4-Chloro-7-trifluoromethyl-10H- benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (TBIC), a putative BK(Ca) 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 Ca(2+)-activated K(+) (BK(Ca)) channel. TBIC concentration-dependently inhibited spontaneous uterine contractions (EC(50) = 4.63 μmol/l; E(max) = 94.85 ± 1.85%; 100 μmol/l, n = 6). It also reduced contractions induced by oxytocin (EC(50) = 4.10 μmol/l; E(max) = 84.3 ± 3.83%; 100 μmol/l, n = 6), prostaglandin F(2)(α) (EC(50) = 2.14 μmol/l; E(max) = 73.70 ± 5.21%; 100 μmol/l, n = 6) and acetylcholine (EC(50) = 4.37 μmol/l; E(max) = 83.67 ± 4.82; 100 μmol/l, n = 6). TBIC decreased KCl (20 mmol/l) -induced contractions (EC(50) = 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.