Sodium pump α2 subunits control myogenic tone and blood pressure in mice

Zhang, Jin; Lee, Moo Yeol; Cavalli, Maurizio; Chen, Ling; Berra‐Romani, Roberto; Balke, C. William; Bianchi, Giuseppe; Ferrari, Paolo; Hamlyn, John M.; Iwamoto, Takahiro; Lingrel, Jerry B.; Matteson, D R; Wier, W. Gil; Blaustein, Mordecai P.

doi:10.1113/jphysiol.2005.091801

Cited by 167 publications

(280 citation statements)

References 63 publications

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“…of three independent experiments are shown P2Y 13 ) have been cloned from mammalian cDNA libraries [14]. Among them, P2X 1 , P2X 2 , P2X 4 , P2X 5 , P2Y 2 , P2Y 4 , and P2Y 6 mRNA species and proteins interacting with anti-P2X 1 , anti-P2Y 2 , and anti-P2Y 6 antibodies have been detected in rodent small arteries [36][37][38][39][40]. Our results show that transient and sustained constrictions of mouse mesenteric arteries evoked by ATP and UTP, respectively, are mainly mediated by P2X 1 and P2Y 6 receptors.…”

Section: Discussionmentioning

confidence: 99%

Myogenic tone in mouse mesenteric arteries: evidence for P2Y receptor-mediated, Na+, K+, 2Cl− cotransport-dependent signaling

Кольцова

Maximov

Kotelevtsev

et al. 2009

Purinergic Signalling

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This study examines the action of agonists and antagonists of P2 receptors on mouse mesenteric artery contractions and the possible involvement of these signaling pathways in myogenic tone (MT) evoked by elevated intraluminal pressure. Both ATP and its non-hydrolyzed analog α,β-ATP triggered transient contractions that were sharply decreased in the presence of NF023, a potent antagonist of P2X 1 receptors. In contrast, UTP and UDP elicited sustained contractions which were suppressed by MRS2567, a selective antagonist of P2Y 6 receptors. Inhibition of Na + , K + , 2Cl − cotransport (NKCC) with bumetanide led to attenuation of contractions in UTP-but not ATPtreated arteries. Both UTP-induced contractions and MT were suppressed by MRS2567 and bumetanide but were insensitive to NF023. These data implicate a P2Y 6 -mediated, NKCC-dependent mechanism in MT of mesenteric arteries. The action of heightened intraluminal pressure on UTP release from mesenteric arteries and its role in the triggering of P2Y 6 -mediated signaling should be examined further.

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Section: Discussionmentioning

confidence: 99%

Myogenic tone in mouse mesenteric arteries: evidence for P2Y receptor-mediated, Na+, K+, 2Cl− cotransport-dependent signaling

Кольцова

Maximov

Kotelevtsev

et al. 2009

Purinergic Signalling

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“…This response was unaffected by ␣-adrenergic blockade and, thus, was not due to catechomaine release from sympathetic neurons in the artery wall. The effect of ouabain also was maintained following endothelium removal (120). The half-maximally effective concentration of ouabain (EC 50 ) was 1.3 nM (120).…”

Section: How Does Low-dose Ouabain Augment Contractility?mentioning

confidence: 94%

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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“…The compound appears as a novel drug that may also target these altered molecular mechanisms in patients. Indeed, previous findings have indicated that rostafuroxin is a potent and safe drug (Ferrari et al, 1999a,b) able to counteract hypertension development, and the related hypertensive effects, induced by mutant a-adducin and ouabain at renal and vascular levels, preventing cardiac and renal hypertrophy in the long run in animal models Zhang et al, 2005). More recently, a pharmacologic clinical trial has shown that rostafuroxin also normalizes BP levels in patients carrying a selective genetic profile that includes genes encoding for adducin variants and enzymes controlling ouabain synthesis and transport (Lanzani et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

Ferrandi

Molinari

Rastaldi

et al. 2014

J Pharmacol Exp Ther

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Glomerulopathies are important causes of morbidity and mortality. Selective therapies that address the underlying mechanisms are still lacking. Recently, two mechanisms, mutant b-adducin and ouabain, have been found to be involved in glomerular podocytopathies and proteinuria through nephrin downregulation. The main purpose of the present study was to investigate whether rostafuroxin, a novel antihypertensive agent developed as a selective inhibitor of Src-SH2 interaction with mutant adducinand ouabain-activated Na,K-ATPase, may protect podocytes from adducin-and ouabain-induced effects, thus representing a novel pharmacologic approach for the therapy of podocytopathies and proteinuria caused by the aforementioned mechanisms. To study the effect of rostafuroxin on podocyte protein changes and proteinuria, mice carrying mutant b-adducin and ouabain hypertensive rats were orally treated with 100 mg/kg per day rostafuroxin. Primary podocytes from congenic rats carrying mutant a-adducin or b-adducin (NB) from Milan hypertensive rats and normal rat podocytes incubated with 10 29 M ouabain were cultured with 10 29 M rostafuroxin. The results indicated that mutant b-adducin and ouabain caused podocyte nephrin loss and proteinuria in animal models. These alterations were reproduced in primary podocytes from NB rats and normal rats incubated with ouabain. Treatment of animals, or incubation of cultured podocytes with rostafuroxin, reverted mutant b-adducin-and ouabain-induced effects on nephrin protein expression and proteinuria. We conclude that rostafuroxin prevented podocyte lesions and proteinuria due to mutant b-adducin and ouabain in animal models. This suggests a potential therapeutic effect of rostafuroxin in patients with glomerular disease progression associated with these two mechanisms.

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Sodium pump α2 subunits control myogenic tone and blood pressure in mice

Cited by 167 publications

References 63 publications

Myogenic tone in mouse mesenteric arteries: evidence for P2Y receptor-mediated, Na+, K+, 2Cl− cotransport-dependent signaling

Myogenic tone in mouse mesenteric arteries: evidence for P2Y receptor-mediated, Na+, K+, 2Cl− cotransport-dependent signaling

How does salt retention raise blood pressure?

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

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