Effects of NS‐1619, an opener of large conductance Ca²⁺‐activated K⁺ (BK) channel, on intracellular Ca²⁺ concentration ([Ca²⁺]_i) and membrane potential were examined in single myocytes freshly isolated from porcine coronary artery. Under current clamp mode, the application of 1 – 30 μM NS‐1619 hyperpolarized the membrane in concentration‐dependent manner. The NS‐1619‐induced hyperpolarization was abolished by the presence of 100 nM iberiotoxin. Application of 1 – 10 μM NS‐1619 hyperpolarized the membrane by approximately 6 mV or less but did not change significantly the [Ca²⁺]_i. When membrane hyperpolarization of 12 mV or so was caused by 30 μM NS‐1619, [Ca²⁺]_i was unexpectedly increased by approximately 200 nM. This increase in [Ca²⁺]_i and the concomitant outward current activation were also observed under voltage‐clamp at holding potential of −40 mV. The increase in [Ca²⁺]_i by 30 μM NS‐1619 occurred mainly in peripheral regions than in the centre of the myocytes. The removal of extracellular Ca²⁺ affected neither the membrane hyperpolarization nor the increase in [Ca²⁺]_i. In the presence of 10 mM caffeine and 10 μM ryanodine, the increase in [Ca²⁺]_i by 30 μM NS‐1619 was not observed and the membrane hyperpolarization was reduced to approximately 67% of the control. These results indicate that the opening of BK channels by NS‐1619 at 30 μM, which is the most frequently used concentration of this agent, is partly due to Ca²⁺ release from caffeine/ryanodine‐sensitive intracellular storage sites but is mainly due to the direct activation of the channels. British Journal of Pharmacology (2001) 132, 828–834; doi:10.1038/sj.bjp.0703885

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