Endothelial Modulation of Ouabain-lnduced Contraction and Sodium Pump Activity in Aortas of Normotensive Wystar-Kyoto and Spontaneously Hypertensive Rats

Ponte, Ana; Marı́n, Jesús; Arribas, Silvia M.; González, Rita; Mt, Barrús; Salaíces, Mercedes; Cf, Sánchez-Ferrer

doi:10.1159/000159145

Cited by 19 publications

(23 citation statements)

References 25 publications

(48 reference statements)

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“…These alterations were associated with changes in the activity of the sodium pump and the expression of the ␣ 1 -and ␣ 2 -isoforms of Na ϩ -K ϩ -ATPase and, in addition, associated with the release of an endothelial factor that negatively modulates vasoconstrictor responses to phenylephrine to a greater extent in arteries from ouabain-treated animals than in controls (45). The latter observation is consistent with known acute actions of ouabain that cause the release of endothelialderived vasodilators such as endothelium-derived hyperpolarizing factor (EDHF), prostacyclin, and nitric oxide (NO) (33,41,43,46,53), all of which could act to negatively modulate the contractile actions of phenylephrine. However, the nature of the endothelial vasodilator factors involved in the negative modulation of the vasoconstrictor responses in arteries from ouabaininduced hypertensive rats remains unclear.…”

supporting

confidence: 82%

“…Results from Nagakawa et al (37) support this idea showing that ouabain induced prostacyclin release from bovine endothelial cells. Moreover, other reports showed that the cyclooxygenase inhibitor indomethacin was unable to alter the acute ouabain vascular effects (41,46). In addition, it has been shown that hypertension modifies the role of cyclooxygenasederived products in vasodilator and vasoconstrictor responses (11,13).…”

Section: Discussionmentioning

confidence: 99%

“…However, endothelium removal enhances the reactivity to phenylephrine to a greater extent in both arteries from ouabain-hypertensive rats, suggesting an increase in negative endothelial modulation. The acute sensitization or contractile effects of ouabain in different vascular beds seem to be modulated by unknown bioassayable endothelial factor(s) (33,37,41,43,46,53). Moreover, ouabain releases prostacyclin and NO from endothelial cells (37,53), as well as a relaxing factor that seems to open potassium channels (43).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, ouabain releases prostacyclin and NO from endothelial cells (37,53), as well as a relaxing factor that seems to open potassium channels (43). However, NO does not appear to be involved in the vasoconstrictor response induced by acute ouabain (41,46) or in the sensitization of vasoconstrictor responses induced by nanomolar concentrations of ouabain (43).…”

Section: Discussionmentioning

confidence: 99%

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Ouabain-induced hypertension is accompanied by increases in endothelial vasodilator factors

Rossoni

Salaíces

Miguel

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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. Ouabain-induced hypertension is accompanied by increases in endothelial vasodilator factors. Am J Physiol Heart Circ Physiol 283: H2110-H2118, 2002. First published July 11, 2002 10.1152/ajpheart.00454.2002The involvement of nitric oxide (NO), prostaglandins, and calcium-dependent potassium channel (K Ca) activators on the negative modulation of phenylephrine-induced contractions was evaluated on the isolated aorta and caudal (CAU) artery obtained from rats treated with ouabain for 5 wk to induce hypertension. In ouabain-treated rats, the reactivity to phenylephrine was reduced in the endothelium-intact aorta but not the CAU segments. Endothelial modulation of phenylephrine contraction, as demonstrated by endothelium removal, NO synthase (NOS) inhibition with N -nitro-L-arginine methyl ester and aminoguanidine, as well as K Ca inhibition with tetraethylammonium, was more pronounced in segments from ouabain-treated animals, and here greater effects were seen in the aorta than in CAU. An increased expression of endothelial NOS and neuronal NOS was seen in the aorta after ouabain treatment. In CAU, only endothelial NOS was detected and ouabain treatment did not alter its expression. These results suggest that ouabain-induced hypertension is accompanied by increased NO release derived from endothelial NOS and neuronal NOS and increased release of an endothelial hyperpolarizing factor that presumably opens K Ca, all of which contribute to the increased negative modulation of the phenylephrine contraction. nitric oxide; endothelial-dependent hyperpolarizing factor; phenylephrine THE PLASMA LEVELS of an endogenous circulating Na ϩ -K ϩ -ATPase inhibitor, characterized as ouabain or a closely related compound (17,36), are increased in several animal models of hypertension (19,39), as well as in human essential hypertension (20). Several studies have shown that chronic administration of ouabain induces hypertension, an effect that seems to be linked to the inhibition of the Na ϩ -K ϩ -ATPase (10,22,23,45,54), although sodium pump inhibition seems not to be the exclusive mechanism of the ouabain-hypertensive effect (26,31,32,52). This enzyme is found in most eukaryotic cells and is the main system involved in the maintenance of sodium homeostasis and the membrane potential, essential factors for controlling vascular tone and blood pressure. It has been suggested that alterations in the activity of the sodium pump might be involved in the genesis or maintenance of hypertensive states (3, 33). Additionally, the hypertension induced by ouabain treatment has been associated with actions in the central nervous system that increase sympathetic activity by activation of the central renin-angiotensin system and impair the arterial baroreceptor reflex (22, 23) and associated with actions in the periphery that produce changes in responsiveness to contractile agents (10,26,45).In some isolated vascular preparations, acutely administered ouabain, at nanomolar concentrations, can enhance the actions of phenylephrine (43). Higher mi...

