Actions of ZD0947, a novel ATP-sensitive K+ channel opener, on membrane currents in human detrusor myocytes.
OBJECTIVE
ATP-sensitive K+ channels (K(ATP) channels) play important roles in regulating the resting membrane potential of detrusor smooth muscle. Actions of ZD0947, a novel KATP channel opener, on both carbachol (CCh)-induced detrusor contractions and membrane currents in human urinary bladder myocytes were investigated.


METHODS
Tension measurements and patch-clamp techniques were utilized to study the effects of ZD0947 in segments of human urinary bladder. Immunohistochemistry was also performed to detect the expression of the sulphonylurea receptor 1 (SUR1) and the SUR2B antigens in human detrusor muscle.


RESULTS
ZD0947 (> or = 0.1 microM) caused a concentration-dependent relaxation of the CCh-induced contraction of human detrusor, which was reversed by glibenclamide. The rank order of the potency to relax the CCh-induced contraction was pinacidil > ZD0947 > diazoxide. In conventional whole-cell configuration, ZD0947 (> or = 1 microM) caused a concentration-dependent inward K+ current which was suppressed by glibenclamide at -60 mV. When 1 mM ATP was included in the pipette solution, application of pinacidil or ZD0947 caused no inward K+ current at -60 mV. Gliclazide (< or =1 microM), a selective SUR1 blocker, inhibited the ZD0947-induced currents (Ki = 4.0 microM) and the diazoxide-induced currents (high-affinity site, Ki1 = 42.4 nM; low-affinity site, Ki2 = 84.5 microM) at -60 mV. Immunohistochemical studies indicated the presence of SUR1 and SUR2B proteins, which are constituents of KATP channels, in the bundles of human detrusor smooth muscle.


CONCLUSIONS
These results suggest that ZD0947 caused a glibenclamide-sensitive detrusor relaxation through activation of glibenclamide-sensitive KATP channels in human urinary bladder.
Aishima
M
M
Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Tomoda
T
T
Yunoki
T
T
Nakano
T
T
Seki
N
N
Yonemitsu
Y
Y
Sueishi
K
K
Naito
S
S
Ito
Y
Y
Teramoto
N
N
D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000145:classification; D002217:Carbachol / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000819:agonists*; D005907:Gliclazide / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007120:Immunochemistry; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D020110:Pinacidil / Q000494:pharmacology; D015221:Potassium Channels / Q000032:analysis / Q000145:classification; D024661:Potassium Channels, Inwardly Rectifying / Q000032:analysis / Q000145:classification; D011955:Receptors, Drug / Q000032:analysis / Q000145:classification; D064233:Sulfonylurea Receptors; D001743:Urinary Bladder / Q000166:cytology / Q000187:drug effects* / Q000502:physiology
C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D004095:Dihydropyridines; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; C463119:ZD0947; D020110:Pinacidil; D002217:Carbachol; D005907:Gliclazide; D003981:Diazoxide; D005905:Glyburide