Cardioprotective effects and concentration-response relationship of aminoalcohol-diterpenoid alkaloids from Aconitum carmichaelii

Wang, Xiaoya; Zhou, Qin‐Mei; Guo, Li; Dai, Ou; Meng, Chun-Wang; Miao, Lu-Lin; Liu, Jie; Lin, Qiao; Peng, Cheng; Xiong, Liang

doi:10.1016/j.fitote.2020.104822

Cited by 16 publications

(11 citation statements)

References 24 publications

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“…An abundance of studies has shown that RS and FZ strengthen the heart, anti-inflammatory, cardiovascular protection, and other intervention and treatment of HF pharmacological effects ( Wang et al, 2021 ; Wang et al, 2020 ; Zhang and Li, 2013 ). Combined with the results of pharmacodynamics, we found that RS-FZ significantly ameliorated myocardial fibrosis, enhanced cardiac function, and reduced the serum HF marker (BNP) level in rats with HF, with an apparent therapeutic effect.…”

Section: Discussionmentioning

confidence: 99%

“…RS-FZ is a classic herb pair often used for HF treatment and contained in many medical preparations ( Huang et al, 2020 ). Furthermore, a large amount of pharmacological experimental studies have shown that both RS and FZ have an independent anti-HF effect ( Liu et al, 2021 ; Wang et al, 2021 ), and the therapeutic effect was enhanced after the compatibility of RS and FZ by increasing myocardial contractility, inhibiting the expression of inflammatory factors and improving hemodynamics, etc ( Liu et al, 2020 ). However, the underlying mechanism of this herb pair is still unclear.…”

Section: Introductionmentioning

confidence: 99%

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The mechanism of Renshen-Fuzi herb pair for treating heart failure—Integrating a cardiovascular pharmacological assessment with serum metabolomics

Chen

Xie

et al. 2022

Front. Pharmacol.

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Background: Renshen-Fuzi herb pair (RS-FZ) is often used in the clinical treatment of heart failure (HF) and has a remarkable therapeutic effect. However, the mechanism of RS-FZ for treating HF remains unclear. In our study, we explored the mechanism of RS-FZ for treating HF.Methods: Evaluation of RS-FZ efficacy by cardiovascular pharmacology. Moreover, Global metabolomics profiling of the serum was detected by UPLC-QTOF/MS. Multivariate statistics analyzed the specific serum metabolites and corresponding metabolic pathways. Combining serum metabolomics with network pharmacology, animal experiments screened and validated the critical targets of RS-FZ intervention in HF.Results: RS-FZ significantly ameliorated myocardial fibrosis, enhanced cardiac function, and reduced the serum HF marker (brain natriuretic peptide) level in rats with HF. Through topological analysis of the “Metabolite-Target-Component” interaction network, we found that 79 compounds of RS-FZ directly regulated the downstream specific serum metabolites by acting on four critical target proteins (CYP2D6, EPHX2, MAOB, and ENPP2). The immunohistochemistry results showed that RS-FZ observably improved the expression of CYP2D6 and ENPP2 proteins while decreasing the expression of EPHX2 and MAOB proteins dramatically.Conclusion: The integrated cardiovascular pharmacological assessment with serum metabolomics revealed that RS-FZ plays a crucial role in the treatment of HF by intervening in CYP2D6, EPHX2, MAOB, and ENPP2 target proteins. It provides a theoretical basis for RS-FZ for treating HF.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The mechanism of Renshen-Fuzi herb pair for treating heart failure—Integrating a cardiovascular pharmacological assessment with serum metabolomics

Chen

Xie

et al. 2022

Front. Pharmacol.

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“…Preparation of compounds (6)(7)(8)(9)(10)(11): Compounds 6 and 8-11 were obtained by hydrolyzing the corresponding esters apetaldine F [19], apetaldine J [20], brevicanine [21], talassicumine A [19], and acobretine C [21], respectively. Compound 7 is a naturally occurring C 19 -diterpenoid alkaloids in Aconitum novoluridum [22] 13 C-NMR (CDCl 3 , 100 MHz) data, see ▶ Table 2 [26].…”

Section: Cammaconine (Compoundmentioning

confidence: 99%

“…To further investigate the structure-cardiac effect relationships, a series of C 19 -diterpenoid alkaloids with 18-OH were prepared. Eight tested compounds (5)(6)(7)(8)(9)(10)(11)(12) demonstrated measurable cardioactivity, of which compound 5 with an N-methyl group and compound 7 with a methoxy at C-16 showed stronger effects on ventricular contraction than the other compounds. Thus, 18-OH is a critical structural feature determining cardiotonic activity, and efficacy is improved by the presence of N-methyl or methoxy at C-16.…”

