Bladder-relaxant properties of the novel benzofuroindole analogue LDD175.
The present study describes the bladder-relaxant properties of LDD175 (4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo [3,2-b]indole-1-carboxylic acid), a novel benzofuroindole compound. LDD175 had no significant effect on the spontaneous and electrically evoked bladder contractions, but produced concentration-dependent relaxation in strips precontracted by 1 micromol/l acetylcholine (pEC(50) = 5.9 +/- 0.2, E(max) = 90.3 +/- 2.6%; 100 micromol/l, n = 6). In high K(+)- (20 and 80 mmol/l) stimulated samples, LDD175 caused a concentration-dependent relaxant activity which was significant in 20 mmol/l K(+) (pEC(50) = 5.6 +/- 0.2, E(max) = 63.1 +/- 4.8%, n = 6), but not in 80 mmol/l K(+) (pEC(50) = 5.1 +/- 0.3, E(max) = 12.7 +/- 2.5%, n = 6). Iberiotoxin (100 nmol/l), a specific BKCa blocker, attenuated the compound's relaxative effect (vehicle = 65.7 +/- 9.2% vs. iberiotoxin 28.0 +/- 3.5%, respectively, n = 3), but not tetraethylammonium chloride (10 mmol/l), a nonselective K(+) channel blocker, barium chloride (10 mmol/l), a conventional K(IR) blocker, and glibenclamide (1 mmol/l), a K(ATP) blocker. LDD175 was evaluated in both endothelium-intact and denuded rat aorta contracted with high K(+). In these preparations, LDD175 did not produce significant inhibition. Administered intravenously to conscious restrained rats, LDD175 (10 mg/kg) did not alter the rat's hemodynamic activity (i.e. blood pressure and heart rate). When tested in the spontaneously hypertensive rats (SHR) for its influence on their voiding behavior, LDD175 (5 and 10 mg/kg) significantly reduced voiding frequency and lengthened void intervals of the animals. These observations: (1) reveal the BKCa channel potentiation of LDD175; (2) support previous claims concerning the bladder (vs. vascular) selectivity of benzofuroindole compounds; (3) demonstrate the efficacy of LDD175 in the animal model of bladder overactivity (SHR). Therefore, the compound may be potentially useful in the treatment of bladder overactivity.
dela Peña
Ike Campomayor
IC
Department of Pharmacology, Sahmyook University, Seoul, Korea.
Yoon
Seo Young
SY
Kim
Sung Mok
SM
Lee
Geum Seon
GS
Ryu
Jong Hoon
JH
Park
Chul-Seung
CS
Kim
Yong Chul
YC
Cheong
Jae Hoon
JH
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001572:Benzofurans / Q000494:pharmacology* / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006339:Heart Rate / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D024681:Potassium Channels, Calcium-Activated / Q000819:agonists; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000187:drug effects*; D053201:Urinary Bladder, Overactive / Q000188:drug therapy*; D014554:Urination / Q000187:drug effects
C540673:4-chloro-7-trifluoromethyl-10H-benzo(4,5)furo(3,2-b)indole-1-carboxylic acid; D001572:Benzofurans; D007211:Indoles; D024681:Potassium Channels, Calcium-Activated