Exogenous Ouabain Is Accumulated in the Adrenals and Mimics the Kinetics of Endogenous Digitalis-like Factor in Rats.

Kitano, Shiro; Morimoto, Shigeto; Nishibe, Akira; Fukuo, Keisuke; Hirotani, Atushi; Nakahashi, Takeshi; Yasuda, Osamu; Ogihara, Toshio

doi:10.1291/hypres.21.47

Cited by 18 publications

(18 citation statements)

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“…Because synthesis of the compound is likely to be a rather slow process, re-uptake into adrenal glands seems possible. 7 Half-maximal increase in heart rate and systolic blood pressure were found at Ϸ5 nmol/L OLC. Unfortunately, no information on the clinical therapeutic range of ouabain exists.…”

Section: Discussionmentioning

confidence: 96%

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Ouabain-Like Compound Changes Rapidly on Physical Exercise in Humans and Dogs

et al. 2005

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Abstract-Ouabain, an inhibitor of the sodium pump, has been identified as a constituent of bovine adrenal glands. We were interested whether the release of this cardiotonic steroid is stimulated by physical exercise. Hence, athletes and healthy dogs were subjected to ergometry. Ouabain-like compound (OLC) was measured in venous blood by enzyme-linked immunosorbent assay as well as by 86 Rb ϩ uptake inhibition (as ouabain equivalents). OLC increased in venous blood of athletes after 15 minutes of ergometry from 2.5Ϯ0.5 to 86.0Ϯ27.2 nmol/L (nϭ51; PϽ0.001), as did the concentration of a circulating inhibitor of the sodium pump from 7.3Ϯ1.7 to 129.8Ϯ51 nmol/L (ouabain equivalents, PϽ0.05). Half-maximal increase in heart rate and systolic blood pressure occurred at 5.1Ϯ1.2 nmol/L and at 30Ϯ1 nmol/L OLC, respectively. On rest, OLC decreased in humans and dogs with a half-life of 3 to 5 minutes. In beagles exposed to moderate exercise on a treadmill for 13 minutes, levels of OLC increased 46-fold (from 3.7Ϯ0.8 to 166.9Ϯ91.8 nmol/L; nϭ6; PϽ0.005). This effect was suppressed when the dogs had been treated for 3 weeks with the ␤ 1 -adrenergic receptor blocker atenolol or the angiotensin-converting enzyme inhibitor benazepril. We conclude that OLC changes rapidly during exercise and is under the control of norepinephrine and angiotensin II. Key Words: angiotensin-converting enzyme inhibitor Ⅲ ␤-blocker Ⅲ circulation Ⅲ endogenous ouabain Ⅲ hypertension Ⅲ sodium pump hypertension O uabain or its isomer has been isolated from blood, adrenals, and hypothalamus 1-3 as one of the endogenous cardiac glycosides circulating in blood plasma. 4 Evidently, ouabain is synthesized in adrenal glands, 1,5,6 but it may also be accumulated there after resorption from the gut. 7 Bovine adrenocortical cells in tissue culture release ouabain on exposure to epinephrine, angiotensin II, or corticotropin. 1,6,8 Whether this in vitro finding translates into the in vivo situation is unclear. If so, physical exercise associated with the increase in epinephrine and norepinephrine should consequently increase endogenous ouabain. Previous studies showed ambiguous results. An increase 9 as well as a decrease of plasma concentrations of ouabain-like compounds (OLCs) 10,11 have been reported. Here, we investigated the effect of physical exercise on the endogenous ouabain plasma concentration in several experimental settings as well as the influence of ␤-blockade and angiotensin-converting enzyme (ACE) inhibition. Materials and MethodsAll chemicals were of the highest purity available. Anti-ouabain antibodies from sheep (CN2710) were from B.R.A.H.M.S. Arzneimittel (Dr A. Bergmann), Henningsdorf, Germany. The antibodies showed cross-reactivities with k-strophanthin 42%, ouabagenin 27%, dihydro-ouabain 0.3%, digitoxin 0.07%, and proscillaridin (Ͻ0.1%), and no cross-reaction (Ͻ0.01%) with strophanthidin, digoxin, digitoxigenin, oleandrin, marinobufagin, bufalin, cinobufagin, cinobufotalin, and 19 other steroid hormones. Human Patients and ControlsWritten inf...

