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.

Nicorandil Promotes Myocardial Capillary and Arteriolar Growth in the Failing Heart of Dahl Salt-Sensitive Hypertensive Rats

“…The dose of nicorandil was determined from our preliminary observations and the results of a previous study. 17 DS rats maintained on the 0.3% NaCl diet after 6 weeks of age served as age-matched controls (DS-C; nϭ8). The diet and tap water were provided ad libitum throughout the experiment.…”

Benefit of nicorandil using an immunologic murine model of experimental colitis

“…As mentioned previously, nicorandil contains a nitrate moiety in its chemical structure, allowing it to function as a NO donor. On the other hand, other investigations [56,57] showed that nicorandil is able to upregulate eNOS expression and increase NO release following ischemia. Thus, it seems that upregulation of eNOS, which leads to acute production of NO, in addition to the NO donor property of nicorandil and the nicotinamide moiety that makes it a potent hydroxyl radical scavenger, is partially or totally responsible for its beneficial effects in remission of IBD.…”

Protective effect of nicorandil on hypoxia-induced apoptosis in HPAECs through inhibition of p38 MAPK phosphorylation

“…Findings of studies on cardiovascular disease have shown that nicorandil protects endothelial function (14) and enhances eNOS expression (16). In a monocrotaline-induced pulmonary arterial hypertension model, similar effects of nicorandil were identified (15).…”

“…A number of studies (14)(15)(16) have demonstrated the critical role of eNOS in PH, particularly in the maintenance of endothelial function. Findings of studies on cardiovascular disease have shown that nicorandil protects endothelial function (14) and enhances eNOS expression (16).…”

“…Previous studies indicated that KATP channels may also affect the endothelin system. Nicorandil inhibits endothelial apoptosis, enhances eNOS expression and preserves endothelial function via activation of the mitoKATP channels in the endothelial cell (12)(13)(14)(15)(16). In addition, KATP channels have been reported to interact with various MAPK signals (3,(17)(18)(19).…”