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Vol. 83, No. 6, 2009
Issue release date: June 2009

Bladder-Relaxant Properties of the Novel Benzofuroindole Analogue LDD175

dela Peña I.C. · Yoon S.Y. · Kim S.M. · Lee G.S. · Ryu J.H. · Park C.-S. · Kim Y.C. · Cheong J.H.
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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 μmol/l acetylcholine (pEC50 = 5.9 ± 0.2, Emax = 90.3 ± 2.6%; 100 μmol/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+ (pEC50 = 5.6 ± 0.2, Emax = 63.1 ± 4.8%, n = 6), but not in 80 mmol/l K+ (pEC50 = 5.1 ± 0.3, Emax = 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 KIR blocker, and glibenclamide (1 mmol/l), a KATP 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.

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  1. de Groat WC: Aneurologic basis for the overactive bladder. Urol 1997;50(suppl 6A):36–52.

    External Resources

  2. Brading AF: A myogenic basis for the overactive bladder. Urol 1997;50(suppl 6A):57–67.

    External Resources

  3. Andersson KE: Advances in the pharmacological control of the bladder. Exp Physiol 1999;84:195–213.
  4. Mills IW, Greenland JE, McMurray G, McCoy R, Ho KM, Noble JG, Brading AF: Studies of the pathophysiology of idiopathic detrusor instability: the physiological properties of the detrusor smooth muscle and its pattern of innervation. J Urol 2000;163:646–651.
  5. Stewart WF, Van Rooyen JB, Cundiff GW: Prevalence and burden of overactive bladder in the United States. World J Urol 2003;20:327–336.
  6. Mundy AR, Stephenson TP: The urge syndrome; in Mundy AR, Stephenson TP, Wein AJ (eds): Urodynamics: Principles, Practice and Application. Edinburgh, Churchill Livingstone, 1984, pp 212–228.
  7. Andersson KE, Mattiason A: Drug treatment of the overactive detrusor. Drugs Today 1988;24:337–348.
  8. Klockner U, Isenberg G: Action potentials and net membrane currents of isolated smooth muscle cells (urinary bladder of the guinea pig). Pflügers Arch 1985;405:329–339.
  9. Zografos P, Li JH, Kau ST: Comparison of the in vitro effects of K+ channel modulators on detrusor and portal vein strips from guinea pigs. Pharmacology 1992;45:216–230.
  10. Brading AF: Ion channels and control of contractile activity in urinary bladder smooth muscle. Jpn J Pharmacol 1992;58(suppl 2): 120–127.
  11. Foster CD, Speakman MJ, Fujii K, Brading AF: The effect of cromakalim on the smooth muscle of human and pig urinary bladder. Br J Urol 1989;63:284–294.
  12. Malmgren A, Andersson KE, Andersson PO, Foveaus M, Sjogren C: The effects of cromakalim (BRL 34915) and pinadicil on normal and hypertrophied rat detrusor in vitro. J Urol 1990;143:828–834.
  13. Wojdan A, Freeden C, Woods M, Oshiro G, Spinelli W, Colatsky TJ, Sheldon JH, Norton NW, Warga D, Antane MM, Antane SA, Butera JA, Argentieri TM: Comparison of the potassium channel openers, WAY-133537, ZD6169, and celikalim on isolated bladder tissue and in vivo bladder instability in rat. J Pharmacol Exp Ther 1999;289:1410–1418.
  14. Yu Y, de Groat WC: Effects of ZD6169, a KATP channel opener, on bladder hyperactivity and spinal c-fos expression evoked by bladder irritation in rats. Brain Res 1998;807:11–18.
  15. Edwards G, Henshaw M, Miller A, Weston AH: Comparison of the effects of several potassium-channel openers on rat bladder and rat portal vein in vitro. Br J Pharmacol 1991;102:679–686.
  16. Chess-Williams R, Martin SW, Korstanje C, Chapple CR: In vitro investigation of the bladder-vascular selectivity of levcromakalim and YM934 in human tissues. BJU Int 1999;83:1050–1054.
