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Nicorandil attenuates monocrotaline-induced vascular endothelial damage and pulmonary arterial hypertension.

Sahara M, Sata M, Morita T, Hirata Y, Nagai R - PLoS ONE (2012)

Bottom Line: Late treatment with nicorandil for the established PAH was also effective in suppressing the additional progression of PAH.These beneficial effects of nicorandil were blocked similarly by glibenclamide and l-NAME.Next, HUVECs were incubated in serum-free medium and then exhibited apoptotic morphology, while these changes were significantly attenuated by nicorandil administration.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan. saharam-tky@umin.ac.jp

ABSTRACT

Background: An antianginal K(ATP) channel opener nicorandil has various beneficial effects on cardiovascular systems; however, its effects on pulmonary vasculature under pulmonary arterial hypertension (PAH) have not yet been elucidated. Therefore, we attempted to determine whether nicorandil can attenuate monocrotaline (MCT)-induced PAH in rats.

Materials and methods: Sprague-Dawley rats injected intraperitoneally with 60 mg/kg MCT were randomized to receive either vehicle; nicorandil (5.0 mg·kg(-1)·day(-1)) alone; or nicorandil as well as either a K(ATP) channel blocker glibenclamide or a nitric oxide synthase (NOS) inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME), from immediately or 21 days after MCT injection. Four or five weeks later, right ventricular systolic pressure (RVSP) was measured, and lung tissue was harvested. Also, we evaluated the nicorandil-induced anti-apoptotic effects and activation status of several molecules in cell survival signaling pathway in vitro using human umbilical vein endothelial cells (HUVECs).

Results: Four weeks after MCT injection, RVSP was significantly increased in the vehicle-treated group (51.0±4.7 mm Hg), whereas it was attenuated by nicorandil treatment (33.2±3.9 mm Hg; P<0.01). Nicorandil protected pulmonary endothelium from the MCT-induced thromboemboli formation and induction of apoptosis, accompanied with both upregulation of endothelial NOS (eNOS) expression and downregulation of cleaved caspase-3 expression. Late treatment with nicorandil for the established PAH was also effective in suppressing the additional progression of PAH. These beneficial effects of nicorandil were blocked similarly by glibenclamide and l-NAME. Next, HUVECs were incubated in serum-free medium and then exhibited apoptotic morphology, while these changes were significantly attenuated by nicorandil administration. Nicorandil activated the phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways in HUVECs, accompanied with the upregulation of both eNOS and Bcl-2 expression.

Conclusions: Nicorandil attenuated MCT-induced vascular endothelial damage and PAH through production of eNOS and anti-apoptotic factors, suggesting that nicorandil might have a promising therapeutic potential for PAH.

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The effects of nicorandil in the reversal protocol.The RVSP (A) and the RV/LV ratio (B) in the vehicle group increased at 21 days after the MCT injection (MCT-21) as compared to the baseline, and additionally increased in the next 2 weeks (MCT-35). Late treatment with nicorandil on days 21–35 prevented the additional increase in these parameters, while these effects were blocked by glibenclamide and l-NAME. #P<0.05 and ##P<0.01 vs. normal control; *P<0.05 and **P<0.01 vs. vehicle (MCT-35); †P<0.05 vs. nicorandil (5.0 mg·kg−1·day−1). (C) The histological findings of the PAs (arrows) in the reversal protocol. Top, HE staining; bottom, EVG staining. Scale bar, 50 µm. (D) Late treatment with nicorandil on days 21–35 prevented further increase in the percent medial wall thickness of the PAs. The indications of the symbols are the same as those in panel (A). (E) Survival analysis in the reversal protocol. Each group comprised 14–15 rats. *P<0.05 vs. vehicle.
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pone-0033367-g005: The effects of nicorandil in the reversal protocol.The RVSP (A) and the RV/LV ratio (B) in the vehicle group increased at 21 days after the MCT injection (MCT-21) as compared to the baseline, and additionally increased in the next 2 weeks (MCT-35). Late treatment with nicorandil on days 21–35 prevented the additional increase in these parameters, while these effects were blocked by glibenclamide and l-NAME. #P<0.05 and ##P<0.01 vs. normal control; *P<0.05 and **P<0.01 vs. vehicle (MCT-35); †P<0.05 vs. nicorandil (5.0 mg·kg−1·day−1). (C) The histological findings of the PAs (arrows) in the reversal protocol. Top, HE staining; bottom, EVG staining. Scale bar, 50 µm. (D) Late treatment with nicorandil on days 21–35 prevented further increase in the percent medial wall thickness of the PAs. The indications of the symbols are the same as those in panel (A). (E) Survival analysis in the reversal protocol. Each group comprised 14–15 rats. *P<0.05 vs. vehicle.

