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

Zhong, Mingli; Zhou, Hongmin; Long, Chao-Liang; Zhang, Yanfang; Cui, Wenyu; Zhang, Hao; Wang, Hai

doi:10.1159/000445383

Cited by 5 publications

(5 citation statements)

References 31 publications

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“…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] .…”

Section: Introductionsupporting

confidence: 50%

“…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] .…”

Section: Discussionmentioning

confidence: 95%

“…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] .…”

Section: Discussionmentioning

confidence: 95%

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

Wang

Long

Cui³

et al. 2016

Acta Pharmacol Sin

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Both iptakalim (Ipt) and natakalim (Nat) activate the SUR2B/Kir6.1 channel, an ATP-sensitive potassium channel (K ATP ) subtype, with high selectivity. In this study we investigated the therapeutic effects of Ipt and Nat against isoproterenol-induced chronic heart failure (ISO-CHF) in rats, and demonstrated a new therapeutic approach to the treatment of CHF through activation of the SUR2B/Kir6.1 channel in endothelial cells. In ISO-CHF rats, oral administration of Nat (1, 3, 9 mg·kg -1 ·d -1 ) or Ipt (3 mg·kg -1 ·d -1 ) for 60 days significantly improved cardiac dysfunction, reversed cardiac remodeling, significantly attenuated the pathological increases in BNP levels, and improved endothelial dysfunction by adjusting the balance between endothelin and NO systems. The therapeutic effects of Nat were prevented by the selective K ATP blocker glibenclamine (Gli, 50 mg·kg -1 ·d -1 ), confirming that these effects were mediated through activation of the SUR2B/Kir6.1 channel in endothelial cells. The molecular mechanisms underlying the therapeutic effects of Nat were further addressed using proteomic methods. We identified 724 proteins in the plasma of ISO-CHF rats; 55 proteins were related to Nat. These differentially expressed proteins were mainly involved in single-organism processes and the regulation of biological quality relative to CHF, including proteasome (Psm) and ATP protein clusters. We screened out PRKAR2β, GAS6/eNOS/NO and NO/PKG/VASP pathways involved in the amelioration of CHF among the 24 enriched pathways. We further confirmed 6 protein candidates, including PRKAR2β, GAS6 and VASP, which were involved in the endothelial mechanisms, and ATP, TIMP3 and AGT, which contributed to its cardiovascular actions. This study demonstrates a new pharmacological approach to the treatment of CHF through activation of the SUR2B/Kir6.1 channel in endothelial cells, and that the eNOS/VASP pathways are involved in its signaling mechanisms.

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Section: Introductionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 95%

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

Wang

Long

Cui³

et al. 2016

Acta Pharmacol Sin

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“…NO is a pleiotropic factor that regulates a variety of functions in the organism. Zhong et al [ 32 ] reported that NO levels were increased in the plasma of rats that were treated with ISO alone. This increase in plasma NO was accompanied by a decreased expression of eNOS and an increased expression of iNOS showing that, in ISO-induced myocardial infarction, elevated NO levels can be considered as a marker of inflammation.…”

Section: Discussionmentioning

confidence: 99%

Vasorelaxant and Antioxidant Effects of Aframomum pruinosum Gagnep. (Zingiberaceae) Seed Extracts May Mediate Their Cardioprotective Activity against Isoproterenol-Induced Myocardial Infarction

Nguelefack‐Mbuyo

Nokam

Tchinda

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Aframomum pruinosum seeds are traditionally used in Cameroon to treat cardiac palpitations. The present work evaluates the cardioprotective effects of the aqueous (AE) and ethanolic (EE) extracts from A. pruinosum seeds against isoproterenol-induced myocardial infarction. Male Wistar rats were pretreated for 14 days with AE or EE at doses of 75 and 150 mg/kg/day or propranolol (10 mg/kg/day). On days 15 and 16, they were injected subcutaneously with isoproterenol (85 mg/kg/day). Blood pressure and heart rate were weekly recorded by tail-cuff plethysmography during pretreatment and 24 hours after the second dose of isoproterenol. At the end of the treatment period, serum Lactate Dehydrogenase (LDH), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), cardiac nitric oxide (NO), myeloperoxidase (MPO), and oxidative stress parameters (SOD, catalase, MDA, and GSH) were assayed. Sections of left ventricle tissue were subjected to histological analysis. The vasorelaxant effects of cumulative concentrations of AE or EE (3–300 µg/mL) were evaluated on intact or endothelium-denuded isolated aorta rings precontracted with noradrenaline (1 µM). The vasorelaxant effects of the plant extracts were also tested in the presence of Nω-nitro-L-arginine methyl ester (L-NAME; 100 µM). AE and EE significantly prevented blood pressure decrease and heart rate increase elicited by isoproterenol. Both plant extracts inhibited the increase in ALT, AST, NO, and MPO but did not prevent LDH surge. Oxidative stress parameters were improved following A. pruinosum pretreatment. AE and EE highly reduced cardiomyocyte necrosis and fibrosis but did not prevent leukocyte infiltration. Both extracts induced a concentration-dependent vasorelaxation that was significantly inhibited by the destruction of the endothelium and by L-NAME. Extracts of A. pruinosum exhibited cardioprotective effects, and EE was the most active. The cardioprotective effects of A. pruinosum extracts could be ascribed to their antioxidant, antinecrotic, and endothelium-dependent vasorelaxant effects.

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“…Chronic heart failure (CHF) occurs as a result of a number of cardiovascular diseases and is a complex pathophysiological process; neurohormonal disorders and ventricular remodeling are important pathophysiological changes for patients with CHF (1). A large dose (>85 mg/kg) of isoproterenol (ISO) may cause diffuse myocardial necrosis and fibrosis, which may gradually develop into dilated cardiomyopathy heart failure (2). ISO may cause myocardial necrosis similar to myocardial infarction, but it maintains effective coronary circulation (3).…”

Section: Introductionmentioning

confidence: 99%

Cardioprotective effects of ulinastatin against isoproterenol-induced chronic heart failure through the PI3K‑Akt, p38 MAPK and NF-κB pathways

Hao

Jiang

et al. 2017

Mol Med Report

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The purpose of the present study was to evaluate the cardioprotective effect of ulinastatin against isoproterenol‑induced chronic heart failure (CHF). Compared with the control group, treatment with ulinastatin decreased interventricular septal thickness and left ventricular posterior wall thickness, and improved the left ventricular ejection fraction, left ventricular fractional shortening and peak E and peak A ratio in the isoproterenol‑induced CHF rat. In addition, ulinastatin suppressed inflammation, oxidative stress and apoptosis in heart tissue from isoproterenol‑induced CHF rats. Ulinastatin induced the activation of the phosphatidylinositol 3‑kinase (PI3K)/RAC‑α serine/threonine protein kinase (Akt) signaling pathway and downregulated the p38 mitogen‑activated protein kinase (MAPK) and nuclear factor (NF)‑κB pathway in isoproterenol‑induced CHF rats. These data demonstrated the cardioprotective effect of ulinastatin against isoproterenol‑induced chronic heart failure through the PI3K‑Akt, p38 MAPK and NF‑κB pathways.

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

Cited by 5 publications

References 31 publications

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

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

Vasorelaxant and Antioxidant Effects of Aframomum pruinosum Gagnep. (Zingiberaceae) Seed Extracts May Mediate Their Cardioprotective Activity against Isoproterenol-Induced Myocardial Infarction

Cardioprotective effects of ulinastatin against isoproterenol-induced chronic heart failure through the PI3K‑Akt, p38 MAPK and NF-κB pathways

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