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Natakalim improves post-infarction left ventricular remodeling by restoring the coordinated balance between endothelial function and cardiac hypertrophy.

Zhou HM, Zhong ML, Zhang YF, Cui WY, Long CL, Wang H - Int. J. Mol. Med. (2014)

Bottom Line: Therefore, the present study was carried out to investigate the hypothesis that natakalim, a novel K(ATP) channel opener, ameliorates post-infarction left ventricular remodeling and failure by correcting endothelial dysfunction.Treatment with natakalim at daily oral doses of 1, 3 or 9 mg/kg/day for 8 weeks prevented these changes.Overall, our findings suggest that natakalim prevents post-infarction hypertrophy and cardiac failure by restoring the coordinated balance between endothelial function and cardiac hypertrophy.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing 100850, P.R. China.

ABSTRACT
Endothelial dysfunction can lead to congestive heart failure and the activation of endothelial ATP-sensitive potassium (K(ATP)) channels may contribute to endothelial protection. Therefore, the present study was carried out to investigate the hypothesis that natakalim, a novel K(ATP) channel opener, ameliorates post-infarction left ventricular remodeling and failure by correcting endothelial dysfunction. The effects of myocardial infarction were assessed 8 weeks following left anterior descending coronary artery occlusion in male Wistar rats. Depressed blood pressure, cardiac dysfunction, evidence of left ventricular remodeling and congestive heart failure were observed in the rats with myocardial infarction. Treatment with natakalim at daily oral doses of 1, 3 or 9 mg/kg/day for 8 weeks prevented these changes. Natakalim also prevented the progression to cardiac failure, which was demonstrated by the increase in right ventricular weight/body weight (RVW/BW) and relative lung weight, signs of cardiac dysfunction, as well as the overexpression of atrial and brain natriuretic peptide mRNAs. Our results also demonstrated that natakalim enhanced the downregulation of endothelium-derived nitric oxide, attenuated the upregulation of inducible nitric oxide synthase-derived nitric oxide (NO), inhibited the upregulated endothelin system and corrected the imbalance between prostacyclin and thromboxane A(2). Overall, our findings suggest that natakalim prevents post-infarction hypertrophy and cardiac failure by restoring the coordinated balance between endothelial function and cardiac hypertrophy.

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Effects of natakalim on plasma concentration of endothelin (ET)-1 and protein expression of endothelin receptors A and B in cardiac tissue of rats with myocardial infarction (MI). (A) Quantification of plasma concentration of ET-1; (B and D) representative images of ETA and ETB protein expression (immunohistological staining, ×100 magnification); (C and E) quantification of relative values of ETA and ETB protein expression. (B and D) Panel 1, sham-oeprated group; panel 2, MI group; panel 3, natakalim 1 mg/kg/day group; panel 4, natakalim 3 mg/kg/day group; panel 5, natakalim 9 mg/kg/day group. The plasma concentration of ET-1 and the cardiac tissue protein levels of ETA and ETB measured by immunohistochemistry were significantly increased in the rats with heart failure. These effects were reversed by treatment with natakalim at all doses for 8 weeks. Serum ET-1 data are expressed as the means ± SD, n=10–12; ETA and ETB data are expressed as the means ± SD, n=6; **P<0.01 vs. sham-operated rats (sham); #P<0.05 and ##P<0.01 vs. rats with MI. Nat, natakalim.
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f5-ijmm-34-05-1209: Effects of natakalim on plasma concentration of endothelin (ET)-1 and protein expression of endothelin receptors A and B in cardiac tissue of rats with myocardial infarction (MI). (A) Quantification of plasma concentration of ET-1; (B and D) representative images of ETA and ETB protein expression (immunohistological staining, ×100 magnification); (C and E) quantification of relative values of ETA and ETB protein expression. (B and D) Panel 1, sham-oeprated group; panel 2, MI group; panel 3, natakalim 1 mg/kg/day group; panel 4, natakalim 3 mg/kg/day group; panel 5, natakalim 9 mg/kg/day group. The plasma concentration of ET-1 and the cardiac tissue protein levels of ETA and ETB measured by immunohistochemistry were significantly increased in the rats with heart failure. These effects were reversed by treatment with natakalim at all doses for 8 weeks. Serum ET-1 data are expressed as the means ± SD, n=10–12; ETA and ETB data are expressed as the means ± SD, n=6; **P<0.01 vs. sham-operated rats (sham); #P<0.05 and ##P<0.01 vs. rats with MI. Nat, natakalim.

Mentions: The serum concentration of ET-1 and the cardiac tissue protein levels of ETA and ETB were significantly increased in the rats following MI (P<0.01; Fig. 5). These findings indicate that the MI-induced CHF led to an increase in the synthesis and release of ET-1 and to the increased expression of ET receptors. Treatment with natakalim for 8 weeks markedly attenuated the elevated serum levels of ET-1 and the production of ETA and ETB proteins in the cardiac tissue; the levels returned to almost normal levels.


