title: Nicorandil and leukocyte activation.
abstract: Nicorandil, a hybrid compound of an ATP-sensitive potassium (KATP ) channel opener and a nitric oxide donor, has been reported to preserve microvascular integrity in patients with reperfused myocardial infarction. The aim of the current study was to test the hypothesis that nicorandil suppresses activation of polymorphonuclear leukocytes (PMNLs), resulting in reduction of PMNL migration into tissue upon ischemia/reperfusion. Nicorandil, along with the mitochondrial KATP channel opener diazoxide and the nitric oxide donors nitroglycerin and isosorbide dinitrate, suppressed pseudopod projection in human PMNLs treated with 10(-9)-formyl-methionyl-leucyl-phenylalanine (FMLP) and subjected to shear stress (5 dyn/cm(2)) with a cone-and-plate shear device. Suppression by nicorandil and diazoxide was reversed by KATP channel blockers, 5 hydroxydecanoate and glibenclamide. FMLP-induced increase of [Ca2+] in PMNLs was suppressed by nicorandil and diazoxide, and 5 hydroxy-decanoate and glibenclamide reversed this suppression. Results of reverse transcription polymerase chain reaction with rat PMNL mRNA indicated the presence of mRNAs of Kir6.2 and Kir6.1 but not mRNAs of sulfonylurea receptor 1 or 2. Isosorbide dinitrate, diazoxide, and nicorandil reduced leukocyte migration and microvascular obstruction in reperfused ischemic tissue of rat mesenteric microcirculation. In conclusion, nicorandil attenuates ischemia/reperfusion-induced PMNL activation via donation of nitric oxide and K channel-related cascade.
authors.affiliation: Department of Integrated Medicine I, Omiya Medical Center, Jichi Medical School, Saitama, Japan. tyasu@omiya.jichi.ac.jp
authors.forename: Takanori
authors.initials: T
authors.lastname: Yasu
authors.forename: Nahoko
authors.initials: N
authors.lastname: Ikeda
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Ishizuka
authors.forename: Eiji
authors.initials: E
authors.lastname: Matsuda
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kawakami
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kuroki
authors.forename: Nobuo
authors.initials: N
authors.lastname: Imai
authors.forename: Hiroto
authors.initials: H
authors.lastname: Ueba
authors.forename: Shunichi
authors.initials: S
authors.lastname: Fukuda
authors.forename: Geert W
authors.initials: GW
authors.lastname: Schmid-Schönbein
authors.forename: Muneyasu
authors.initials: M
authors.lastname: Saito
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006321:Heart / Q000187:drug effects; D006801:Humans; D007511:Ischemia / Q000188:drug therapy; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D008833:Microcirculation / Q000187:drug effects; D020108:Nicorandil / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000628:therapy; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015221:Potassium Channels; D020108:Nicorandil; D009569:Nitric Oxide; D002118:Calcium