Mentions: In the reversal protocol, we evaluated whether nicorandil was also effective against established PAH. The RVSP and the RV/LV ratio in the vehicle group increased to 38.7±4.7 mm Hg and 0.33±0.06 at 21 days after the MCT injection (P<0.05 vs. the normal control, respectively), and moreover, these parameters increased to 55.0±4.6 mm Hg and 0.47±0.04 at 35 days (P<0.01 vs. the normal control, respectively) (Figure 5A and 5B). Late treatment with nicorandil on days 21–35 prevented the additional increases in the RVSP and RV/LV ratio, as the values in the nicorandil-treated group were 37.3±2.9 mm Hg and 0.33±0.03 at day 35 (P<0.05 vs. the vehicle, respectively). Histological analysis revealed that nicorandil prevented additional medial wall thickening of the PAs in MCT-injured lungs (Figure 5C and 5D). The survival analysis revealed that nicorandil improved the survival rate in rats with established PAH in the reversal protocol (Figure 5E). The survival rate at 42 days after the MCT injection was 13% in the vehicle group and 40% in the nicorandil-treated group (P<0.05). In contrast, these beneficial effects of nicorandil were blocked by glibenclamide and l-NAME, respectively.


Nicorandil attenuates monocrotaline-induced vascular endothelial damage and pulmonary arterial hypertension.

Sahara M, Sata M, Morita T, Hirata Y, Nagai R - PLoS ONE (2012)

The effects of nicorandil in the reversal protocol.The RVSP (A) and the RV/LV ratio (B) in the vehicle group increased at 21 days after the MCT injection (MCT-21) as compared to the baseline, and additionally increased in the next 2 weeks (MCT-35). Late treatment with nicorandil on days 21–35 prevented the additional increase in these parameters, while these effects were blocked by glibenclamide and l-NAME. #P<0.05 and ##P<0.01 vs. normal control; *P<0.05 and **P<0.01 vs. vehicle (MCT-35); †P<0.05 vs. nicorandil (5.0 mg·kg−1·day−1). (C) The histological findings of the PAs (arrows) in the reversal protocol. Top, HE staining; bottom, EVG staining. Scale bar, 50 µm. (D) Late treatment with nicorandil on days 21–35 prevented further increase in the percent medial wall thickness of the PAs. The indications of the symbols are the same as those in panel (A). (E) Survival analysis in the reversal protocol. Each group comprised 14–15 rats. *P<0.05 vs. vehicle.
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Related In: Results  -  Collection

