The search for a hypothalamic Na+,K+-ATPase inhibitor.

Haber, Edgar; Haupert, Garner T.

doi:10.1161/01.hyp.9.4.315

Cited by 89 publications

(21 citation statements)

References 51 publications

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“…There are reports that EO also may be produced in the brain (38) and that elevated cerebrospinal fluid levels (39) are associated with hypertension without an elevation in the circulating EO level (48).…”

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

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

129

121

View full text Add to dashboard Cite

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“…OLC exhibiting Na+,K+-ATPase inhibitory activity has been extracted and partially purified from mammalian brain, hypothalamus and cerebrospinal fluid [6,7,16] 6-OH-DA Fig. 2.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the levels of ouabain‐like compound by central catecholamine neurons in rats

1995

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Catecholamine regulates the Na+,K+-ATPase activity in the central nervous system and the Na+,K+-ATPase has been shown to have endogenous ligands (ouabain-like compound; OLC). To examine the relationship between OLC and central adrenergic neurons, we evaluated the effects of central sympathectomies with intracerebroventricular (i.c.v.) injection of 6-hydroxydopamine (6-OHDA; 250/xg) on brain and plasma OLC levels and brain catecholamine levels. In centrally sympathectomized rats, hypothalamic OLC content and plasma OLC level were significantly decreased by 90% (P< 0.01) and 70% (P < 0.01), respectively, in accordance with reduced brain norepinephrine content compared with control rats pretreated by i.c.v, injection of vehicle (ascorbic acid). On the other hand, peripheral sympathectomy with a similar manner did not affect plasma OLC level at all. These findings suggest that central adrenergic neurons may be involved in the synthesis and/or release of circulating OLC.

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“…1 Because the cardiac glycoside binding site of the Na ϩ ,K ϩ -ATPase has been evolutionarily conserved and because the only known specific regulators of the enzyme in man are the plant kingdom cardiac glycosides such as ouabain (Oua), the notion arose that mammalian analogs to the cardiac glycosides might exist. 2 Over the past 2 decades, a number of investigators have reported extraction of Na ϩ pump inhibitory activity from body fluid and tissue sources, and this inhibitor has been linked to the pathogenesis of experimental volume-expanded and human essential hypertension. 2,3 Structural analysis has indicated that one of these compounds, isolated from mammalian brain and human plasma, appears to be Oua itself or a closely related isomer.…”

mentioning

confidence: 99%

“…2 Over the past 2 decades, a number of investigators have reported extraction of Na ϩ pump inhibitory activity from body fluid and tissue sources, and this inhibitor has been linked to the pathogenesis of experimental volume-expanded and human essential hypertension. 2,3 Structural analysis has indicated that one of these compounds, isolated from mammalian brain and human plasma, appears to be Oua itself or a closely related isomer. 4 The source of the ouabain-like compound (OLC) is debated and not settled.…”

mentioning

confidence: 99%

Ouabain-Binding Protein(s) From Human Plasma

et al. 2002

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Abstract-Conservation of the binding site on mammalian Na ϩ ,K ϩ -ATPase for cardiac glycosides and the importance of the Na ϩ pump in mammalian cellular physiology has stimulated the search for a mammalian analog of these plant compounds. One candidate, isolated from brain and blood, appears to be ouabain itself or a closely related isomer, the ouabain-like compound. Little is known about the circulating form. Because human steroid hormones circulate with carrier proteins, we produced a ouabain-specific monoclonal antibody (mAb 1-10) and used it to probe normal human plasma for ouabain-protein carrier complex. Ouabain-like biological activity was isolated in association with protein bands of 80, 50, and 25 kDa. These proteins appear to be human immunoglobulins or immunoglobulin-like because they are recognized by anti-human immunoglobulin antibodies, but not by anti-mouse immunoglobulin antibodies. The protein-containing fractions inhibit the binding of mAb 1-10 to immobilized ouabain, and with further purification on protein A, the immunoglobulin-like protein binds radioactive ouabain with an IC 50 of 200 to 600 nmol/L, but binds digoxin with 100-fold less affinity, suggesting specificity for ouabain or its isomer. Active protein fractions after purification on C 18 inhibit Na ϩ pump activity in human erythrocytes (IC 50Ϸ 4 nmol/L, ouabain equivalents), and this chromatography appears to dissociate the ouabain-like compound from the immunoglobulin protein(s). These immunoglobulin-like molecules may represent a subset of immunoglobulins (Յ0.5% of total protein A immunoglobulin) that function as a reservoir and delivery system for ouabain-like compounds in the modulation of human Na ϩ ,K ϩ -ATPase in vivo. (Hypertension. 2002;40:220-228.)

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The search for a hypothalamic Na+,K+-ATPase inhibitor.

Cited by 89 publications

References 51 publications

How does salt retention raise blood pressure?

How does salt retention raise blood pressure?

Modulation of the levels of ouabain‐like compound by central catecholamine neurons in rats

Ouabain-Binding Protein(s) From Human Plasma

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