title: Functional inhibition of urea transporter UT-B enhances endothelial-dependent vasodilatation and lowers blood pressure via L-arginine-endothelial nitric oxide synthase-nitric oxide pathway.
abstract: Mammalian urea transporters (UTs), UT-A and UT-B, are best known for their role in urine concentration. UT-B is especially distributed in multiple extrarenal tissues with abundant expression in vascular endothelium, but little is known about its role in vascular function. The present study investigated the physiological significance of UT-B in regulating vasorelaxations and blood pressure. UT-B deletion in mice or treatment with UT-B inhibitor PU-14 in Wistar-Kyoto rats (WKYs) and spontaneous hypertensive rats (SHRs) reduced blood pressure. Acetylcholine-induced vasorelaxation was significantly augmented in aortas from UT-B null mice. PU-14 concentration-dependently produced endothelium-dependent relaxations in thoracic aortas and mesenteric arteries from both mice and rats and the relaxations were abolished by N(ω)-nitro-L-arginine methyl ester. Both expression and phosphorylation of endothelial nitric oxide synthase (eNOS) were up-regulated and expression of arginase I was down-regulated when UT-B was inhibited both in vivo and in vitro. PU-14 induced endothelium-dependent relaxations to a similar degree in aortas from 12 weeks old SHRs or WKYs. In summary, here we report for the first time that inhibition of UT-B plays an important role in regulating vasorelaxations and blood pressure via up-regulation of L-arginine-eNOS-NO pathway, and it may become another potential therapeutic target for the treatment of hypertension.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Chi-Wai
authors.initials: CW
authors.lastname: Lau
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Yingli
authors.initials: Y
authors.lastname: Jia
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Weiling
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Anatomy and Neuroscience Center, Chongqing Medical University, Chongqing, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Ran
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Baoxue
authors.initials: B
authors.lastname: Yang
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D004232:Diuretics / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D017353:Gene Deletion; D015870:Gene Expression; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D023421:Models, Animal; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics; D000096982:Urea Transporters
chemical_list: D001120:Arginine; D004232:Diuretics; D026901:Membrane Transport Proteins; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D000096982:Urea Transporters