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pone-0033367-g005: The effects of nicorandil in the reversal protocol.The RVSP (A) and the RV/LV ratio (B) in the vehicle group increased at 21 days after the MCT injection (MCT-21) as compared to the baseline, and additionally increased in the next 2 weeks (MCT-35). Late treatment with nicorandil on days 21–35 prevented the additional increase in these parameters, while these effects were blocked by glibenclamide and l-NAME. #P<0.05 and ##P<0.01 vs. normal control; *P<0.05 and **P<0.01 vs. vehicle (MCT-35); †P<0.05 vs. nicorandil (5.0 mg·kg−1·day−1). (C) The histological findings of the PAs (arrows) in the reversal protocol. Top, HE staining; bottom, EVG staining. Scale bar, 50 µm. (D) Late treatment with nicorandil on days 21–35 prevented further increase in the percent medial wall thickness of the PAs. The indications of the symbols are the same as those in panel (A). (E) Survival analysis in the reversal protocol. Each group comprised 14–15 rats. *P<0.05 vs. vehicle.
Mentions: In the reversal protocol, we evaluated whether nicorandil was also effective against established PAH. The RVSP and the RV/LV ratio in the vehicle group increased to 38.7±4.7 mm Hg and 0.33±0.06 at 21 days after the MCT injection (P<0.05 vs. the normal control, respectively), and moreover, these parameters increased to 55.0±4.6 mm Hg and 0.47±0.04 at 35 days (P<0.01 vs. the normal control, respectively) (Figure 5A and 5B). Late treatment with nicorandil on days 21–35 prevented the additional increases in the RVSP and RV/LV ratio, as the values in the nicorandil-treated group were 37.3±2.9 mm Hg and 0.33±0.03 at day 35 (P<0.05 vs. the vehicle, respectively). Histological analysis revealed that nicorandil prevented additional medial wall thickening of the PAs in MCT-injured lungs (Figure 5C and 5D). The survival analysis revealed that nicorandil improved the survival rate in rats with established PAH in the reversal protocol (Figure 5E). The survival rate at 42 days after the MCT injection was 13% in the vehicle group and 40% in the nicorandil-treated group (P<0.05). In contrast, these beneficial effects of nicorandil were blocked by glibenclamide and l-NAME, respectively.

Bottom Line: Late treatment with nicorandil for the established PAH was also effective in suppressing the additional progression of PAH.These beneficial effects of nicorandil were blocked similarly by glibenclamide and l-NAME.Next, HUVECs were incubated in serum-free medium and then exhibited apoptotic morphology, while these changes were significantly attenuated by nicorandil administration.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan. saharam-tky@umin.ac.jp

ABSTRACT

Background: An antianginal K(ATP) channel opener nicorandil has various beneficial effects on cardiovascular systems; however, its effects on pulmonary vasculature under pulmonary arterial hypertension (PAH) have not yet been elucidated. Therefore, we attempted to determine whether nicorandil can attenuate monocrotaline (MCT)-induced PAH in rats.

Materials and methods: Sprague-Dawley rats injected intraperitoneally with 60 mg/kg MCT were randomized to receive either vehicle; nicorandil (5.0 mg·kg(-1)·day(-1)) alone; or nicorandil as well as either a K(ATP) channel blocker glibenclamide or a nitric oxide synthase (NOS) inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME), from immediately or 21 days after MCT injection. Four or five weeks later, right ventricular systolic pressure (RVSP) was measured, and lung tissue was harvested. Also, we evaluated the nicorandil-induced anti-apoptotic effects and activation status of several molecules in cell survival signaling pathway in vitro using human umbilical vein endothelial cells (HUVECs).

Results: Four weeks after MCT injection, RVSP was significantly increased in the vehicle-treated group (51.0±4.7 mm Hg), whereas it was attenuated by nicorandil treatment (33.2±3.9 mm Hg; P<0.01). Nicorandil protected pulmonary endothelium from the MCT-induced thromboemboli formation and induction of apoptosis, accompanied with both upregulation of endothelial NOS (eNOS) expression and downregulation of cleaved caspase-3 expression. Late treatment with nicorandil for the established PAH was also effective in suppressing the additional progression of PAH. These beneficial effects of nicorandil were blocked similarly by glibenclamide and l-NAME. Next, HUVECs were incubated in serum-free medium and then exhibited apoptotic morphology, while these changes were significantly attenuated by nicorandil administration. Nicorandil activated the phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways in HUVECs, accompanied with the upregulation of both eNOS and Bcl-2 expression.

Conclusions: Nicorandil attenuated MCT-induced vascular endothelial damage and PAH through production of eNOS and anti-apoptotic factors, suggesting that nicorandil might have a promising therapeutic potential for PAH.

Show MeSH
Related in: MedlinePlus