title: Involvement of the phosphatidylinositol kinase pathway in augmentation of ATP-sensitive K(+) channel currents by hypo-osmotic stress in rat ventricular myocytes.
abstract: The objective of this study was to investigate the mechanisms of increase in the efficacy of ATP-sensitive K(+) channel (KATP) openings by hypo-osmotic stress. The whole-cell KATP currents (IK,ATP) stimulated by 100 μmol/L pinacidil, a K(+) channel opening drug, were significantly augmented during hypo-osmotic stress (189 mOsmol/L) compared with normal conditions (303 mOsmol/L). The EC50 and Emax value for pinacidil-activated IK,ATP (measured at 0 mV) was 154 μmol/L and 844 pA, respectively, in normal solution and 16.6 μmol/L and 1266 pA, respectively, in hypo-osmotic solution. Augmentation of IK,ATP during hypo-osmotic stress was attenuated by wortmannin (50 μmol/L), an inhibitor of phosphatidylinositol 3- and 4-kinases, but not by (i) phalloidin (30 μmol/L), an actin filament stabilizer, (ii) the absence of Ca(2+) from the internal and external solutions, and (iii) the presence of creatine phosphate (3 mmol/L), which affects creatine kinase regulation of the KATP channels. In the single-channel recordings, an inside-out patch was made after approximately 5 min exposure of the myocyte to hypo-osmotic solution. However, the IC50 value for ATP under such conditions was not different from that obtained in normal osmotic solution. In conclusion, hypo-osmotic stress could augment cardiac IK,ATP through intracellular mechanisms involving the phosphatidylinositol kinase pathway.
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Mitsuyama
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yokoshiki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Irie
authors.forename: Masaya
authors.initials: M
authors.lastname: Watanabe
authors.forename: Kazuya
authors.initials: K
authors.lastname: Mizukami
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D048429:Cell Size; D003402:Creatine Kinase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015640:Ion Channel Gating / Q000187:drug effects; D054086:KATP Channels / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D049990:Membrane Transport Modulators / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D009997:Osmotic Pressure; D010590:Phalloidine / Q000494:pharmacology; D010725:Phosphocreatine / Q000378:metabolism; D020110:Pinacidil / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D015398:Signal Transduction; D013997:Time Factors; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D054086:KATP Channels; D049990:Membrane Transport Modulators; D047428:Protein Kinase Inhibitors; D010725:Phosphocreatine; D010590:Phalloidine; D020110:Pinacidil; D019870:1-Phosphatidylinositol 4-Kinase; D003402:Creatine Kinase; D011188:Potassium; D002118:Calcium; D000077191:Wortmannin