Abstract
The inhibitory effects of flavoxate hydrochloride (piperidinoethyl-3-methylflavone-8-carboxylate; hereafter referred as flavoxate) on voltage-dependent nifedipine-sensitive inward Ba2+ currents (I Ba) in human detrusor myocytes were investigated at different temperatures using conventional whole-cell patch-clamp techniques. When the bath-solution temperature was increased from 22°C to 30°C, I Ba peak amplitude was enhanced by approximately twice at several test potentials. Neither the I Ba threshold nor the membrane potentials for the I Ba maximum peak amplitude was affected by the temperature change. The concentration-response curves of flavoxate at both 30°C (K i = 5.1 μM) and 37°C (K i = 4.6 μM) were slightly shifted to the left in comparison with that at 22°C (K i = 10.3 μM). Similar results were also obtained in the presence of nifedipine (K i = 14 nM at 22°C vs. K i = 2.5 nM at 30°C and K i = 2.1 nM at 37°C). Altering the bath-solution temperature from 22°C to 30°C shifted the steady-state inactivation curve of I Ba at −90 mV to the left. At 30°C, the steady-state inactivation curve of I Ba in the presence of flavoxate was also shifted to the left in comparison with that in the absence of flavoxate. Either 3-isobutyl-1-methylxanthine (IBMX) or theophylline, a phosphodiesterase inhibitor, caused little effects on I Ba, although cyclic nucleotides (dibutyryl cAMP and 8-Br-cGMP) inhibited I Ba. These results suggest that the inhibitory actions of flavoxate on I Ba in human detrusor myocytes were slightly changed at different experimental temperatures and that flavoxate directly blocked voltage-dependent L-type Ca2+ channels, not through the inhibition of phosphodiesterase activity pathway.
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References
Allen TJA, Mikala G (1998) Effects of temperature on human L-type cardiac Ca2+ channels expressed in Xenopus oocytes. Pflügers Arch 436:238–247
Andersson KE, Yoshida M (2003) Antimuscarinics and the overactive detrusor-which is the main mechanism of action? Eur Urol 43:1–5
Cazzulani P, Panzarasa R, Luca C, Oliva D, Graziani G (1984) Pharmacological studies on the mode of action of flavoxate. Arch Int Pharmacodyn Ther 268:301–312
Conti M, Setnikar I (1975) Flavoxate, a potent phosphodiesterase inhibitor. Arch Int Pharmacodyn Ther 213:186–189
Haeusler G, Leitich H, van Trotsenburg M, Kaider A, Tempfer CB (2002) Drug therapy of urinary urge incontinence: a systematic review. Obstet Gynecol 100:1003–1016
Hosey MM, Lazdunski M (1988) Calcium channels: molecular pharmacology, structure and regulation. J Membr Biol 104:81–105
Howlett SE, Gordon S (1990) [3H]-Nitrendipine binding in normal and cardiomyopathic hamster hearts: modulation by temperature, verapamil and diltiazem. J Mol Cell Cardiol 22:975–985
Iguchi M, Nakajima T, Hisada T, Sugimoto T, Kurachi Y (1992) On the mechanism of papaverine inhibition of the voltage-dependent Ca++ current in isolated smooth muscle cells from the guinea pig trachea. J Pharmacol Exp Ther 263:194–200
Kajioka S, Nakayama S, McMurray G, Abe K, Brading AF (2002) Ca2+ channel properties in smooth muscle cells of the urinary bladder from pig and human. Eur J Pharmacol 443:19–29
Kaseda M, Sato A, Sato Y, Torigata Y (1975) Effects of flavoxate hydrochloride (AK-123) on the vesical functions in rats. Clin Physiol 5:540–547
Kimura Y, Sasaki Y, Hamada K, Fukui H, Ukai Y, Yoshikuni Y, Kimura K, Sugaya K, Nishizawa O (1996) Mechanisms of the suppression of the bladder activity by flavoxate. Int J Urol 3:218–227
Kohler FP, Morales PA (1968) Cystometric evaluation of flavoxate hydrochloride in normal and neurogenic bladders. J Urol 100:729–730
