Comparative studies of ZD0947, a novel ATP-sensitive K(+) channel opener, on guinea pig detrusor and aortic smooth muscles.
The effects of ZD0947, a novel urinary bladder selective ATP-sensitive potassium channel (K(ATP) channel) opener, on carbachol-induced contractions of isolated guinea pig urinary bladder strips were investigated to compare its ability to relax norepinephrine-induced contraction of the aorta. Electrophysiological techniques were also utilized to compare the effects of ZD0947 on membrane currents between guinea pig detrusor and aortic myocytes. ZD0947 caused a significant reduction of the carbachol-induced contractile activity, demonstrating a biphasic relaxation (the first and second components). Although glibenclamide antagonized the effects of two components for the ZD0947-induced relaxation, gliclazide, a selective sulphonylurea receptor 1 (SUR1) antagonist, reduced the effects of the first component but not the second component of the ZD0947-induced relaxation. ZD0947 also reduced the norepinephrine-induced contraction of the aorta. ZD0947 reduced electrical excitability of detrusor smooth muscles, inhibiting spike discharges and also hyperpolarizing the membrane as measured with microelectrodes. In conventional whole-cell configuration, ZD0947 caused a glibenclamide-sensitive K(+) current (i.e., K(ATP) current) at a holding potential of -60 mV in guinea pig detrusor and aortic myocytes. The current density of ZD0947-induced K(ATP) currents in guinea pig detrusor myocytes was significantly larger than that in aortic smooth muscle cells. These results show that ZD0947 caused a significant relaxation through the activation of K(ATP) channels in detrusor muscle.
Yunoki
Takakazu
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
Tomoda
Toshihisa
T
Aishima
Manami
M
Shibata
Atsushi
A
Naito
Seiji
S
Teramoto
Noriyoshi
N
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology*; D004594:Electrophysiology; D006168:Guinea Pigs; D007537:Isometric Contraction / Q000187:drug effects; D054086:KATP Channels / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D001743:Urinary Bladder / Q000166:cytology / Q000187:drug effects; D053201:Urinary Bladder, Overactive / Q000188:drug therapy
D004095:Dihydropyridines; D054086:KATP Channels; C463119:ZD0947; D002217:Carbachol; D009638:Norepinephrine