Bretylium, an organic quaternary amine, inhibits the Na,K-ATPase by binding to the extracellular K-site

Helms, J. Bernd; Arnett, Krista L.; Gatto, Craig; Milanick, Mark A.

doi:10.1016/j.bcmd.2004.01.013

Cited by 8 publications

(5 citation statements)

References 18 publications

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“…As for another molecule with a non-steroidal skeleton [24][25][26] , brazilein exhibited a different inhibition curve with a maximum inhibition rate of about 50%, which could be suggested by in vivo ECG research. In this study, deslanoside (about 400-560 g/kg) induced a series of ECG changes in cardiac glycosides at therapeutic doses, followed by ventricular arrhythmias and death.…”

Section: Discussionmentioning

confidence: 99%

Study on Cardioactive Effects of Brazilein

Zhao¹,

Yang²,

Tao³

et al. 2006

Pharmacology

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Brazilein (6a,7-dihydro-3,6a,10-trihydroxy-benz[b]indeno[1,2-d]pyran-9(6H)-one) is a compound obtained in a large amount from Caesalpinia sappan ethanol extracts with a high purity of about 98%. In isolated cardiac tissues, we found that brazilein exhibited a positive inotropic action in a concentration-dependent manner with little effect on heart rate and coronary perfusion. To study its possible mode of action, isolated rat hearts were treated with propranolol. This treatment did not alter the cardiotonic effect of brazilein, suggesting that this effect does not involve stimulation of β-adrenoceptors. On the other hand, an analysis of the interaction between Na⁺,K⁺-ATPase and brazilein was carried out. Albino guinea pig erythrocytes (mainly α1-Na⁺,K⁺-ATPase isoforms) enriched with Na⁺,K⁺-ATPase isoforms were utilized to compare the inhibition promoted by brazilein with that of classical inhibitors such as the cardiac glycoside deslanoside. Analysis of inhibition curves revealed that unlike deslanoside, brazilein had a relatively low affinity for erythrocyte isoforms and failed to completely inhibit the Na⁺,K⁺-ATPase activity. The extent of the maximum inhibition rate was about 50%. The inhibitory effect of brazilein was not antagonized by 10 mmol/l K⁺, as observed with deslanoside. Electrocardiogram research in vivo showed that brazilein did not induce the ventricular arrhythmias observed with deslanoside, suggesting that brazilein might have a less adverse effect and higher therapeutic index than cardiac glycosides. In light of all the above-mentioned observations, it can be concluded that brazilein, a molecule with a non-steroidal skeleton, produced its positive inotropic effect through inhibiting Na⁺,K⁺-ATPase and could thus serve as a structural paradigm to develop new inotropic drugs.

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Section: Discussionmentioning

confidence: 99%

Study on Cardioactive Effects of Brazilein

Zhao¹,

Yang²,

Tao³

et al. 2006

Pharmacology

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“…Aún falta mucho por comprender acerca de las NPP y de fármacos que puedan serútiles para el tratamiento de la malaria, en especial que actúen frente a este blanco. Es necesario considerar y tener en cuenta estudios previos de inhibidores sobre canales en otras células que puedan servir como punto de partida para encontrar un fármaco potencial contra el Plasmodium; como el Bretilio, un antiarrítmico que funciona sobre la bomba de Na + , comportándose como K + e inhibiendo la bomba, quedando atrapado en la conformación E2 P/ catión (Helms et al, 2004); por lo que sería un indicio para sustancias derivadas deéste y con posible acción sobre PSAC. Así mismo, indagar más sobre las proteínas y genes implicados en todo el proceso de las NPP, como la inhibición de la Plasmepsina V, que al caracterizarse bien la posición de sus aminoácidos esenciales, tal como la Arg en P3, puede ser un gran indicio para nuevas clases de inhibidores (Taglialatela et al, 2015).…”

Section: Nuevas Consideracionesunclassified

Nuevas rutas de permeabilidad en <i>Plasmodium falciparum</i>: consideraciones como blanco farmacológico y avances de los potenciales inhibidores

Castañeda-Agudelo

Pabón-Vidal

2021

Actual. Biol.

