title: Novel effect of 2-aminoethoxydiphenylborate through inhibition of calcium sensitization induced by Rho kinase activation in human detrusor smooth muscle.
abstract: Since the introduction of 2-aminoethoxydiphenylborate (2-APB) as a membrane permeable modulator of inositol (1,4,5)-trisphosphate receptors, subsequent studies have revealed additional actions of this chemical on multiple Ca(2+)-permeable ionic channels in the plasma membrane. However, no reports have yet examined 2-APB as a modulator targeting contractile machinery in smooth muscle, independent of Ca(2+) mobilization, namely Ca(2+) sensitization. Here, we assessed whether or not 2-APB affects intracellular signaling pathways of Ca(2+) sensitization for contraction using α-toxin permeabilized human detrusor smooth muscle. Although contractions were induced by application of Ca(2+)-containing bath solutions, 2-APB had little effect on contractions induced by 1 µM Ca(2+) alone but significantly reversed the carbachol-induced augmentation of Ca(2+)-induced contraction in the presence of guanosine triphosphate (carbachol-induced Ca(2+) sensitization). The rho kinase inhibitor Y-27632 and protein kinase C inhibitor GF-109203X also reversed the carbachol-mediated Ca(2+) sensitization. Additional application of 2-APB caused a small but significant further attenuation of the contraction in the presence of GF-109203X but not in the presence of Y-27632. Like carbachol, the rho kinase activator; sphingosylphosphorylcholine, protein kinase C activator; phorbol 12,13 dibutyrate, and myosin light chain phosphatase inhibitor; calyculin-A all induced Ca(2+) sensitization. However, the inhibitory activity of 2-APB was limited with sphingosylphosphorylcholine-induced Ca(2+) sensitization. This study revealed a novel inhibitory effect of 2-APB on smooth muscle contractility through inhibition of the rho kinase pathway.
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan.
authors.forename: Nouval
authors.initials: N
authors.lastname: Shahab
authors.forename: Shunichi
authors.initials: S
authors.lastname: Kajioka
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Maya
authors.initials: M
authors.lastname: Hayashi
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Nakayama
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takeda
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Masuda
authors.forename: Seiji
authors.initials: S
authors.lastname: Naito
mesh_terms: D000368:Aged; D000577:Amides / Q000494:pharmacology; D001427:Bacterial Toxins / Q000494:pharmacology; D001896:Boron Compounds / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D006460:Hemolysin Proteins / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000502:physiology
chemical_list: D000577:Amides; D001427:Bacterial Toxins; D001896:Boron Compounds; D006460:Hemolysin Proteins; D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C021091:staphylococcal alpha-toxin; C108830:Y 27632; C109986:2-aminoethoxydiphenyl borate; D054460:rho-Associated Kinases; C070515:bisindolylmaleimide I; D002118:Calcium