diabetes mellitus
The effect of pinacidil, an opener of ATP‐sensitive K + (K ATP ) channels, on large‐conductance Ca 2+ ‐activated K+ (BK Ca ) channels was investigated in cultured endothelial cells of human umbilical veins. In whole cell configuration, pinacidil (30 μM) increased the amplitude of K + outward currents ( I K ). Charybdotoxin (100 nM), but not glibenclamide (10 μM), suppressed pinacidil‐induced increase in I K . Neither carbonyl cyanide m ‐chlorophenyl hydrazone (CCCP; 10 μM), an inhibitor of mitochondrial Ca 2+ ‐uniporter, nor cyclosporin A (200 nM), an inhibitor of the mitochondrial permeability transition pore, affected pinacidil‐induced increase in I K . In inside‐out patch configuration, bath application of pinacidil (30 μM) did not change single channel conductance but increased the activity of BK Ca channels. Pinacidil (30 μM) shifted the activation curve of BK Ca channels to less positive membrane potential by approximately 15 mV. Pinacidil stimulated the activity of these channels in a concentration‐dependent manner. The EC 50 value for pinacidil‐induced channel activity was 20 μM. After BK Ca channels had been enhanced by Evans blue (100 μM), subsequent application of pinacidil (100 μM) did not further increase the channel activity. These results clearly indicate that in addition to the activation of K ATP channels, pinacidil can also stimulate BK Ca channels in endothelial cells. These effects could contribute to the regulation of vascular tone if similar results were found in endothelial cells in vivo. Drug Dev. Res. 48:6–16, 1999. © 1999 Wiley‐Liss, Inc.