Spironolactone and Its Main Metabolite, Canrenoic Acid, Block Human Ether-a-Go-Go–Related Gene Channels

Caballero, Ricardo; Moreno, Ignacio; González, Teresa; Arias, C.; Valenzuela, Carmen; Delpón, Eva; Tamargo, Juan

doi:10.1161/01.cir.0000048189.58449.f7

Cited by 63 publications

(65 citation statements)

References 18 publications

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“…The correction factor was calculated for each test pulse at negative potentials where the current declined because of channel closure. The corrected current at the return step (+20 mV) was plotted as a function of voltage of the 20-ms test pulses to obtain the steady-state inactivation curve [27,31,32]. Peak current amplitudes at the return step to +20 mV were prominently decreased by ChT (300 µM), consistent with the results presented thus far.…”

Section: Effect Of Cht On Voltage Dependence and Kinetics Of Herg Chasupporting

confidence: 82%

Functional consequences of methionine oxidation of hERG potassium channels

Limberis

Martin

et al. 2007

Biochemical Pharmacology

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Reactive species oxidatively modify numerous proteins including ion channels. Oxidative sensitivity of ion channels is often conferred by amino acids containing sulfur atoms, such as cysteine and methionine. Functional consequences of oxidative modification of methionine in hERG1 (human ether à go-go related gene 1), which encodes cardiac I Kr channels, are unknown. Here we used chloramine-T (ChT), which preferentially oxidizes methionine, to examine the functional consequences of methionine oxidation of hERG channels stably expressed in a human embryonic kidney cell line (HEK 293) and native hERG channels in a human neuroblastoma cell line (SH-SY5Y). ChT (300 µM) significantly decreased whole-cell hERG current in both HEK 293 and SH-SY5Y cells. In HEK 293 cells, the effects of ChT on hERG current were time-and concentration-dependent, and were markedly attenuated in the presence of enzyme methionine sulfoxide reductase A that specifically repairs oxidized methionine. After treatment with ChT, the channel deactivation upon repolarization to −60 or −100 mV was significantly accelerated. The effect of ChT on channel activation kinetics was voltage-dependent; activation slowed during depolarization to +30 mV but accelerated during depolarization to 0 or −10 mV. In contrast, the reversal potential, inactivation kinetics, and voltage-dependence of steady-state inactivation remained unaltered. Our results demonstrate that the redox status of methionine is an important modulator of hERG channel.

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Section: Effect Of Cht On Voltage Dependence and Kinetics Of Herg Chasupporting

confidence: 82%

Functional consequences of methionine oxidation of hERG potassium channels

Limberis

Martin

et al. 2007

Biochemical Pharmacology

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“…One possibility is that these effects may be caused, at least in part, by effects of its primary metabolite, canrenoic acid. 54 It may be that either spironolactone, which does achieve extremely high concentrations, and/or canrenoic acid signals through the sodium pump in an analogous fashion to ouabain and other cardiac steroids. 33,53 However, this possibility was not addressed in the current report.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms for Aldosterone and Spironolactone-Induced Positive Inotropic Actions in the Rat Heart

