4-Chloro-7-Trifluoromethyl-10H- Benzo[4,5]furo[3,2-b]Indole-1-Carboxylic Acid (TBIC), a Putative BKCa Channel Opener with Uterine Relaxant Activities

Abstract

In the present study, we examined the uterine relaxant activity of 4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (TBIC), a putative opener of the large conductance Ca²⁺-activated K⁺ (BK_Ca) channel. TBIC concentration-dependently inhibited spontaneous uterine contractions (EC₅₀ = 4.63 µmol/l; E_max = 94.85 ± 1.85%; 100 µmol/l, n = 6). It also reduced contractions induced by oxytocin (EC₅₀ = 4.10 µmol/l; E_max = 84.3 ± 3.83%; 100 µmol/l, n = 6), prostaglandin F₂_α (EC₅₀ = 2.14 µmol/l; E_max = 73.70 ± 5.21%; 100 µmol/l, n = 6) and acetylcholine (EC₅₀ = 4.37 µmol/l; E_max = 83.67 ± 4.82; 100 µmol/l, n = 6). TBIC decreased KCl (20 mmol/l) -induced contractions (EC₅₀ = 3.04 µmol/l; E_max = 94.0 ± 3.12%; 100 µmol/l, n = 6) indicating its K⁺ channel opening activity. BK_Ca channel blockers penitrem A (100 nmol/l) and tetraethylammonium chloride (1 mmol/l) attenuated the inhibitory activities of TBIC (p < 0.001) but not other K⁺ channel blockers such as barium chloride and glibenclamide (K_IR and K_ATP channel blockers, respectively). These results demonstrate the uterine relaxant effects of TBIC in a mechanism of action largely referable to the potentiation of the BK_Ca channels. We have provided evidence for the potential use of TBIC as a tocolytic agent and support for the utility of BK_Ca channel openers in pathophysiologic conditions involving smooth muscle hyperactivity.