Inhibition of intestinal motility by the putative BK(Ca) channel opener LDD175.
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.
Dela Peña
Ike Campomayor
IC
College of Pharmacy, Sahmyook University, Seoul, 139-742, Korea.
Yoon
Seo Young
SY
Kim
Sung Mok
SM
Lee
Geum Seon
GS
Park
Chul-Seung
CS
Kim
Yong Chul
YC
Cheong
Jae Hoon
JH
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D018678:Cholinergic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000819:agonists* / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D010276:Parasympatholytics / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology
C540673:4-chloro-7-trifluoromethyl-10H-benzo(4,5)furo(3,2-b)indole-1-carboxylic acid; D001572:Benzofurans; D002120:Calcium Channel Agonists; D018678:Cholinergic Agents; D007211:Indoles; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010276:Parasympatholytics; D026902:Potassium Channel Blockers