title: Heme oxygenase-2 products activate IKCa: role of CO and iron in guinea pig portal vein smooth muscle cells.
abstract: Hemin (10 microM) and carbon monoxide (CO) increased iberiotoxin-blockable IKCa in portal vein smooth muscle cells. CO-induced IKCa activation was abolished by 10 microM ODQ, 10 microM cyclopiazonic acid and 1 microM KT5823. The hemin-induced effect on IKCa was abolished by pretreatment with Sn-protoporphyrin IX, a heme oxygenase inhibitor and Fe2+ chelator but was insensitive to inhibitors of soluble guanylate cyclase (GC) and cGMP-dependent protein kinase (PKG). There was no effect of hemin on IKCa in the presence of 3 microM dithiotreitol into the bath or 3 mM glutathione into the pipette solution. Superoxide dismutase (1000 U/ml) or catalase (3000 U/ml) added into the pipette solution also abolished the effect of hemin on IKCa in this tissue. Additionally, 10 microM hemin could not influence IKCa in Ca2+-free external solution or in the presence of 30 microM SKF 95356. It was concluded that CO increases IKCa via its "conventional" signaling pathway, which involves soluble GC and PKG activation and subsequent stimulation of sarcoplasmic reticulum Ca2+ pump activity resulting in Ca2+-dependent activation of IKCa due to the accumulation of Ca2+ into the space near the plasma membrane. On the other hand, internally produced CO could not yield the same IKCa increase, while Fe2+ derived from heme oxygenase 2-dependent degradation of hemin in portal vein smooth muscle cells gives rise to reactive oxygen species namely hydroxyl and superoxide radicals. Both radicals are responsible for the SKF 95356-sensitive non-selective cation channel activation, the Ca2+ influx and the subsequent increase of Ca2+ concentration near the plasma membrane that augments the KCa channel activity.
authors.affiliation: Institute of Biophysics, Bulgarian Academy of Sciences, Department of Membrane Ion Channels, Sofia, Bulgaria.
authors.forename: Kiril L
authors.initials: KL
authors.lastname: Hristov
authors.forename: Hristo S
authors.initials: HS
authors.lastname: Gagov
authors.forename: Dimitar
authors.initials: D
authors.lastname: Itzev
authors.forename: Dessislava B
authors.initials: DB
authors.lastname: Duridanova
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism*; D002374:Catalase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology / Q000502:physiology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006168:Guinea Pigs; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006427:Hemin / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007501:Iron / Q000378:metabolism; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011169:Portal Vein / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology*; D011524:Protoporphyrins / Q000378:metabolism; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D024681:Potassium Channels, Calcium-Activated; D011524:Protoporphyrins; D006427:Hemin; D002248:Carbon Monoxide; C028025:protoporphyrin IX; D007501:Iron; D002374:Catalase; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2; D013482:Superoxide Dismutase; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D005978:Glutathione; D002118:Calcium