The Ca²⁺-activated Cl^– current (IClCa) has been characterised in a variety of smooth muscle preparations where activation causes membrane depolarisation and increased cellular excitability. Although this current is known to play a fundamental role in smooth muscle excitation-contraction coupling the molecular identity of channel protein remains elusive. Various studies have shown that blockers of IClCa augment the large conductance Ca²⁺-activated K⁺ current (BKCa) suggesting that there may be some structural similarity between the two channels. Consequently we have investigated whether modulators of BKCa channels also affect IClCa in mouse portal vein smooth muscle cells. Mice were humanely killed. IClCa was measured in the whole cell configuration with an internal solution containing (mM): 106 CsCl, 20 TEA-Cl, 10 Hepes, 10 BAPTA, 0.42 MgCl₂, 3 Na₂ATP, 0.2 GTP(Na) and either 250 or 500nM free Ca²⁺. The external solution contained 126 NaCl, 11 glucose, 10 Hepes, 1.2 MgCl₂ and 1.5 CaCl₂. Values are given as means ± S.E.M. Application of the BKCa activators NS1619 (30 μM) and isopimaric acid (IpA, 3 μM) increased the late outward component of IClCa (termed I_late) by 159 ± 26% (n = 9) and 240 ± 16% (n = 5), respectively. Neither reagent affected the kinetics of the relaxation or the reversal potential of the current. NS1619 had no affect on the apparent Ca²⁺ sensitivity. The chloride channel blocker niflumic acid (NFA, 100 μM) alone both augmented and inhibited IClCa in a voltage-dependent manner as described previously (Piper et al. 2002) whereas the BKCa inhibitor Paxilline (Px, 1 μM) produced inhibition only, decreasing ilate by 66 ± 6% (n = 4). Whilst neither reagent alone completely inhibited IClCa, NFA and Px in combination completely blocked all components of the current and abolished the time-dependent relaxation (n = 5). The NS1619-enhanced current was partially inhibited by 100μM NFA (n = 3) and 1μM Px (n = 2), whilst a complete block of the current occurred when both reagents were combined. The IpA-enhanced current was partially inhibited by Px (n = 2), and transiently enhanced by NFA (n = 2). However, a combination of NFA and Px on the IpA-enhanced current again resulted in an almost complete block (n = 4). These data show that agents known to interact with BKCa produce similar effects on IClCa and may provide important insights into the channel responsible for this conductance.