Role of ouabain-like compound in the rostral ventrolateral medulla in rats.

Teruya, Hiroshi; Yamazato, Masanobu; Muratani, Hiromi; Sakima, Atsushi; Takishita, Shuichi; Terano, Yoshitake; Fukiyama, Koshiro

doi:10.1172/jci119469

Cited by 26 publications

(12 citation statements)

References 46 publications

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“…The sympathetic hyperactivity induced by ouabain and the consequent increase in blood pressure appear to involve the central renin-angiotensin system. This observation is supported by reports that the sympathetic hyperactivity induced by ouabain is prevented by an AT1 receptor blocker (50)(51)(52), suggesting that the central renin-angiotensin system could be the sympathoexcitatory component involved in the hypertensinogenic effect of ouabain. In addition, the acute hypertensinogenic effect of ouabain is attenuated in transgenic rats that are deficient in brain angiotensinogen (54).…”

Section: Acute Effects Of Ouabain On the Central Nervous Systemsupporting

confidence: 71%

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Hypertensive effects of the iv administration of picomoles of ouabain

Padilha

Salaíces

Vassallo

et al. 2011

Braz J Med Biol Res

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Ouabain, an endogenous digitalis compound, has been detected in nanomolar concentrations in the plasma of several mammals and is associated with the development of hypertension. In addition, plasma ouabain is increased in several hypertension models, and the acute or chronic administration of ouabain increases blood pressure in rodents. These results suggest a possible association between ouabain and the genesis or development and maintenance of arterial hypertension. One explanation for this association is that ouabain binds to the α-subunit of the Na + pump, inhibiting its activity. Inhibition of this pump increases intracellular Na + , which reduces the activity of the sarcolemmal Na + /Ca 2+ exchanger and thereby reduces Ca 2+ extrusion. Consequently, intracellular Ca 2+ increases and is taken up by the sarcoplasmic reticulum, which, upon activation, releases more calcium and increases the vascular smooth muscle tone. In fact, acute treatment with ouabain enhances the vascular reactivity to vasopressor agents, increases the release of norepinephrine from the perivascular adrenergic nerve endings and promotes increases in the activity of endothelial angiotensin-converting enzyme and the local synthesis of angiotensin II in the tail vascular bed. Additionally, the hypertension induced by ouabain has been associated with central mechanisms that increase sympathetic tone, subsequent to the activation of the cerebral renin-angiotensin system. Thus, the association with peripheral mechanisms and central mechanisms, mainly involving the renin-angiotensin system, may contribute to the acute effects of ouabain-induced elevation of arterial blood pressure.

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Section: Acute Effects Of Ouabain On the Central Nervous Systemsupporting

confidence: 71%

“…These effects of ouabain are due at least in part to activation of the central and peripheral renin-angiotensin system (31,28,(50)(51)(52).…”

Section: General Considerationsmentioning

confidence: 99%

Hypertensive effects of the iv administration of picomoles of ouabain

Padilha

Salaíces

Vassallo

et al. 2011

Braz J Med Biol Res

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“…37 The sympathoexcitatory and pressor responses to central infusion of aldosterone and Na + -rich aCSF can be prevented by central infusion of the sodium channel blocker benzamil or an ouabain blocker, 27,38 and the pressor responses elicited by central infusion of aldosterone or ouabain can be blocked by an AT 1 blocker. 27,39 In the RVLM, microinjection of an ouabain-like compound 40 or angiotensin II 21 elicits a pressor response and sympathoexcitation. Collectively, these data suggest that aldosterone in the RVLM might activate central mechanism(s) involving the MR-ENaC-ouabain pathway, thereby causing sympathetic hyperactivity and hypertension.…”