  17. Brune M, Fey T, Brioni J, Sullivan J, Williams M, Carroll W, Coghlan M, Gopalakrishnan M: (–)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637): a novel ATP-sensitive potassium channel opener efficacious in suppressing urinary bladder contractions. II. In vivo characterization. J Pharmacol Exp Ther 2002;303:387–394.
  18. Fabiyi AC, Gopalakrishnan M, Lynch III JJ, Brioni JD, Coghlan MJ, Brune ME: In vivo evaluation of the potency and bladder-vascular selectivity of the ATP-sensitive potassium channel openers (–)-cromacalim, ZD-6169 and WAY-133537 in rats. BJU Int 2003;91:284–290.
  19. Komersova K, Rogerson JW, Conway EL, Lim TC, Brown DJ, Krum H, Jackman GP, Murdoch R, Louis WJ: The effect of levcromakalim (BRL 38227) on bladder function in patients with high spinal cord lesions. Br J Clin Pharmacol 1995;39:207–209.
  20. Buckner SA, Milicic I, Daza AV, Coghlan MJ, Gopalakrishnan M: Spontaneous phasic activity of the pig urinary bladder smooth muscle: characteristics and sensitivity to potassium channel modulators. Br J Pharmacol 2002;135:639–648.
  21. Hu S, Kim HS: On the differential effects of the BKCa channel openers NS004 and NS1608 in porcine coronary arterial cells. Eur J Pharmacol 1996;294:357–360.
  22. Siemer C, Bushfield M, Newgreen D, Grissmer S: Effect of NS1608 on MaxiK channels in smooth muscle cells from urinary bladder. J Membr Biol 2000;173:57–66.
  23. Malysz J, Buckner SA, Daza AV, Milicic I, Perez-Medrano A, Gopalakrishnan M: Functional characterization of large conductance calcium-activated K(+) channel openers in bladder and vascular smooth muscle. Naunyn Schmiedebergs Arch Pharmacol 2004;369:481–489.
  24. Butera JA, Antane SA, Hirth B, Lennox JR, Sheldon JH, Norton NW, Warga D, Argentieri TM: Synthesis and potassium channel opening activity of substituted 10H-benzo[4,5]furo[3,2-b]indole-and 5,10-dihydro-indeno [1,2-b]indole-1-carboxylic acids. Bioorg Med Chem Lett 2001;11:2093–2097.
  25. Gormemis AE, Ha TS, Im I, Jung KY, Lee JY, Park CS, Kim YC: Benzofuroindole analogues as potent BKCa channel openers. Chembiochem 2005;6:1745–1748.
  26. Ha TS, Lim HL, Lee GE, Kim YC, Park CS: Electrophysiological characterization of benzofuroindole-induced potentiation of large-conductance Ca2+-activated K+ channels. Mol Pharmacol 2006;69:1007–1014.
  27. McMurray G, Casey JH, Naylor AM: Animal models in urological disease and sexual dysfunction. Br J Pharmacol 2006;147:S62–S79.
  28. Imai T, Okamoto T, Yamamoto Y, Tanaka H, Koike K, Shigenobu K, Tanaka Y: Effects of different types of K+ channel modulators on the spontaneous myogenic contraction of guinea pig urinary bladder smooth muscle. Acta Physiol Scand 2001;173:323–333.
  29. Buckner SA, Oheim KW, Morse PA, Knepper SM, Hancock AA: Alpha 1-adrenoreceptor-induced contractility in rat aorta is mediated by alpha 1D subtype. Eur J Pharmacol 1996;400:287–295.
  30. Chang CP, Dworetzky SI, Wang J, Goldstein ME: Differential expression of the alpha and beta subunits of the large-conductance calcium-activated potassium channel: implication for channel diversity. Brain Res Mol Brain Res 1997;45:33–40.
  31. Meredith AL, Thorneloe KS, Werner ME, Nelson MT, Aldrich RW: Overactive bladder and incontinence in the absence of the BK large conductance Ca2+-activated K+ channel. J Biol Chem 2004;279:36746–36752.
  32. Ohi Y, Yamamura H, Nagano N, Ohya S, Muraki K, Watanabe M, Imaizumi Y: Local Ca2+ transients and distribution of BK channels and ryanodine receptors in smooth muscle cells of guinea pig vas deferens and urinary bladder. J Physiol 2001;534:313–326.
  33. Shieh CC, Coghlan M, Sullivan JP, Gopalakrishnan M: Potassium channels: molecular defects, diseases and therapeutic opportunities. Pharmacol Rev 2000;52:557–594.