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Con base en la persistencia de los casos de malaria, dados por múltiples razones, entre las cuales se encuentra la resistencia de Plasmodium falciparum a los antimálaricos establecidos para su tratamiento, surge la necesidad de encontrar nuevos compuestos antimaláricos frente a otros blancos terapéuticos. En vista de ello, las Nuevas Rutas de Permeabilidad (NPP) han sido un objetivo promisorio y a partir de su descubrimiento, se han realizado diversos estudios enfocados en comprender su mecanismo y los componentes utilizados para el transporte de solutos y otras moléculas a través de la membrana del eritrocito. El objetivo de esta revisión de tema es presentar una recopilación de los estudios más significativos realizados en torno a las NPP. Para ello, se revisó la literatura para conocer el estado del desarrollo de las investigaciones referentes al tema, consultando bases de datos electrónicas y combinando los descriptores o palabras clave: (NPP AND malaria, AND Plasmodium falciparum AND inhibitors), además, se realizaron búsquedas secundarias en las listas de referencias bibliográficas de los artículos identificados. Luego de revisar los artículos de la literatura publicados entre los años 1980 y 2019, se concluye que muchos estudios han sido dedicados a la búsqueda de inhibidores de esta vía con fines terapéuticos y hay gran cantidad de moléculas candidatas como el híbrido MA-DFO y las diaminidas que han mostrado actividad en modelos de malaria tanto in vitro como in vivo.

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“…In one case, we measured the [H + ] activation of 86 Rb + uptake at fixed [Rb + ] in the presence of different concentrations of inhibitory cations. Specifically, we compared Na + and the Na + -like inhibitor guanidium [25] to the K + -like inhibitors, bretylium and TPA [26, 27]. Typically, in a standard inhibitor analysis, apparent Km and Vmax values would be calculated and the dependence of 1/Vmax and Km/Vmax on the [inhibitor] determined using a replot.…”

Section: Specifically Examining Extracellular H Effects In Red Cellsmentioning

confidence: 99%

Red blood cell Na pump: Insights from species differences

Gatto

Milanick

2009

Blood Cells, Molecules, and Diseases

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The red blood cell membrane is specialized to exchange chloride and bicarbonate; usually the pH gradient, the chloride ratio, and the membrane potential are tightly coupled. We review the evidence that led to the ability to separately vary inside and outside pH in red cells. The effect of pH on Na pump activity and on the selectivity of the inside and the outside transport sites is reviewed. In red blood cells, at high pH, the outside site is not selective. An increase in protons leads to an increase in K + affinity, thus making the site more selective. The pK for this site is different in rats and humans; because of the high conservation of residues in these two species, there are only a few possible residues that can account for this difference. On the inside, work from unsided preparations suggests that, at high pH, the transport site is highly selective for Na + . Once again, an increase in protons leads to an increase in K + affinity, but now the result is a less selective site. During their maturation, reticulocytes lose many membrane proteins. The type and fractional loss is species dependent. For example, most reticulocytes lose most of their Na pumps, retaining about 100 pumps per cell, but animals from the order Carnivora lose all their pumps. We review some of the evidence that PKC phosphorylation of N-terminus serines is responsible for endocytosis in other cell types and species variation in this region.

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Bretylium, an organic quaternary amine, inhibits the Na,K-ATPase by binding to the extracellular K-site

Cited by 8 publications

References 18 publications

Study on Cardioactive Effects of Brazilein

Study on Cardioactive Effects of Brazilein

Nuevas rutas de permeabilidad en <i>Plasmodium falciparum</i>: consideraciones como blanco farmacológico y avances de los potenciales inhibidores

Red blood cell Na pump: Insights from species differences

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