Section: Discussionmentioning

confidence: 99%

Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats

et al. 2012

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Mineralocorticoid receptor (MR) is recognized as a target for therapeutic intervention in hypertension and heart failure. MRs in the central nervous system are thought to have an important role in blood pressure regulation. Thus, we examined whether activation of the MR pathway in the rostral ventrolateral medulla (RVLM) of the brainstem contributes to the neural mechanism of hypertension in stroke-prone spontaneously hypertensive rats (SHRSPs). We microinjected eplerenone, aldosterone or Na + -rich artificial cerebrospinal fluid (aCSF) into the RVLM of anesthetized Wistar-Kyoto (WKY) rats and SHRSPs. Arterial pressure (AP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were recorded. The expressions of the MR protein and the serumand glucocorticoid-regulated kinase protein (Sgk1), which is a marker of MR activity, in the RVLM were measured by western blot analysis. Bilateral microinjection of eplerenone into the RVLM decreased AP and RSNA in WKY rats and SHRSPs, and the decreases in those variables were significantly greater in SHRSPs than WKY rats. Microinjection of aldosterone or Na + -rich aCSF into the RVLM increased AP and RSNA dose-dependently. The increases in those variables were significantly greater in SHRSPs than in WKY rats. The pressor responses of aldosterone or Na + -rich aCSF were attenuated by the prior injection of eplerenone in SHRSPs. Sgk1 expression levels in the RVLM were significantly greater in SHRSPs than in WKY rats. These findings suggest that activation of MRs in the RVLM enhances sympathetic activity, thereby contributing to the neural mechanism of hypertension in the SHRSP.

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“…Although the exact chemical structure of this factor(s) is still debated, current evidence suggests that it is closely related to or identical to ouabain (Hamlyn et al, 1991), marinobufagenin , proscillardin A (Sich et al, 1996), or bufalin (Hilton et al, 1996). Digoxin-specific Fab has been shown to neutralize the effects of exogenous ouabain on central nervous system-mediated changes in blood pressure (Teruya et al, 1997), Rb uptake in erythrocytes (Balzan et al, 1991), and vascular smooth muscle contraction (Krep et al, 1995). Additional studies have shown that digoxin-specific Fab has the ability to neutralize an endogenous factor with Na ϩ /K ϩ ATPase inhibitory activity similar to ouabain produced in human peritoneal dialysate (Krep et al, 1995;Tao et al, 1996), cord blood of neonates (Balzan et al, 1991), and rat brain (Huang and Leenen, 1996).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Neutralizing Activity of Digoxin-Specific Fab toward Ouabain-Like Steroids

Pullen

Brooks²,

Edwards³

2004

J Pharmacol Exp Ther

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Digoxin-specific Fab (Digibind) is a mixture of antidigoxin Fab fragments prepared from sheep sera and is used as a treatment for digoxin poisoning. Digoxin-specific Fab has been shown to neutralize an endogenous Na ϩ /K ϩ ATPase inhibitor (endogenous digoxin-like Na ϩ /K ϩ ATPase regulatory factor; EDLF) in rats and humans and to lower blood pressure. Although the exact structure of EDLF is unknown, compounds identical to or structurally related to ouabain, bufalin, and marinobufagenin have been detected in mammalian plasma. In this study, some structural characteristics of EDLF were inferred from the ability of digoxin-specific Fab to neutralize the Na ϩ /K ϩ ATPase inhibitory activity of several known cardenolides and bufodienolides. Additional structural information was obtained from [ 3 H]ouabain binding and enzyme-linked immunosorbent assay experiments. Digoxin-specific Fab had the ability to interact to some extent with all of the cardenolides and bufodienolides tested. However, digoxin-specific Fab was more than 20-fold more potent in neutralizing ouabain and bufalin than marinobufagenin. The antihypertensive effect of digoxin-specific Fab seen in preeclampsia and animal models of hypertension may therefore be due to a molecule identical to or structurally similar to ouabain or bufalin.

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Role of ouabain-like compound in the rostral ventrolateral medulla in rats.

Cited by 26 publications

References 46 publications

Hypertensive effects of the iv administration of picomoles of ouabain

Hypertensive effects of the iv administration of picomoles of ouabain

Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats

Characterization of the Neutralizing Activity of Digoxin-Specific Fab toward Ouabain-Like Steroids

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