Section: Introductionmentioning

confidence: 99%

Metabolite Profiling of Talatisamine in Heart Tissue After Oral Administration and Analysis of Cardiac Bioactivities

et al. 2022

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The lateral roots of the Aconitum carmichaelii (“Fuzi”) have been used for centuries as a cardiotonic in China. The diterpenoid alkaloid talatisamine (TA) is a major bioactive component of Fuzi, but the identity and bioactivities of TA metabolites have not been examined in detail. In this study, metabolite profiling of TA was performed in rat heart by UPLC-MS following oral administration. Metabolites were identified by comparing protonated molecules, fragmentation patterns, and chromatographic behaviors with those of standard compounds. Metabolites of TA were then prepared and tested for cardiotonic activity on isolated frog hearts. The metabolite cammaconine, a C19 diterpenoid alkaloid with a hydroxyl group at C-18, exhibited substantial cardiotonic activity during frog heart perfusion. To further investigate the structure–cardiac effect relationships, a series of C19-diterpenoid alkaloids with 18-OH were prepared. Eight tested compounds (5–12) demonstrated measurable cardioactivity, of which compound 5 with an N-methyl group and compound 7 with a methoxy at C-16 showed stronger effects on ventricular contraction than the other compounds. Thus, 18-OH is a critical structural feature determining cardiotonic activity, and efficacy is improved by the presence of an N-methyl or methoxy at C-16. Preliminary mechanistic studies suggested that the cardiotonic effect of compound 5 is mediated by enhanced cellular calcium influx. Metabolites of TA with these structural features may be useful therapeutics to prevent heart failure.

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“…Alkaloids are considered the most predominant active ingredients in A. carmichaelii, which can be divided into three groups, including diester-diterpenoid alkaloids, monoester-diterpenoid alkaloids (MDAs), and alcohol-amine alkaloids. Some earlier studies demonstrated that diester-diterpenoid alkaloids, especially aconitine, are powerful agents for treating hypertension and contribute to their strong cardiovascular effects ( Wang et al, 2020b ). Unfortunately, they are not considered for clinical use owing to their toxic effects ( Lin et al, 2004 ).…”

Section: Introductionmentioning

confidence: 99%

A Novel Modulator of the Renin–Angiotensin System, Benzoylaconitine, Attenuates Hypertension by Targeting ACE/ACE2 in Enhancing Vasodilation and Alleviating Vascular Inflammation

et al. 2022

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The monoester alkaloids in Aconitum carmichaelii, including benzoylaconitine (BAC), benzoylmesaconine, and benzoylhypaconitine, were found to have anti-hypertensive effects in spontaneously hypertension rats (SHRs), of which BAC is the strongest. However, its antihypertensive target and underlying molecular mechanisms remain unclear. In this study, first, we screened the antihypertensive targets of BAC by using the CVDPlatform (www.cbligand.org/CVD) and found that ACE/ACE2 are the most possible targets. Then, we verified the effect of BAC on ACE/ACE2 by virtual docking, SPR, enzyme activity assay, and HUVECs cell experiment. We found that BAC could bind with ACE/ACE2, inhibit ACE activity and protein expression, and activate ACE2 enzyme activity. Using vascular function test in vitro, we found that BAC could target ACE/ACE2 to enhance endothelium-dependent vasorelaxation. In BAC-treated SHRs, the levels of ACE and AngII in serum were reduced while Ang (1–7) was increased significantly, and the expression of ACE was reduced, which suggested that BAC can inhibit ACE and activate ACE2 to inhibit AngI to AngII and promote AngII to Ang (1–7) to inhibit vasoconstriction and finally attenuate hypertension. Furthermore, the signaling pathways with regard to vasorelaxation and vascular inflammation were investigated. The results showed that BAC could significantly activate Akt/eNOS, increase NO production, and promote endothelial-related vasodilation; BAC could also reduce inflammatory factors TNF-α and IL6, inhibition of COX-2 expression, and IKB-α phosphorylation to reduce vascular inflammation in SHRs. In brief, BAC targets ACE/ACE2 to enhance endothelium-dependent vasorelaxation and reduce vascular inflammation to attenuate hypertension as a potential modulator of the renin–angiotensin system.

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Cardioprotective effects and concentration-response relationship of aminoalcohol-diterpenoid alkaloids from Aconitum carmichaelii

Cited by 16 publications

References 24 publications

The mechanism of Renshen-Fuzi herb pair for treating heart failure—Integrating a cardiovascular pharmacological assessment with serum metabolomics

The mechanism of Renshen-Fuzi herb pair for treating heart failure—Integrating a cardiovascular pharmacological assessment with serum metabolomics

Metabolite Profiling of Talatisamine in Heart Tissue After Oral Administration and Analysis of Cardiac Bioactivities

A Novel Modulator of the Renin–Angiotensin System, Benzoylaconitine, Attenuates Hypertension by Targeting ACE/ACE2 in Enhancing Vasodilation and Alleviating Vascular Inflammation

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