Manzini S, Parlani M, Astolfi M, Maggi CA, Meli A (1988) Differential temperature-dependency of electrophysiological and inotropic actions of nifedipine, verapamil and cinnarizine in K+-depolarized ventricular myocardium. Gen Pharmacol 19:253–259
Narayanan S, Cerulli A, Kahler KH, Ouslander JG (2007) Is drug therapy for urinary incontinence used optimally in long-term care facilities? Am Med Dir Assoc 8:98–104
Nobile M, Carbone E, Lux HD, Zucker H (1990) Temperature sensitivity of Ca2+ currents in chick sensory neurones. Pflügers Arch 415:658–663
Quignard JF, Frapier JM, Harricane MC, Albat B, Nargeot J, Richard S (1997) Voltage-gated calcium channel currents in human coronary myocytes. Regulation by cyclic GMP and nitric oxide. J Clin Invest 99:185–193
Rosen AD (1996) Temperature modulation of calcium channel function in GH3 cells. Am J Physiol 271:C863–C868
Ruiz-Velasco V, Zhong J, Hume JR, Keef KD (1998) Modulation of Ca2+ channels by cyclic nucleotide cross activation of opposing protein kinases in rabbit portal vein. Circ Res 82:557–565
Shiels HA, Vornanen M, Farrell AP (2000) Temperature-dependence of L-type Ca2+ channel current in atrial myocytes from rainbow trout. J Exp Biol 203:2771–2780
Teramoto N, Brading AF (1996) Activation by levcromakalim and metabolic inhibition of glibenclamide-sensitive K channels in smooth muscle cells of pig proximal urethra. Br J Pharmacol 118:635–642
Tomoda T, Aishima M, Takano N, Nakano T, Seki N, Yonemitsu Y, Sueishi K, Naito S, Ito Y, Teramoto N (2005) The effects of flavoxate hydrochloride on voltage-dependent L-type Ca2+ currents in human urinary bladder. Br J Pharmacol 146:25–32
Uckert S, Stief CG, Odenthal KP, Truss MC, Lietz B, Jonas U (2000) Responses of isolated normal human detrusor muscle to various spasmolytic drugs commonly used in the treatment of the overactive bladder. Arzneimittelforschung 50:456–460
Wang R, Karpinski E, Pang PKT (1991) Temperature dependence of L-type calcium channel currents in isolated smooth muscle cells from the rat tail artery. J Thermal Biol 16:83–87
Wasserstrom JA, Vites AM (1999) Activation of contraction in cat ventricular myocytes: effects of low Cd2+ concentration and temperature. Am J Physiol 277:H488–H498
Yoshimura N, Sasa M, Yoshida O, Takaori S (1992) Inhibitory effects of Hachimijiogan on micturition reflex via locus coeruleus. Folia Pharmacol Jpn 99:161–166
Zhu HL, Hirst GDS, Ito Y, Teramoto N (2005) Modulation of voltage-dependent Ba2+ currents in the guinea-pig gastric antrum by cyclic nucleotide-dependent pathways. Br J Pharmacol 146:129–138
Acknowledgements
We thank Prof. Alison F. Brading (University, Department of Pharmacology, Oxford, UK) for her helpful discussion and critical reading of the manuscript. This work was supported by a Grant-in-Aid from the Japan Science and Technology Agency (Noriyoshi Teramoto, Grant Number 12-037-2006 and Grant Number 1139-2007) and a Grant-in-Aid for Exploratory Research from the Japanese Society for the Promotion of Science (Noriyoshi Teramoto, Grant Number 19650733). Dr Hai-Lei Zhu was awarded a Grant-in-Aid from the Japan Society for the Promotion of Science (FY2007 JSPS Postdoctoral Fellowship for Foreign Researcher, P07196).
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Tomoda, T., Zhu, HL., Iwasa, K. et al. Effects of flavoxate hydrochloride on voltage-dependent Ba2+ currents in human detrusor myocytes at different experimental temperatures. Naunyn-Schmied Arch Pharmacol 376, 195–203 (2007). https://doi.org/10.1007/s00210-007-0190-6
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DOI: https://doi.org/10.1007/s00210-007-0190-6