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supporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Ouabain-induced hypertension is accompanied by increases in endothelial vasodilator factors

Rossoni

Salaíces

Miguel

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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“…In contrast to this study, which favors dysfunction of the microvascular DVR endothelium during chronic ouabain exposure, an increased vasodilatory influence attributable to upregulation of eNOS and nNOS and increased NO production was observed in the rat aorta (39). Ouabain may augment release of both a diffusible vasodilator and vasoconstrictor from the spontaneously hypertensive rat aortic endothelium (36). Most recently, a role for the endothelium was uncovered by Dostanic et al (12); depending on the presence or absence of the endothelium, ouabain either attenuated or enhanced, respectively, phenylephrine-induced contraction of murine aortic rings.…”

Section: Discussioncontrasting

confidence: 99%

Chronic ouabain treatment induces vasa recta endothelial dysfunction in the rat

Cao¹,

Payne²,

Lee-Kwon³

et al. 2009

American Journal of Physiology-Renal Physiology

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([Ca 2ϩ ]CYT) signaling. In this study, we examined the expression of the ouabain-sensitive Na-K-ATPase ␣2 subunit in the rat renal vasculature and tested effects of acute ouabain exposure and chronic ouabain treatment on DVR. Immunostaining with antibodies directed against the ␣2 subunit verified its expression in both DVR pericytes and endothelium. Acute application of ouabain (100 or 500 nM) augmented the DVR nitric oxide generation stimulated by acetylcholine (ACh; 10 M). At a concentration of 1 mM, ouabain constricted microperfused DVR, whereas at 100 nM, it was without effect. Acute ouabain (100 nM) did not augment constriction by angiotensin II (0.5 or 10 nM), whereas L-nitroarginine methyl esterinduced contraction of DVR was slightly enhanced. Ouabain-hypertensive (OH) rats were generated by chronic ouabain treatment (30 g ⅐ kg Ϫ1 ⅐ day Ϫ1 , 5 wk). The acute endothelial [Ca 2ϩ ]CYT elevation by ouabain (100 nM) was absent in DVR endothelia of OH rats. The [Ca 2ϩ ]CYT response to 10 nM ACh was also eliminated, whereas the response to 10 M ACh was not. The endothelial [Ca 2ϩ ]CYT response to bradykinin (100 nM) was significantly attenuated. We conclude that endothelial responses may offset the ability of acute ouabain exposure to enhance DVR vasoconstriction. Chronic exposure to ouabain, in vivo, leads to hypertension and DVR endothelial dysfunction, manifested as reduced [Ca 2ϩ ]CYT responses to both ouabain-and endothelium-dependent vasodilators. kidney; medulla; microcirculation; nitric oxide; blood flow "OUABAIN-LIKE FACTORS" (OLF), synthesized by the adrenal gland and hypothalamus, inhibit Na ϩ /K ϩ exchange (19, 46) and activate signaling cascades (6, 7, 44) by binding to Na-KATPase ␣-subunits. In rodents, the ␣1 isoform of Na-KATPase that maintains Na ϩ and K ϩ gradients across cell membranes has very low affinity (K d Ͼ 10 M) for ouabain. In contrast, the ␣2 and ␣3 isoforms have high affinity for ouabain (K d Ͻ 50 nM), but are less abundantly expressed (3, 48). It has been proposed that targeting of the ␣2 isoform to cellular microdomains where ER/SR protrusions abut the plasma membrane (4, 7) may modulate intracellular Na ϩ and reduce Ca 2ϩ extrusion via Na ϩ /Ca 2ϩ exchange to enhance Ca 2ϩ sequestration into ER/SR stores. Evidence favoring that hypothesis has been accumulating. Low-dose (10 -100 nM) ouabain enhances Ca 2ϩ release in smooth muscle and endothelium (2, 35) and increases resting cytoplasmic Ca 2ϩ ([Ca 2ϩ ] CYT ) and myogenic tone (35,48).A role for OLF in hypertension is also well supported. Chronic administration of ouabain into rodents induces hypertension (26, 28), and many patients with essential hypertension have high plasma ouabain levels (43). Transgenic mice in which the ␣2 Na-K-ATPase binding site for ouabain has been mutated are resistant to both ouabain-and ACTH-induced hypertension, supporting a causal role in hypertension for both ouabain and the ␣2 ouabain receptor (12, 13).Detailed mechanisms by which ouabain induces hypertension remain to be elucidated. ...

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Time-dependent increases in ouabain-sensitive Na+, K+-ATPase activity in aortas from diabetic rats: The role of prostanoids and protein kinase C

et al. 2010

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Endothelial Modulation of Ouabain-lnduced Contraction and Sodium Pump Activity in Aortas of Normotensive Wystar-Kyoto and Spontaneously Hypertensive Rats

Cited by 19 publications

References 25 publications

Ouabain-induced hypertension is accompanied by increases in endothelial vasodilator factors

Ouabain-induced hypertension is accompanied by increases in endothelial vasodilator factors

Chronic ouabain treatment induces vasa recta endothelial dysfunction in the rat

Time-dependent increases in ouabain-sensitive Na+, K+-ATPase activity in aortas from diabetic rats: The role of prostanoids and protein kinase C

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