Inhibition of intestinal motility by the putative BKCa channel opener LDD175

Abstract

LDD175 (4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid) is a benzofuroindole compound characterized previously as a potent opener of the large conductance calcium activated (BK(Ca)) channels. Activators of the BK(Ca) channels are potential therapies for smooth muscle hyperactivity disorders. The present study investigates the influence of LDD175 on the mechanical activity of the ileum smooth muscle. LDD175 inhibited spontaneous contractions of the ileum in a concentration-dependent manner (pEC(50)=5.9 +/- 0.1) (E (max)=96 +/- 1.0% at 100 muM, n=3). It also remarkably inhibited contractions due to acetylcholine (ACh) (pEC(50)=5.3 +/- 0.1)(E (max)=97.7 +/- 2.3%, n=6) and electrical field stimulation (EFS) (pEC(50)=5.5 +/- 0.1) (E (max)=83.3 +/- 6.0%, n=6). In strips precontracted by 20 mM KCl, LDD175 significantly reduced the contractions yielding a pEC(50) of 6.1 +/- 0.1 and E (max) of 96.6 +/- 0.9%, (n=6). In 60 mM KCl, a concentration-dependent inhibition was observed with respective pEC(50) and E (max) values of 4.1 +/- 0.1 and 50.8 +/- 5.0% (n=3). BK(Ca) channel blockers iberiotoxin (IbTX) and tetraethylammonium chloride (TEA, 1 mM) attenuated the relaxative effect of LDD175 but not barium chloride (BaCl(2)), and glibenclamide (K(IR) and K(ATP) channel blockers, respectively). These data demonstrate the antispasmodic activity of LDD175 attributable to the potentiation of the BK(Ca) channels.