  34. Herrera G, Etherton B, Nausch B, Nelson M: Negative feedback regulation of nerve-mediated contractions by KCa channels in mouse urinary bladder smooth muscle. Am J Physiol Regul Integr Comp Physiol 2005;289:R402–R409.
  35. Thorneloe KS, Meredith AL, Knorn AM, Aldrich RW, Nelson MT: Urodynamic properties and neurotransmitter dependence of urinary bladder contractility in the BK channel deletion model of overactive bladder. Am J Physiol Renal Physiol 2005;289:F604–F610.
  36. Liu SP, Volfson I, Levin RM: Effects of hypoxia, calcium, carbachol, atropine and tetrodotoxin on the filling of the in-vitro rabbit whole bladder. J Urol 1998;160:913–919.
  37. Herrera GM, Heppner TJ, Nelson MT: Regulation of urinary bladder smooth muscle contractions by ryanodine receptors and BK and SK channels. Am J Physiol Regul Integr Comp Physiol 2000;279:60–68.
  38. Kinder RB, Mundy AR: Pathophysiology of idiopathic detrusor instability and detrusor hyperreflexia: an in vitro study of human detrusor muscle. Br J Urol 1987;60:509–515.
  39. Brading AF: The pathophysiological changes in the bladder obstructed by benign prostatic hyperplasia. Br J Urol 1994;74:133.
  40. Fry CH, Sui GP, Severs NJ: Spontaneous activity of electrical coupling in human detrusor smooth muscle: implications for detrusor overactivity? Urol 2004;63:3–10.
  41. Mora TC, Suarez-Kurtz G: Effects of NS1608, a BKCa channel agonist, on the contractility of guinea-pig urinary bladder in vitro. Br J Pharmacol 2005;144:636–641.
  42. Matsui M, Motomura D, Karasawa H, Fujikawa T, Jiang J, Komiya Y, Takahashi S, Taketo M: Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc Natl Acad Sci USA 2000;97:9579–9584.
  43. Vial C, Evans R: P2X receptor expression in mouse urinary bladder and the requirement of P2X(1) receptors for functional P2X receptor responses in the mouse urinary bladder smooth muscle. Br J Pharmacol 2000;131:1489–1495.
  44. Andersson KE: Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev 1993;45:253–308.
  45. Uchiyama T, Chess-Williams R: Muscarinic receptor subtypes of the bladder and gastrointestinal tract. J Smooth Muscle Res 2004;40:237–247.
  46. Yang S, An J, Shim J, Park C, Huh I, Sohn U: The mechanism of contraction by 2-chloroadenosine in cat detrusor muscle cells. J Urol 2000;163:652–658.
  47. Frazier EP, Peters SL, Braverman AS, Ruggieri MR, Michel MC: Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and β-adrenoreceptors. Naunyn Schmiedebergs Arch Phamacol 2007;377:449–462.
  48. Hampel C, Wienhold N, Benken N, Eggersmann C, Thuroff J: Definition of overactive bladder and epidemiology of urinary incontinence. Urology 1997;50:4–14.
  49. Jaggar JH, Porter VA, Lederer WJ, Nelson MT: Calcium sparks in smooth muscle. Am J Physiol 2000;278:C235–C256.
  50. Ghatta S, Nimmagadda D, Xu X, O’Rourke ST: Large-conductance, calcium-activated potassium channels: structural and functional implications. Pharmacol Ther 2006;110:103–116.
  51. Clemow DB, Spitsbergen JM, McCarty R, Steers WD, Tuttle JB: Altered NGF regulation may link a genetic predisposition for hypertension with hyperactive voiding. J Urol 1999;161:1372–1377.
  52. Yanasigawa T, Teshigawara T, Taira N: Cytoplasmic calcium and the relaxation of canine coronary arterial smooth muscle produced by cromakalim, pinadicil and nicorandil. Br J Pharmacol 1990;101:157–165.
  53. Triverde S, Potter-Lee L, Li JH, Yasay GD, Russell K, Ohnmacht CJ, Empfield JR, Trainor DA, Kau ST: Calcium dependent-K channels in guinea pig and human urinary bladder. Biochem Biophys Res Commun 1995;213:404–409.
  54. Kobayashi H, Adachi-Akahane S, Nagao T: Involvement of BKCa channels in the relaxation of detrusor muscle via β-adrenoreceptors. Eur J Pharmacol 2000;404:231–238.

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