Tungstate Activates Bk Channels In A Beta Subunit- And Mg2+-Dependent Manner: Relevance For Arterial Vasodilatation

Aims Tungstate reduces blood pressure in experimental animal models of both hypertension and metabolic syndrome, although the underlying mechanisms are not fully understood. Given that the large-conductance voltage-and Ca2+-dependent K+ (BK) channel is a key element in the control of arterial tone, our aim was to evaluate whether BK channel modulation by tungstate can contribute to its antihypertensive effect.Methods and results Patch-clamp studies of heterologously expressed human BK channels (alpha + beta(1-4) subunits) revealed that cytosolic tungstate (1 mM) induced a significant left shift (similar to 20 mV) in the voltage-dependent activation curve only in BK channels containing alpha beta(1) or alpha beta(4) subunits, but reduced the amplitude of K+ currents through all BK channels tested. The beta(1)-dependent activation of BK channels by tungstate was enhanced at cytosolic Ca2+ levels reached during myocyte contraction, and prevented either by removal of cytosolic Mg2+ or by mutations rendering the channel insensitive to Mg2+. A lower concentration of tungstate (0.1 mM) induced voltage-dependent activation of the vascular BK alpha beta(1) channel without reducing current amplitude, and consistently exerted a vasodilatory action on wild-type but not on beta(1)-knockout mouse arteries pre-contracted with endothelin-1.Conclusion Tungstate activates BK channels in a beta subunit-and Mg2+-dependent manner and induces vasodilatation only in mouse arteries that express the BK beta(1) subunit.