et al. 2004

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Abstract-Previously, we reported that aldosterone and spironolactone have inotropic effects in the isolated perfused heart.To address the mechanisms underlying these inotropic effects, we examined the effects of aldosterone and spironolactone on isolated cardiac myocyte shortening, intracellular calcium ( ). Collectively, these data strongly suggest that the inotropic actions of aldosterone and spironolactone are caused by different mechanisms of action. Aldosterone appeared to increase inotropy primarily through increased cytosolic pH, whereas spironolactone increased myosin ATPase calcium sensitivity and diastolic calcium concentration. Key Words: mineralocorticoid Ⅲ cardiac function Ⅲ heart failure Ⅲ calcium T he Randomized ALdactone Evaluation Study (RALES) demonstrated significant reductions in morbidity and mortality when spironolactone, the aldosterone mineralocorticoid receptor antagonist, was included in the treatment of heart failure. 1 This study, along with many translational reports, strongly developed the concept that aldosterone may play an important, deleterious effect in human congestive heart failure. [2][3][4][5] In addition, we have previously observed that aldosterone has rapid, inotropic effects in the isolated perfused rat heart; 6 however, rapid, inotropic effects were observed as early as the 1960s. 7,8 This rapid, inotropic effect of aldosterone almost certainly occurs through nongenomic mechanism(s).Nongenomic actions of aldosterone were first identified by Wehling et al in smooth muscle cells. 9 -12 These actions were classified as nongenomic because of their speed, lack of inhibition by spironolactone, and independence from new protein synthesis. Based on these characteristics, nongenomic effects of aldosterone have been reported from a number of laboratories in renal epithelial cells, 13 vascular smooth muscle cells, 14,15 skeletal muscle cells, 16 and colonic. The molecular basis of these nongenomic effects of aldosterone actions have been ascribed to changes in intracellular pH (pHi), [17][18][19] 20 -25 Although it has been observed that aldosterone does have rapid effects on protein kinase C activity in cultured cardiac cells, 26 and that aldosterone has rapid effects on cardiac sodiumhydrogen exchange, 27 the molecular mechanism of the rapid inotropic effect of aldosterone is still unclear.The spironolactone issue is less well defined and perhaps of greater interest because of the favorable results of the RALES trial. 1 We previously observed that substantial inotropy could be observed with levels of spironolactone that were comparable to those achieved with this agent in standard clinical practice. Moreover, the inotropic effect of spironolactone was found to be additive to that of aldosterone when both agents were administered together. These studies strongly suggest that although aldosterone and spironolactone are similar in structure, they have independent mechanism(s) of actions. Therefore, the objective of the present study was

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“…5 Because spironolactone is a nonspecific MR antagonist, these effects do not necessarily involve MR. 6 Spironolactone also reduced infarct size and improved the recovery of left ventricular pressure (LVP) after 45 minutes of global ischemia in the isolated perfused rat heart. 7 Interestingly, spironolactone did not block aldosterone-induced vasoconstriction, which worsens cardiac contractile and metabolic function in the ischemic heart.…”

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confidence: 99%

Cardioprotective Effects of Eplerenone in the Rat Heart

et al. 2006

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Abstract-Mineralocorticoid receptor antagonism with eplerenone reduces mortality in heart failure, possibly because of blockade of the deleterious effects of aldosterone. To investigate these effects, rat Langendorff hearts were exposed to aldosterone and/or eplerenone. Under normal conditions, aldosterone increased left ventricular pressure and decreased coronary flow. Eplerenone did not block these effects. Eplerenone reduced infarct size (from 68Ϯ2% to 53Ϯ4%; PϽ0.05) and increased left ventricular pressure recovery (from 44Ϯ2% to 60Ϯ5%; PϽ0.05) after 45 minutes of coronary artery occlusion and 3 hours of reperfusion, whereas aldosterone did not affect these parameters. To verify the origin of cardiac aldosterone, hearts were perfused with 3 to 30 nmol/L aldosterone and either frozen immediately or exposed to washout. Without washout, cardiac aldosterone was 1.5 times aldosterone in coronary effluent (CE), that is, too high to be explained on the basis of its presence in extracellular fluid. The cardiac levels of aldosterone correlated with its CE levels (rϭ0.81; PϽ0.01), and both were unaffected by eplerenone. During washout, tissue aldosterone disappeared monophasically (half life, 9Ϯ1 minutes), and CE aldosterone disappeared biphasically (half life 1Ϯ0 and 8Ϯ1 minutes, respectively). During buffer perfusion, cardiac aldosterone was at or below the detection limit. In conclusion, eplerenone improves the condition of the heart after ischemia and reperfusion. This does not relate to interference with the inotropic and vasoconstrictor effects of aldosterone. The majority of cardiac aldosterone, if not all, is derived from the circulation. The rapid, mineralocorticoid receptor-independent kinetics of aldosterone suggest that its accumulation in the heart involves cell surface binding rather than internalization.

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Spironolactone and Its Main Metabolite, Canrenoic Acid, Block Human Ether-a-Go-Go–Related Gene Channels

Abstract: Background-It has been demonstrated that spironolactone (SP) decreases the QT dispersion in chronic heart failure. In this study, the effects of SP and its metabolite, canrenoic acid (CA), on human ether-a-go-go-related gene (HERG) currents were analyzed.

Cited by 63 publications

References 18 publications

Functional consequences of methionine oxidation of hERG potassium channels

Functional consequences of methionine oxidation of hERG potassium channels

Mechanisms for Aldosterone and Spironolactone-Induced Positive Inotropic Actions in the Rat Heart

Cardioprotective Effects of Eplerenone in the Rat Heart

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