A circulating inhibitor of (Na+ + K+) ATPase associated with essential hypertension

Hamlyn, John M.; Ringel, Richard; Schaeffer, J; Levinson, Paul; Hamilton, Bruce P.; Kowarski, A. Avinoam; Blaustein, Mordecai P.

doi:10.1038/300650a0

Cited by 544 publications

(197 citation statements)

References 20 publications

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“…These ideas, and a preliminary report that a circulating Na ϩ pump inhibitor was directly correlated with BP in normotensive and hypertensive subjects (46), led to the intensive search for such a compound. This search culminated in the report, in 1991, that endogenous ouabain (EO), a substance either identical to the plant compound, or a stereoisomer, was the culprit (43).…”

Section: Endogenous Ouabain and Other Endogenous Cardiotonic Steroidsmentioning

confidence: 99%

How does salt retention raise blood pressure?

Blaustein¹,

Zhang²,

Ling³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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129

121

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A critical question in hypertension research is: How is long-term blood pressure controlled? Excessive NaCl ingestion or NaCl retention by the kidneys and the consequent tendency toward plasma volume expansion lead to hypertension. Nevertheless, the precise mechanisms linking salt to high blood pressure are unresolved. The discovery of endogenous ouabain, an adrenocortical hormone, provided an important clue. Ouabain, a selective Na ϩ pump inhibitor, has cardiotonic and vasotonic effects. Plasma endogenous ouabain levels are significantly elevated in Ϸ40% of patients with essential hypertension and in animals with several forms of salt-dependent hypertension. Also, prolonged ouabain administration induces hypertension in rodents. Mice with mutant Na ϩ pumps or Na/Ca exchangers (NCX) and studies with a ouabain antagonist and an NCX blocker are revealing the missing molecular mechanisms. These data demonstrate that ␣ 2 Na ϩ pumps and NCX1 participate in long-term regulation of vascular tone and blood pressure. Pharmacological agents or mutations in the ␣ 2 Na ϩ pump that interfere with the action of ouabain on the pump, and reduced NCX1 expression or agents that block NCX all impede the development of salt-dependent or ouabain-induced hypertension. Conversely, nanomolar ouabain, reduced ␣ 2 Na ϩ pump expression, and smooth muscle-specific overexpression of NCX1 all induce hypertension. Furthermore, ouabain and reduced ␣ 2 Na ϩ pump expression increase myogenic tone in isolated mesenteric small arteries in vitro, thereby tying these effects directly to the elevation of blood pressure. Thus, endogenous ouabain, and vascular ␣ 2 Na ϩ pumps and NCX1, are critical links between salt and hypertension. New pharmacological agents that act on these molecular links have potential in the clinical management of hypertension.ouabain; Na ϩ pump; Na/Ca exchanger; Ca 2ϩ ; myogenic tone HYPERTENSION, DEFINED AS A diastolic blood pressure (BP) Ն 90 mmHg and/or systolic BP Ն 140 mmHg, is endemic in Westernized societies. This is a very important public health issue because hypertension is a major risk factor for premature death and disability from heart attack, heart failure, stroke, and many other afflictions (16,59). In the United States, alone, Ϸ20% of the population (i.e., Ϸ50 million individuals) are hypertensive; moreover, more than half of all individuals over the age of 60 years have hypertension. In a small fraction of cases, the hypertension is due to specific causes, such as renal vascular disease or excessive secretion of aldosterone (primary aldosteronism) or catecholamines (pheochromocytoma). The vast majority (Ϸ90%) of patients, however, have elevated BP of unknown cause; hence the terms, primary or essential hypertension. The immediate cause for the elevated BP in nearly all chronic hypertensive persons is excessive narrowing of the small (resistance) arteries. Nevertheless, a key question in any discussion of hypertension is: What specific mechanisms actually lead to the abnormal arterial constriction and elevation ...

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Section: Endogenous Ouabain and Other Endogenous Cardiotonic Steroidsmentioning

confidence: 99%

How does salt retention raise blood pressure?

Blaustein¹,

Zhang²,

Ling³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

129

121

View full text Add to dashboard Cite

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“…Plasma levels of endogenous cardiac glycosides are high in several animal models of hypertension, as well as in human essential hypertension and preeclampsia (10)(11)(12)(13)(14)(15)(16)(17). In addition, marked increases in endogenous ouabain-like compounds occur in congestive heart failure, both in animal models and human patients (18)(19)(20).…”

mentioning

confidence: 99%

“…Although several studies have shown a correlation between elevated endogenous cardiac glycosides and certain pathological conditions, the physiological function of endogenous cardiac glycoside-like compounds is still uncertain (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Plasma levels of endogenous cardiac glycosides are high in several animal models of hypertension, as well as in human essential hypertension and preeclampsia (10)(11)(12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation

