Opposing roles of smooth muscle BK channels and ryanodine receptors

24 In depolarized smooth muscle cells of pressurized cerebral arteries, ryanodine 25 receptors (RyRs) generate “Ca sparks” that activate large conductance, Ca26 and voltage-sensitive potassium (BK) channels to oppose pressure-induced 27 (myogenic) constriction. Here, we show that BK channels and RyRs have 28 opposing roles in the regulation of arterial tone in response to sympathetic nerve 29 activation by electrical field stimulation (EFS). Inhibition of BK channels with 30 paxilline increased both myogenic and nerve-induced constrictions of 31 pressurized, resistance-sized mesenteric arteries from mice. Inhibition of RyRs 32 with ryanodine increased myogenic constriction, but it decreased nerve-evoked 33 constriction along with a reduction in the amplitude of nerve-evoked increases in 34 global intracellular Ca. In the presence of L-type voltage-dependent Ca 35 channel (VDCC) antagonists, nerve stimulation failed to evoke a change in 36 arterial diameter, and BK channel and RyR inhibitors were without effect, 37 suggesting that nerveinduced constriction is dependent on activation of VDCCs. 38 Collectively, these results indicate that BK channels and RyRs have different 39 roles in the regulation of myogenic versus neurogenic tone: whereas BK 40 channels and RyRs act in concert to oppose myogenic vasoconstriction, BK 41 channels oppose neurogenic vasoconstriction and RyRs augment it. A scheme 42 for neurogenic vasoregulation is proposed in which RyRs act in conjunction with 43 VDCCs to regulate nerve-evoked constriction in mesenteric resistance arteries. 44