Effects of flavoxate hydrochloride on voltage-dependent Ba2+ currents in human detrusor myocytes at different experimental temperatures.
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 degrees C to 30 degrees 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 degrees C (Ki = 5.1 microM) and 37 degrees C (Ki = 4.6 microM) were slightly shifted to the left in comparison with that at 22 degrees C (Ki = 10.3 microM). Similar results were also obtained in the presence of nifedipine (Ki = 14 nM at 22 degrees C vs. Ki = 2.5 nM at 30 degrees C and Ki = 2.1 nM at 37 degrees C). Altering the bath-solution temperature from 22 degrees C to 30 degrees C shifted the steady-state inactivation curve of I Ba at -90 mV to the left. At 30 degrees 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.
Tomoda
Toshihisa
T
Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi Ward, Fukuoka 812-8582, Japan.
Zhu
Hai-Lei
HL
Iwasa
Kazuomi
K
Aishima
Manami
M
Shibata
Atsushi
A
Seki
Narihito
N
Naito
Seiji
S
Teramoto
Noriyoshi
N
D001464:Barium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D005422:Flavoxate / Q000494:pharmacology*; D006801:Humans; D008297:Male; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D013696:Temperature
D002121:Calcium Channel Blockers; D010276:Parasympatholytics; D010726:Phosphodiesterase Inhibitors; D001464:Barium; D005422:Flavoxate; D009543:Nifedipine