Disruption of Na + ,HCO 3 − Cotransporter NBCn1 (slc4a7) Inhibits NO-Mediated Vasorelaxation, Smooth Muscle Ca 2+ Sensitivity, and Hypertension Development in Mice
| Autor: | Susie Mogensen, Christian Aalkjaer, Annette Füchtbauer, Jeppe Praetorius, Edgaras Stankevičius, Vladimir V. Matchkov, Ebbe Boedtkjer, Ernst-Martin Füchtbauer, Ulf Simonsen |
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| Rok vydání: | 2011 |
| Předmět: |
medicine.medical_specialty
Electrical impedance myography business.industry Intracellular pH Anatomy Nitric oxide chemistry.chemical_compound Endocrinology medicine.anatomical_structure chemistry Physiology (medical) Internal medicine Knockout mouse medicine Fluorescence microscope Cardiology and Cardiovascular Medicine Cotransporter business Rho-associated protein kinase Artery |
| Zdroj: | Circulation. 124:1819-1829 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | Background— Disturbances in pH affect artery function, but the mechanistic background remains controversial. We investigated whether Na + ,HCO 3 − cotransporter NBCn1, by regulating intracellular pH (pH i ), influences artery function and blood pressure regulation. Methods and Results— Knockout of NBCn1 in mice eliminated Na + ,HCO 3 − 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 Ca 2+ 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 Ca 2+ 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 CO 2 /HCO 3 − , 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. |
| Databáze: | OpenAIRE |
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