title: Fenamates block gap junction coupling and potentiate BKCa channels in guinea pig arteriolar cells.
abstract: We determined the actions of the fenamates, flufenamic acid (FFA) and niflumic acid (NFA), on gap junction-mediated intercellular coupling between vascular smooth muscle cells (VSMC) in situ of acutely isolated arteriole segments from the three vascular beds: the spiral modiolar artery (SMA), anterior inferior cerebellar artery (AICA) and mesenteric artery (MA), and on non-junctional membrane channels in dispersed VSMCs. Conventional whole-cell recording methods were used. FFA reversibly suppressed the input conductance (Ginput) or increased the input resistance (Rinput) in a concentration dependent manner, with slightly different IC50s for the SMA, AICA and MA segments (26, 33 and 56 μM respectively, P>0.05). Complete electrical isolation of the recorded VSMC was normally reached at ≥ 300 μM. NFA had a similar effect on gap junction among VSMCs with an IC50 of 40, 48 and 62 μM in SMA, AICA and MA segments, respectively. In dispersed VSMCs, FFA and NFA increased outward rectifier K(+)-current mediated by the big conductance calcium-activated potassium channel (BKCa) in a concentration-dependent manner, with a similar EC50 of ∼300 μM for both FFA and NFA in the three vessels. Iberiotoxin, a selective blocker of the BKCa, suppressed the enhancement of the BKCa by FFA and NFA. The KV blocker 4-AP had no effect on the fenamates-induced K(+)-current enhancement. We conclude that FFA and NFA blocked the vascular gap junction mediated electrical couplings uniformly in arterioles of the three vascular beds, and complete electrical isolation of the recorded VSMC is obtained at ≧300μM; FFA and NFA also activate BKCa channels in the arteriolar smooth muscle cells in addition to their known inhibitory effects on chloride channels.
authors: Department of Physiology, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, PR China.
authors: Xin-Zhi
authors: XZ
authors: Li
authors: Ke-Tao
authors: KT
authors: Ma
authors: Bing-Cai
authors: BC
authors: Guan
authors: Li
authors: L
authors: Li
authors: Lei
authors: L
authors: Zhao
authors: Zhong-Shuang
authors: ZS
authors: Zhang
authors: Jun-Qiang
authors: JQ
authors: Si
authors: Zhi-Gen
authors: ZG
authors: Jiang
mesh_terms: D000818:Animals; D001160:Arterioles; D005439:Flufenamic Acid / Q000494:pharmacology*; D017629:Gap Junctions / Q000187:drug effects* / Q000502:physiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D009544:Niflumic Acid / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology*
chemical_list: D024681:Potassium Channels, Calcium-Activated; D009544:Niflumic Acid; D005439:Flufenamic Acid