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Disruption of Na+,HCO3⁻ cotransporter NBCn1 (slc4a7) inhibits NO-mediated vasorelaxation, smooth muscle Ca²âº sensitivity, and hypertension development in mice.

Boedtkjer, Ebbe; Praetorius, Jeppe; Matchkov, Vladimir V; Stankevicius, Edgaras; Mogensen, Susie; Füchtbauer, Annette C; Simonsen, Ulf; Füchtbauer, Ernst-Martin; Aalkjaer, Christian.
Circulation; 124(17): 1819-29, 2011 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-21947296

BACKGROUND:

Disturbances in pH affect artery function, but the mechanistic background remains controversial. We investigated whether Na(+), HCO3- transporter NBCn1, by regulating intracellular pH(pH1), influences artery function and blood pressure regulation.

METHODS AND RESULTS:

Knockout of NBCn1 in mice eliminated Na+, HCO3⁻ cotransport and caused a lower steady-state pH(i) in mesenteric artery smooth muscle and endothelial cells in situ evaluated by fluorescence microscopy. Using myography, arteries from NBCn1 knockout mice showed reduced acetylcholine-induced NO-mediated relaxations and lower rho-kinase-dependent norepinephrine-stimulated smooth muscle Ca²âº sensitivity. Acetylcholine-stimulated NO levels (electrode measurements) and N-nitro-l-arginine methyl ester-sensitive l-arginine conversion (radioisotope measurements) were reduced in arteries from NBCn1 knockout mice, whereas relaxation to NO-donor S-nitroso-N-acetylpenicillamine, acetylcholine-induced endothelial Ca²âº responses (fluorescence microscopy), and total and Ser-1177 phosphorylated endothelial NO-synthase expression (Western blot analyses) were unaffected. Reduced NO-mediated relaxations in arteries from NBCn1 knockout mice were not rescued by superoxide scavenging. Phosphorylation of myosin phosphatase targeting subunit at Thr-850 was reduced in arteries from NBCn1 knockout mice. Evaluated by an in vitro assay, rho-kinase activity was reduced at low pH. Without CO2/HCO3⁻, no differences in pH(i), contraction or relaxation were observed between arteries from NBCn1 knockout and wild-type mice. Based on radiotelemetry and tail-cuff measurements, NBCn1 knockout mice were mildly hypertensive at rest, displayed attenuated blood pressure responses to NO-synthase and rho-kinase inhibition and were resistant to developing hypertension during angiotensin-II infusion.

CONCLUSIONS:

Intracellular acidification of smooth muscle and endothelial cells after knockout of NBCn1 inhibits NO-mediated and rho-kinase-dependent signaling in isolated arteries and perturbs blood pressure regulation.
Selo DaSilva