Natakalim improves post-infarction left ventricular remodeling by restoring the coordinated balance between endothelial function and cardiac hypertrophy.

Zhou HM, Zhong ML, Zhang YF, Cui WY, Long CL, Wang H - Int. J. Mol. Med. (2014)

Effects of natakalim on plasma concentration of endothelin (ET)-1 and protein expression of endothelin receptors A and B in cardiac tissue of rats with myocardial infarction (MI). (A) Quantification of plasma concentration of ET-1; (B and D) representative images of ETA and ETB protein expression (immunohistological staining, ×100 magnification); (C and E) quantification of relative values of ETA and ETB protein expression. (B and D) Panel 1, sham-oeprated group; panel 2, MI group; panel 3, natakalim 1 mg/kg/day group; panel 4, natakalim 3 mg/kg/day group; panel 5, natakalim 9 mg/kg/day group. The plasma concentration of ET-1 and the cardiac tissue protein levels of ETA and ETB measured by immunohistochemistry were significantly increased in the rats with heart failure. These effects were reversed by treatment with natakalim at all doses for 8 weeks. Serum ET-1 data are expressed as the means ± SD, n=10–12; ETA and ETB data are expressed as the means ± SD, n=6; **P<0.01 vs. sham-operated rats (sham); #P<0.05 and ##P<0.01 vs. rats with MI. Nat, natakalim.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4199399&req=5

f5-ijmm-34-05-1209: Effects of natakalim on plasma concentration of endothelin (ET)-1 and protein expression of endothelin receptors A and B in cardiac tissue of rats with myocardial infarction (MI). (A) Quantification of plasma concentration of ET-1; (B and D) representative images of ETA and ETB protein expression (immunohistological staining, ×100 magnification); (C and E) quantification of relative values of ETA and ETB protein expression. (B and D) Panel 1, sham-oeprated group; panel 2, MI group; panel 3, natakalim 1 mg/kg/day group; panel 4, natakalim 3 mg/kg/day group; panel 5, natakalim 9 mg/kg/day group. The plasma concentration of ET-1 and the cardiac tissue protein levels of ETA and ETB measured by immunohistochemistry were significantly increased in the rats with heart failure. These effects were reversed by treatment with natakalim at all doses for 8 weeks. Serum ET-1 data are expressed as the means ± SD, n=10–12; ETA and ETB data are expressed as the means ± SD, n=6; **P<0.01 vs. sham-operated rats (sham); #P<0.05 and ##P<0.01 vs. rats with MI. Nat, natakalim.
Mentions: The serum concentration of ET-1 and the cardiac tissue protein levels of ETA and ETB were significantly increased in the rats following MI (P<0.01; Fig. 5). These findings indicate that the MI-induced CHF led to an increase in the synthesis and release of ET-1 and to the increased expression of ET receptors. Treatment with natakalim for 8 weeks markedly attenuated the elevated serum levels of ET-1 and the production of ETA and ETB proteins in the cardiac tissue; the levels returned to almost normal levels.

Bottom Line: Therefore, the present study was carried out to investigate the hypothesis that natakalim, a novel K(ATP) channel opener, ameliorates post-infarction left ventricular remodeling and failure by correcting endothelial dysfunction.Treatment with natakalim at daily oral doses of 1, 3 or 9 mg/kg/day for 8 weeks prevented these changes.Overall, our findings suggest that natakalim prevents post-infarction hypertrophy and cardiac failure by restoring the coordinated balance between endothelial function and cardiac hypertrophy.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing 100850, P.R. China.

ABSTRACT
Endothelial dysfunction can lead to congestive heart failure and the activation of endothelial ATP-sensitive potassium (K(ATP)) channels may contribute to endothelial protection. Therefore, the present study was carried out to investigate the hypothesis that natakalim, a novel K(ATP) channel opener, ameliorates post-infarction left ventricular remodeling and failure by correcting endothelial dysfunction. The effects of myocardial infarction were assessed 8 weeks following left anterior descending coronary artery occlusion in male Wistar rats. Depressed blood pressure, cardiac dysfunction, evidence of left ventricular remodeling and congestive heart failure were observed in the rats with myocardial infarction. Treatment with natakalim at daily oral doses of 1, 3 or 9 mg/kg/day for 8 weeks prevented these changes. Natakalim also prevented the progression to cardiac failure, which was demonstrated by the increase in right ventricular weight/body weight (RVW/BW) and relative lung weight, signs of cardiac dysfunction, as well as the overexpression of atrial and brain natriuretic peptide mRNAs. Our results also demonstrated that natakalim enhanced the downregulation of endothelium-derived nitric oxide, attenuated the upregulation of inducible nitric oxide synthase-derived nitric oxide (NO), inhibited the upregulated endothelin system and corrected the imbalance between prostacyclin and thromboxane A(2). Overall, our findings suggest that natakalim prevents post-infarction hypertrophy and cardiac failure by restoring the coordinated balance between endothelial function and cardiac hypertrophy.

Show MeSH
Related in: MedlinePlus