Immunoreactive endogenous ouabain primary aldosteronism and essential hypertension: relationship with plasma renin, aldosterone and blood pressure levels

Rossi, Gianpaolo; Manunta, Paolo; Hamlyn, John M.; Pavan, Edoardo; Toni, Renzo De; Semplicini, Andrea; Pessina, Achille C.

doi:10.1097/00004872-199510000-00013

Cited by 135 publications

(112 citation statements)

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“…This could be the rationale for colocalization of high ouabain affinity Na ϩ pumps and Na ϩ ͞Ca 2ϩ exchangers in these PM areas. This might reveal how an endogenous ouabain isomer (12,(37)(38)(39), which circulates at nanomolar concentrations (40) and is present in the brain (38,39), could, by modulating the activity of these high ouabain affinity Na ϩ pumps (28,37), play a role in many physiological, and even pathophysiological, processes (12). Finally, this may also explain why the isoformspecific features of the ouabain binding regions of ␣2 and ␣3 have been so well conserved during the evolution of higher animals (4,10).…”

Section: Resultsmentioning

confidence: 99%

Na ⁺ pump low and high ouabain affinity α subunit isoforms are differently distributed in cells

Juhaszova

Blaustein

1997

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

280

246

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Three isoforms (␣1, ␣2, and ␣3) of the catalytic (␣) subunit of the plasma membrane (PM) Na ؉ pump have been identified in the tissues of birds and mammals. These isoforms differ in their affinities for ions and for the Na ؉ pump inhibitor, ouabain. In the rat, ␣1 has an unusually low affinity for ouabain. The PM of most rat cells contains both low (␣1) and high (␣2 or ␣3) ouabain affinity isoforms, but precise localization of specific isoforms, and their functional significance, are unknown. We employed high resolution immunocytochemical techniques to localize ␣ subunit isoforms in primary cultured rat astrocytes, neurons, and arterial myocytes. Isoform ␣1 was ubiquitously distributed over the surfaces of these cells. In contrast, high ouabain affinity isoforms (␣2 in astrocytes, ␣3 in neurons and myocytes) were confined to a reticular distribution within the PM that paralleled underlying endoplasmic or sarcoplasmic reticulum. This distribution is identical to that of the PM Na͞Ca exchanger. This raises the possibility that ␣1 may regulate bulk cytosolic Na ؉ , whereas ␣2 and ␣3 may regulate Na ؉ and, indirectly, Ca 2؉ in a restricted cytosolic space between the PM and reticulum. The high ouabain affinity Na ؉ pumps may thereby modulate reticulum Ca 2؉ content and Ca 2؉ signaling.

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Section: Resultsmentioning

confidence: 99%

Na ⁺ pump low and high ouabain affinity α subunit isoforms are differently distributed in cells

Juhaszova

Blaustein

1997

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

280

246

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“…These substances include digoxin (102,103), proscilaridin A (101), and the bufodienolides (67,70). Only plasma EO levels, however, have been directly correlated with BP in humans (89,97) and in several animal models of hypertension (43,75,115,117). Elevated EO levels were observed in about 40% of patients with untreated essential hypertension (97) in patients with primary aldosteronism (97) and in those with ACTHinduced hypertension (32,33).…”

Section: Endogenous Ouabain and Other Endogenous Cardiotonic Steroidsmentioning

confidence: 99%

“…Only plasma EO levels, however, have been directly correlated with BP in humans (89,97) and in several animal models of hypertension (43,75,115,117). Elevated EO levels were observed in about 40% of patients with untreated essential hypertension (97) in patients with primary aldosteronism (97) and in those with ACTHinduced hypertension (32,33). Elevated EO levels were also observed in rodents with DOCA-salt hypertension (41,43), ACTH-hypertension (20, 20a, 115), reduced renal mass hypertension (108), and in salt-sensitive Milan strain rats on a high-salt diet (22,23).…”

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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“…Trabalhos da literatura demonstraram que aproximadamente 50% dos pacientes com HA essencial apresentavam valores elevados de OUA plasmática (PIERDOMENICO et al, 2001;ROSSI et al, 1995) e que há uma relação entre a elevação da pressão arterial e a quantidade de OUA plasmática em indivíduos hipertensos (HAMLYN et al, 1982). Além disso modelos animais de HA, como a hipertensão renal (OVERBECK et al, 1976) e o modelo DOCA-sal (HAMLYN, 1989;HAMLYN; HAMILTON; MANUNTA, 1996), também apresentam como características as concentrações plasmáticas elevadas de ouabaína endógena.…”

Section: A Na + K + Atpase E a Ouabaínaunclassified

“…Entre os modelos animais de HA experimental encontra-se o induzido pela OUA, em que o tratamento crônico de ratos com esse digitálico mimetiza o aumento observado no plasma (2 a 5 nmol/L) em pacientes com HA essencial (MANUNTA et al, 1994;PIERDOMENICO et al, 2001;ROSSI et al, 1995). Além disso, o tratamento crônico com OUA em animais é bem descrito na literatura como sendo capaz de induzir a HA (DI-FILIPPO et al, 2003;HUANG et al, 1994;LEENEN, 1999;MANUNTA et al, 1994; HAMILTON; HAMLYN, 2001; ROSSONI et al, 2002a e b;XAVIER et al, 2004a, b e c).…”

Section: A Ouabaína E a Hipertensão Arterial 32unclassified

Estudo dos mecanismos envolvidos no remodelamento de artérias de resistência de ratos hipertensos induzidos pelo tratamento com ouabaína.

