Endothelial Epithelial Sodium Channel Inhibition Activates Endothelial Nitric Oxide Synthase via Phosphoinositide 3-Kinase/Akt in Small-Diameter Mesenteric Arteries
Author
dc.contributor.author
Pérez, Francisco R.
Author
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Venegas, Fabiola
es_CL
Author
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González, Magdalena
es_CL
Author
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Andrés, Sergio
es_CL
Author
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Vallejos, Catalina
es_CL
Author
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Riquelme Pino, Gloria
es_CL
Author
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Sierralta Jara, Jimena
es_CL
Author
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Michea Acevedo, Luis
es_CL
Admission date
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2014-01-06T14:51:04Z
Available date
dc.date.available
2014-01-06T14:51:04Z
Publication date
dc.date.issued
2009
Cita de ítem
dc.identifier.citation
Hypertension. 2009;53:1000-1007
en_US
Identifier
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doi: 10.1161/HYPERTENSIONAHA.108.128520
Identifier
dc.identifier.uri
https://repositorio.uchile.cl/handle/2250/129092
General note
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Artículo de publicación ISI
en_US
Abstract
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Recent studies have shown that the epithelial sodium channel (ENaC) is expressed in vascular tissue. However,
the role that ENaC may play in the responses to vasoconstrictors and NO production has yet to be addressed. In this
study, the contractile responses of perfused pressurized small-diameter rat mesenteric arteries to phenylephrine and
serotonin were reduced by ENaC blockade with amiloride (75.1 3.2% and 16.9 2.3% of control values, respectively;
P 0.01) that was dose dependent (EC50 88.9 1.6 nmol/L). Incubation with benzamil, another ENaC blocker, had
similar effects. , , and ENaC were identified in small-diameter rat mesenteric arteries using RT-PCR and Western
blot with specific antibodies. In situ hybridization and immunohistochemistry localized ENaC expression to the tunica
media and endothelium of small-diameter rat mesenteric arteries. Patch-clamp experiments demonstrated that primary
cultures of mesenteric artery endothelial cells expressed amiloride-sensitive sodium currents. Mechanical ablation of the
endothelium or inhibition of eNOS with N -nitro-L-arginine inhibited the reduction in contractility caused by ENaC
blockers. ENaC inhibitors increased eNOS phosphorylation (Ser 1177) and Akt phosphorylation (Ser 473). The presence
of the phosphoinositide 3-kinase inhibitor LY294002 blunted Akt phosphorylation and eNOS phosphorylation and the
decrease in the response to phenylephrine caused by blockers of ENaC, indicating that the phosphoinositide
3-kinase/Akt pathway was activated after ENaC inhibition. Finally, we observed that the effects of blockers of ENaC
were flow dependent and that the vasodilatory response to shear stress was enhanced by ENaC blockade. Our results
identify a previously unappreciated role for ENaC as a negative modulator of eNOS and NO production in
resistance arteries.