Nicorandil enhances cardiac endothelial nitric oxide synthase expression via activation of adenosine triphosphate-sensitive K channel in rat

Citation
S. Horinaka et al., Nicorandil enhances cardiac endothelial nitric oxide synthase expression via activation of adenosine triphosphate-sensitive K channel in rat, J CARDIO PH, 38(2), 2001, pp. 200-210
Citations number
43
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Journal title
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
ISSN journal
0160-2446 → ACNP
Volume
38
Issue
2
Year of publication
2001
Pages
200 - 210
Database
ISI
SICI code
0160-2446(200108)38:2<200:NECENO>2.0.ZU;2-N
Abstract
In the heart, nitric oxide activates an adenosine triphosphate (ATP)-sensit ive K (K-ATP) channel that is constructed of two subunits, i.e., an ATP-bin ding cassette protein sulfonylurea receptor (SUR2) and a pore-forming inwar d rectifier (Kir6.1 or 6.2). However, whether this K-ATP channel affects ni tric oxide activation is unknown. Our aim was to assess whether pharmacolog ic 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 an d 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 tr anscription polymerase chain reaction (RT-PCR) and Western blot analysis. N icorandil caused tachycardia without a change in blood pressure, whereas gl ibenclamide 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 contr ol), 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 l evel was constant. Western blot analysis revealed that nicorandil caused a 1.6-fold increase in eNOS protein levels (p < 0.01 versus control). This in crease was completely inhibited by glibenclamide. In conclusion, up-regulat ion of eNOS mRNA and protein levels by nicorandil, and inhibition of this u pregulation by glibenclamide, were demonstrated in normotensive conscious r at hearts. Nicorandil appears to enhance cardiac eNOS expression via activa tion of a K-ATP channel.