Dostanic-Larson

Huysse

Lorenz

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

173

190

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The Na,K-ATPase contains a binding site for cardiac glycosides, such as ouabain, digoxin, and digitoxin, which is highly conserved among species ranging from Drosophila to humans. Although advantage has been taken of this site to treat congestive heart failure with drugs such as digoxin, it is unknown whether this site has a natural function in vivo. Here we show that this site plays an important role in the regulation of blood pressure, and it specifically mediates adrenocorticotropic hormone (ACTH)-induced hypertension in mice. We used genetically engineered mice in which the Na,K-ATPase ␣2 isoform, which is normally sensitive to cardiac glycosides, was made resistant to these compounds. Chronic administration of ACTH caused hypertension in WT mice but not in mice with an ouabain-resistant ␣2 isoform of Na,K-ATPase. This finding demonstrates that the cardiac glycoside binding site of the Na,K-ATPase plays an important role in blood pressure regulation, most likely by responding to a naturally occurring ligand. Because the ␣1 isoform is sensitive to cardiac glycosides in humans, we developed mice in which the naturally occurring ouabain-resistant ␣1 isoform was made ouabain-sensitive. Mice with the ouabainsensitive ''human-like'' ␣1 isoform and an ouabain-resistant ␣2 isoform developed ACTH-induced hypertension to greater extent than WT animals. This result indicates that the cardiac glycoside binding site of the ␣1 isoform can also mediate ACTH-induced hypertension. Taken together these results demonstrate that the cardiac glycoside binding site of the ␣ isoforms of the Na,K-ATPase have a physiological function and supports the hypothesis for a role of the endogenous cardiac glycosides. adrenocorticotropic hormone ͉ hypertension ͉ endogenous cardiac glycosides

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“…Recently, we have demonstrated a marked increase in cell Na+ in vascular smooth muscle (VSM) after inhibition of the sodium pump (9, 10), which raised the question of whether increases in cytosolic Na+ could influence cytosolic Ca2+ in VSM via mitochondrial Na+-dependent Ca2+ release. Inhibition of the sodium pump may contribute to the pathogenesis of hypertension by influencing cytosolic Ca2+ via Na+ : Ca2+ exchange across the cell membrane (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Sodium-Dependent Calcium Release from Vascular Smooth Muscle Mitochondria.

2000

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Interest in mitochondrial calcium (Ca2+) uptake and release waned as it became apparent that sarcoplasmic reticulum calcium stores dominate the control of cytoplasmic calcium concentration.Our recent demonstration of a very large rise in vascular smooth muscle (VSM) cytoplasmic sodium (Na+) concentration after inhibition of the sodium, potassium-ATPase (sodium pump) led us to several questions. Do VSM mitochondria show Na+-dependent Ca2+ release? Are the documented changes in cytoplasmic Na+ concentration sufficient to cause Ca2+ release? Do features of the cardiac mitochondrial exchange system, including differential sensitivity to a number of calcium antagonists and cation specificity, apply to VSM?We isolated mitochondria from bovine aorta and mesenteric arteries and employed arsenazo III as the Ca2+ indicator. Mitochondria from arterial vessels accumulated added calcium (up to 50 nmol Ca2+/mg protein) and released Ca2+ on exposure to Na+. This concentration-dependent relationship was linear from 0 to 10 mM of Nat, and it plateaued between 20 mM and 40 mM of Nat. VSM mitochondria exposed to 20 mM Na+ released 118±25 nmol Ca2+ per mg mitochondrial protein in 20 min, when a new equilibrium was reached. Lithium (Li+), in contrast to Na+, produced much smaller amounts of Ca2+ release from the VSM mitochondria. Na+-dependent Ca2+ release was antagonized in a concentration-dependent manner by diltiazem (0-320 pM) with a Ki of 10.2 hM. Nifedipine had a lesser effect, and verapamil produced almost no inhibition. VSM mitochondria responses resemble those from heart mitochondria in that Na+-dependent Ca2+ release is present with a similar range of sensitivity to Na+ and a similar pattern of influence of diltiazem, nifedipine and verapamil. However, the influence of Li+ on Ca2+ release was much smaller and the amount of the Ca2+ released was much greater for VSM mitochondria compared with that reported for heart mitochondria. The large amount of Ca2+ released and the range of Na+ concentration that provoked Ca2+ release being within the physiologically achievable range raise the interesting possibility that these mechanisms may modify intramitochondrial cytosolic Ca2+ concentration, and hence could potentially contribute to the contractile response that follows inhibition of the sodium pump. (Hypertens Res 2000; 23: 39-45)

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A circulating inhibitor of (Na+ + K+) ATPase associated with essential hypertension

Cited by 544 publications

References 20 publications

How does salt retention raise blood pressure?

How does salt retention raise blood pressure?

The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation

Sodium-Dependent Calcium Release from Vascular Smooth Muscle Mitochondria.

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