Insights into the mechanism of Na+,K+-ATPase inhibition by 2-methoxy-3,8,9-trihydroxy coumestan

Pôças, Elisa Suzana Carneiro; Touza, Natália Araújo; Pimenta, Paulo Henrique Cotrim; Leitão, Fernanda; Neto, Chaquip D.; Silva, Alcides J. M. da; Costa, Paulo R.R.; Noël, François

doi:10.1016/j.bmc.2008.09.007

Cited by 10 publications

(2 citation statements)

References 19 publications

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“…However, this nonspecific inhibition is usually achieved at concentrations much higher (at mM range) than the ones observed with our valepotriates. Also, as the cytotoxic effect of valepotriates is prevented by antioxidants with free sulfydryl groups [31], and we have shown that a mechanism of ATPase inhibition may be the oxidation of the enzymeʼs free thiol residues at the catalytic site [25], we suggest that such mechanism may be at least partially responsible for the effect of valepotriates on Na + /K + -ATPase. Surprisingly, the relative structural similarity of the potent and specific SERCA inhibitor thapsigargin and valepotriates was not translated experimentally.…”

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confidence: 80%

“…In EDL preparation, there is no significant thapsigargin-insensitive activity (from plasma membrane Ca 2+ -ATPase, PMCA), so only SERCA activity was considered. H + /K + -ATPase activity: In a medium containing 5 µg/mL nigericin and (in mM) 2 MgCl 2 , 2 ATPNa 2 , 40 Tris-HCl buffer (pH 7.4) in the presence (total activity) or absence (basal activity) of 10 NH 4 Cl and 10 KCl, the reaction was carried out by incubation of gastric epithelium preparation at 37°C for 2 h. Specific H + /K + -ATPase activity corresponded to the difference between the total and basal activity [25].…”

Section: Inhibition Of Atpase Activitymentioning

confidence: 99%

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In VitroEffect of Valepotriates Isolated fromValeriana glechomifoliaon Rat P-Type ATPases

Bettero¹,

Salles²,

Figueira³

et al. 2011

Planta Med

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Valepotriates are iridoids found in variable amounts in Valerianaceae and might be among the bioactive compounds which confer anxiolytic properties to the Valeriana species. On the other hand, unspecific cytotoxicity has also been described. Presently, however, no particular molecular target has been defined for these compounds. Here we studied the effect of valtrate, acevaltrate, and 1- β-acevaltrate isolated from Valeriana glechomifolia on the enzymatic activity of rat P-type ATPases. Valepotriates did not affect rat skeletal muscle sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) activity at the highest concentration used (100 µM). In contrast, the same concentration inhibited roughly half of the total H⁺/K⁺-ATPase activity from rat gastric epithelium (valtrate 54.6 ± 3.2 %, acevaltrate 60.7 ± 7.3 %, 1- β-acevaltrate 50.2 ± 3.1 %; mean ± SEM, n = 3-5). Finally, these substances showed the highest inhibitory potency toward Na⁺/K⁺-ATPase, and the inhibition curves obtained provided a similar IC₅₀ (in µM) for rat kidney α1 isoform (valtrate 21.2, acevaltrate 22.8, 1- β-acevaltrate 24.4) and brain hemispheres α2/ α3 isoforms (valtrate 19.4, acevaltrate 42.3, 1- β-acevaltrate 38.3). Our results suggest that P-type ATPases are differentially inhibited by valepotriates and that Na⁺/K⁺-ATPase might be one of their molecular targets in vivo.

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confidence: 80%

Section: Inhibition Of Atpase Activitymentioning

confidence: 99%

In VitroEffect of Valepotriates Isolated fromValeriana glechomifoliaon Rat P-Type ATPases

Bettero¹,

Salles²,

Figueira³

et al. 2011

Planta Med

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Synthesis of Novel Pterocarpen Analogues via [3 + 2] Coupling‐Elimination Cascade of α,α‐Dicyanoolefins with Quinone Monoimines

Chen

Zhao

Cheng

et al. 2019

Journal of Heterocyclic Chem

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Ivermectin is a nonselective inhibitor of mammalian P-type ATPases

Pimenta

Noël

2009

Naunyn-Schmied Arch Pharmacol

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Ivermectin is a large spectrum antiparasitic drug that is very safe at the doses actually used. However, as it is being studied for new applications that would require higher doses, we should pay attention to its effects at high concentrations. As micromolar concentrations of ivermectin have been reported to inhibit the sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA), we decided to investigate its putative inhibitory effect on other two important P-type ATPases, namely the Na(+) , K(+)-ATPase and H(+)/K(+)-ATPase. We first extended the data on SERCA, using preparations from rat enriched in SERCA1a (extensor digitorum longus) and 1b (heart) isoforms. Secondly, we tested the effect of ivermectin in two preparations of rat Na(+), K(+)-ATPase in order to appreciate its putative selectivity towards the alpha(1) isoform (kidney) and the alpha(2)/alpha(3) isoforms (brain), and in an H(+)/K(+)-ATPase preparation from rat stomach. Ivermectin inhibited all these ATPases with similar IC(50) values (6-17 microM). With respect to the inhibition of the Na(+), K(+)-ATPase, ivermectin acts by a mechanism different from the classical cardiac glycosides, based on selectivity towards the isoforms, sensibility to the antagonistic effect of K(+) and to ionic conditions favoring different conformations of the enzyme. We conclude that ivermectin is a nonselective inhibitor of three important mammalian P-type ATPases, which is indicative of putative important adverse effects if this drug were used at high doses. As a consequence, we propose that novel analogs of ivermectin should be developed and tested both for their parasitic activity and in vitro effects on P-type ATPases.

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Insights into the mechanism of Na+,K+-ATPase inhibition by 2-methoxy-3,8,9-trihydroxy coumestan

Cited by 10 publications

References 19 publications

In VitroEffect of Valepotriates Isolated fromValeriana glechomifoliaon Rat P-Type ATPases

In VitroEffect of Valepotriates Isolated fromValeriana glechomifoliaon Rat P-Type ATPases

Synthesis of Novel Pterocarpen Analogues via [3 + 2] Coupling‐Elimination Cascade of α,α‐Dicyanoolefins with Quinone Monoimines

Ivermectin is a nonselective inhibitor of mammalian P-type ATPases

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