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

Abstract

Endothelial dysfunction can lead to congestive heart failure and the activation of endothelial ATP-sensitive potassium (KATP) channels may contribute to endothelial protection. Therefore, the present study was carried out to investigate the hypothesis that natakalim, a novel KATP 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 A2. Overall, our findings suggest that natakalim prevents post-infarction hypertrophy and cardiac failure by restoring the coordinated balance between endothelial function and cardiac hypertrophy.

Natakalim Ameliorates Isoproterenol-Induced Chronic Heart Failure by Protecting against Endothelial Dysfunction

“…En-dothelial cells regulate the functions of the cardiovascular system by secreting nitric oxide (NO), endothelin-1 (ET-1), prostacyclin (PGI 2 ), and other bioactive substances, which play important roles in the pathophysiology of heart failure [3][4][5][6] .…”

Pharmacological evidence: a new therapeutic approach to the treatment of chronic heart failure through SUR2B/Kir6.1 channel in endothelial cells

“…We investigated the effects of both Ipt and Nat in PO-CHF and explored the effects of Nat in MI-CHF and ISO-CHF. Our results in the independent experiments indicated that both Ipt and Nat could restore endothelial function and improve PO-CHF, MI-CHF, ISO-CHF, and HCVR [7][8][9][10] .…”

“…In our previous study, the effects of Ipt were observed in PO-CHF at doses of 1, 3, and 9 mg/kg, and Nat effect was observed in the PO-CHF and MI-CHF experiments. These results showed that both Ipt and Nat could significantly improve the hemodynamics, cardiac disorders, and cardiac remodeling, and could decrease the levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) [7][8][9][10] . In the present study, we observed the effects of Nat at doses of 1, 3, and 9 mg/kg, and the results were in accordance with previously obtained results [7][8][9][10] .…”

“…These results showed that both Ipt and Nat could significantly improve the hemodynamics, cardiac disorders, and cardiac remodeling, and could decrease the levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) [7][8][9][10] . In the present study, we observed the effects of Nat at doses of 1, 3, and 9 mg/kg, and the results were in accordance with previously obtained results [7][8][9][10] . Therefore, these results demonstrated that the two SUR2B/ Kir6.1 channel openers showed equivalent effects against CHF in the same experiment and that the drugs with different chemical structures aimed at the same target had similar Antagonism of the KCB, Gli, against the SUR2B/Kir6.1 channel opener, Nat, in vivo SUR2B/Kir6.1 channels are mainly distributed in blood vessels and are closely associated with endothelial func tion [6,14,15] .…”

“…The myocardial samples were routinely fixed in 2.5% glutaraldehyde in 0.1 mol/L phosphate buffer (pH 7.3) and post-fixed in buffered 1% osmium tetroxide. TEM (Hitachi H-7650, Japan) and immunohistological staining were performed in accordance with previously reported methods [8,9] .…”