Neto¹,

de²

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Estudo dos mecanismos envolvidos no remodelamento de artérias de resistência de ratos hipertensos induzidos pelo tratamento com ouabaínaTese apresentada ao Programa de Pós-Graduação em Fisiologia Humana USP/ Instituto de Ciências Biomédicas/ ICB, para obtenção do Título de Doutor em Fisiologia Humana. mg/kg/dia; v.o.; grupo HH). O grupo OUA apresentou elevação dos valores de pressão arterial e, ambos os co-tratamentos preveniram a resposta pressórica da OUA. As AMR dos ratos OUA apresentaram redução do diâmetro interno (Di), da área de secção transversa e do número de núcleos e aumento na rigidez, na quantidade de colágeno total e espécies reativas de oxigênio, as quais foram bloqueadas por todos co-ttos, exceto pela HH. Em AMR de ratos OUA, o SRA e a COX-2 participam da resposta pressórica, do remodelamento hipotrófico para dentro e da rigidez. Esses ajustes estão associados ao stress oxidativo e a deposição de colágeno na parede vascular estimulados pela capacidade da OUA em promover a ativação do receptor AT1 e da COX-2. The chronic administration of ouabain (OUA) induces hypertension in rats, functional and structural alterations in mesenteric resistance arteries (MRA). It is well known that OUA-induced hypertension is blocked by AT1 receptor antagonism and the COX-2 inhibition. However, the participation of these pathways in MRA remodeling in this model of hypertension remains unknown. This study aimed to investigate the role of the renin angiotensin system (RAS) and COX pathways on MRA remodeling induced by OUA. Male Wistar rats (45 days) were treated for 5 weeks with OUA (30 µg/kg/day, s.c.) and co-treated with losartan potassium (15 mg/kg/day, p.o.), aspirin (100 mg/kg/day; p.o.), nimesulide (20 mg/kg /day, p.o.) or hydralazine hydrochloride (44 mg/kg/day) plus hydrochlorothiazide (9.4 mg/kg/day; p.o.; HH group). The OUA group showed high blood pressure and both co-treatments prevented the pressor response of OUA. MRA of OUA rats showed reduced inner diameter and cross sectional area and increased arterial stiffness, the amount of total collagen and reactive oxygen species in the vascular wall, which were blocked by all co-treatments except for HH. In AMR from OUA rats, RAS and COX-2 participate in the pressor response, the inward hypotrophic remodeling and stiffness. These adjustments are the result of oxidative stressand increasing collagen deposition in the vascular wall stimulated by the OUA ability to stimulate the activation of AT1 receptor and COX-2.Keyworlds: Vascular remodeling. Ouabain. Arterial hypertension. Quanto à sua origem, a HA pode ser classificada como HA primária ou secundária. A HA primária é a forma de maior prevalência na população (90%). Essa forma da HA não possui causas definidas, mas está associada a muitos fatores de risco, como fatores hereditários, uma dieta pouco saudável, sedentarismo, stress ou abuso de bebidas alcoólicas. Por sua vez, a HA secundária tem prevalência de 3 a 5% e está associada à alguma condição clínica, como hiperaldosteronismo primário, feocromocitoma e ...

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Immunoreactive endogenous ouabain primary aldosteronism and essential hypertension: relationship with plasma renin, aldosterone and blood pressure levels

Cited by 135 publications

References 0 publications

Na ⁺ pump low and high ouabain affinity α subunit isoforms are differently distributed in cells

Na ⁺ pump low and high ouabain affinity α subunit isoforms are differently distributed in cells

How does salt retention raise blood pressure?

Estudo dos mecanismos envolvidos no remodelamento de artérias de resistência de ratos hipertensos induzidos pelo tratamento com ouabaína.

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Immunoreactive endogenous ouabain primary aldosteronism and essential hypertension: relationship with plasma renin, aldosterone and blood pressure levels

Cited by 135 publications

References 0 publications

Na + pump low and high ouabain affinity α subunit isoforms are differently distributed in cells

Na + pump low and high ouabain affinity α subunit isoforms are differently distributed in cells

How does salt retention raise blood pressure?

Estudo dos mecanismos envolvidos no remodelamento de artérias de resistência de ratos hipertensos induzidos pelo tratamento com ouabaína.

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Product

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Na ⁺ pump low and high ouabain affinity α subunit isoforms are differently distributed in cells

Na ⁺ pump low and high ouabain affinity α subunit isoforms are differently distributed in cells