title: Nicorandil enhances cardiac endothelial nitric oxide synthase expression via activation of adenosine triphosphate-sensitive K channel in rat.
abstract: In the heart, nitric oxide activates an adenosine triphosphate (ATP)-sensitive K (K(ATP)) channel that is constructed of two subunits, i.e., an ATP-binding cassette protein sulfonylurea receptor (SUR2) and a pore-forming inward rectifier (Kir6.1 or 6.2). However, whether this K(ATP) channel affects nitric oxide activation is unknown. Our aim was to assess whether pharmacologic activation of the K(ATP) channel by nicorandil contributes to endothelial nitric oxide synthase (eNOS) levels. A total of 21 7-week old male Sprague-Dawley rats were used. Seven were treated by intraperitoneal injection of nicorandil at 3 mg/kg/d; seven were treated with intraperitoneal nicorandil at 3 mg/kg/d after glibenclamide at 12 mg/kg/d twice a day p.o.; and seven were left untreated (controls). At 24 h after treatment, blood pressure and heart rate were measured, and eNOS, SUR2, Kir6.1, and Kir6.2 mRNA levels and eNOS protein levels in the left ventricle were determined by reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. Nicorandil caused tachycardia without a change in blood pressure, whereas glibenclamide had no effect on the nicorandil-induced change in heart rate or on blood pressure. RT-PCR revealed that nicorandil increased the eNOS and SUR2 mRNA levels by 2.2- and 2.0-fold, respectively, (p < 0.01 versus control), and that these increases were completely inhibited by glibenclamide. A significant correlation was observed between eNOS and SUR2 mRNA levels in all experimental rats (r = 0.760, p < 0.001). However, Kir6.1 or 6.2 mRNA level was constant. Western blot analysis revealed that nicorandil caused a 1.6-fold increase in eNOS protein levels (p < 0.01 versus control). This increase was completely inhibited by glibenclamide. In conclusion, up-regulation of eNOS mRNA and protein levels by nicorandil, and inhibition of this upregulation by glibenclamide, were demonstrated in normotensive conscious rat hearts. Nicorandil appears to enhance cardiac eNOS expression via activation of a K(ATP) channel.
authors.affiliation: Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Tochigi, Japan. horinaka@dokkyomed.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Horinaka
authors.forename: N
authors.initials: N
authors.lastname: Kobayashi
authors.forename: T
authors.initials: T
authors.lastname: Higashi
authors.forename: K
authors.initials: K
authors.lastname: Hara
authors.forename: S
authors.initials: S
authors.lastname: Hara
authors.forename: H
authors.initials: H
authors.lastname: Matsuoka
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D005905:Glyburide / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology; D008297:Male; D020108:Nicorandil / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D064233:Sulfonylurea Receptors; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D018528:ATP-Binding Cassette Transporters; C577512:Abcc9 protein, rat; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014665:Vasodilator Agents; D020108:Nicorandil; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D005905:Glyburide