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Section: Discussionmentioning

confidence: 96%

“…4 Evidently, ouabain is synthesized in adrenal glands, 1,5,6 but it may also be accumulated there after resorption from the gut. 7 Bovine adrenocortical cells in tissue culture release ouabain on exposure to epinephrine, angiotensin II, or corticotropin. 1,6,8 Whether this in vitro finding translates into the in vivo situation is unclear.…”

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confidence: 99%

Ouabain-Like Compound Changes Rapidly on Physical Exercise in Humans and Dogs

et al. 2005

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“…Ouabain is synthesized in adrenal cortical cells and released there from in vitro upon hormonal stimuli like ACTH, angiotensin II and epinephrine (10,(23)(24)(25); about 3-5 % of ouabain found in the diet may also be absorbed and stored in the adrenocortical cells (26). It is unclear so far which physiological stimuli except anoxia (8) may in vivo release ouabain from its intracellular stores.…”

Section: Discussionmentioning

confidence: 99%

Endogenous Ouabain and Its Binding Globulin: Effects of Physical Exercise and Study on the Globulin's Tissue Distribution

Antolović

Bauer

Mohadjerani³

et al. 2000

Hypertens Res

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Ouabain, that has been isolated from bovine adrenals and hypothalamus, is a new cardiotonic steroid hormone, which is either synthesized in the adrenals or stored there after it has absorbed from the diet. Little is known in vivo which events may lead to the release of ouabain into blood. Moreover, a binding protein for cardiotonic steroids exists in blood, which binds cardiac glycosides with high affinity. It may affect the action of endogenous ouabain on heart and circulation, but the physiological function of this protein is unclear. To realize, which physiological stimuli in vivo may affect blood concentrations of endogenous ouabain and which function the cardiotonic binding protein may have in modulating ouabain effects, the effect of physical exercise on endogenous ouabain was studied and the tissue distribution of its binding protein was investigated. We found that endogenous ouabain changes rapidly in blood upon physical exercise and behaves like expected for a hormone of circulation. The cardiotonic steroid binding globulin shows the highest concentration in the kidney, which suggests that sodium pumps of the kidney are protected against its inhibition by ouabain which would lead not only to natriuresis but also to a deleterious loss of glucose, amino acids and phosphate. (Hypertens Res 2000; 23 Suppl: S93-S98)

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“…Interestingly, both orally and parenterally administered cardiotonic steroids are taken up by the adrenal glands. The intestines only absorb 3-5% of orally administered cardiotonic steroids (Greeff & Fox 1984, Boulanger et al 1993, Kitano et al 1998. The mechanism of regulation of this process is unknown, as is the contribution of absorbed cardiotonic steroids to circulating plasma levels.…”

Section: Introductionmentioning

confidence: 99%

Advances in understanding the role of cardiac glycosides in control of sodium transport in renal tubules

Khundmiri¹

2014

Journal of Endocrinology

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Cardiotonic steroids have been used for the past 200 years in the treatment of congestive heart failure. As specific inhibitors of membrane-bound Na C /K C ATPase, they enhance cardiac contractility through increasing myocardial cell calcium concentration in response to the resulting increase in intracellular Na concentration. The half-minimal concentrations of cardiotonic steroids required to inhibit Na C /K C ATPase range from nanomolar to micromolar concentrations. In contrast, the circulating levels of cardiotonic steroids under physiological conditions are in the low picomolar concentration range in healthy subjects, increasing to high picomolar levels under pathophysiological conditions including chronic kidney disease and heart failure. Little is known about the physiological function of low picomolar concentrations of cardiotonic steroids. Recent studies have indicated that physiological concentrations of cardiotonic steroids acutely stimulate the activity of Na C /K C ATPase and activate an intracellular signaling pathway that regulates a variety of intracellular functions including cell growth and hypertrophy. The effects of circulating cardiotonic steroids on renal salt handling and total body sodium homeostasis are unknown. This review will focus on the role of low picomolar concentrations of cardiotonic steroids in renal Na C /K C ATPase activity, cell signaling, and blood pressure regulation.

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Exogenous Ouabain Is Accumulated in the Adrenals and Mimics the Kinetics of Endogenous Digitalis-like Factor in Rats.

Abstract: Ouabain has been isolated as an endogenous pathogenetic factor in salt-induced hypertension and has been shown to be rich in the adrenals.

Cited by 18 publications

References 18 publications

Ouabain-Like Compound Changes Rapidly on Physical Exercise in Humans and Dogs

Ouabain-Like Compound Changes Rapidly on Physical Exercise in Humans and Dogs

Endogenous Ouabain and Its Binding Globulin: Effects of Physical Exercise and Study on the Globulin's Tissue Distribution

Advances in understanding the role of cardiac glycosides in control of sodium transport in renal tubules

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