Molecular and Cellular PharmacologyUnique action of sodium tanshinone II-A sulfonate (DS-201) on the Ca2+ dependent BKCa activation in mouse cerebral arterial smooth muscle cells

Sodium tanshinone II-A sulfonate (DS-201) is a water-soluble derivative of tanshinone IIA, a main active constituent of Salvia miltiorrhiza which has been used for treatments of cardio- and cerebro-vascular diseases. DS-201 activates large conductance Ca2+-sensitive K+ channels (BKCa) in arterial smooth muscle cells, and reduces the vascular tone. Here we investigated the effect of DS-201 on the BKCa channel kinetics by analyzing single channel currents. Smooth muscle cells were freshly isolated from mouse cerebral arteries. Single channel currents of BKCa were recorded by patch clamp. DS-201 increased the total open probability (NPo) of BKCa in a concentration-dependent manner. But this action required intracellular Ca2+, and the effect depended on the Ca2+ concentration ([Ca2+]free). DS-201 activated BKCa with the half maximal effective concentration (EC50) of 111.5 μM at 0.01 μM [Ca2+]free, and 68.5 μM at 0.1 μM [Ca2+]free. The effect of DS-201 on NPo was particularly strong in the range of [Ca2+]free between 0.1 and 1 μM. Analysis of the channel kinetics revealed that DS-201 had only the effect on the channel closing without affecting the channel opening, which was a striking contrast to the effect of [Ca2+]free, that is characterized by changing the channel opening without changing the channel closing. DS-201 may be bound to the open state of BKCa, and have an inhibitory effect on the transition from the open to closed state. By this way DS-201 may enhance the activity of BKCa, and exhibit a strong vasodilating effect against vasoconstriction in the range of [Ca2+]free between 0.1 and 1 μM.