title: Aliskiren prevents hypertension and reduces asymmetric dimethylarginine in young spontaneously hypertensive rats.
abstract: Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, decreases NO synthesis. Plasma ADMA concentrations increase markedly in hypertension. We tested whether the development of hypertension and the increases in ADMA in spontaneously hypertensive rats (SHR) are prevented by aliskiren, a renin inhibitor. Male SHRs and normotensive Wistar Kyoto (WKY) control rats, aged 4 weeks (pre-hypertensive stage), were assigned to 4 groups: untreated SHRs and WKY rats, and SHRs that received oral aliskiren 10 and 30 mg/kg/day for 6 weeks. All rats were sacrificed at age 10 weeks. Blood pressure decreased at age 6, 8, and 10 weeks in SHRs that received high-dose aliskiren. Aliskiren mitigated the increases in plasma ADMA in SHRs. Renal ADMA levels were lower in SHRs that received high-dose aliskiren versus SHRs. SHRs experienced decreased plasma and kidney l-Arg-to-ADMA ratios versus control rats, which were reverted by 30 mg/kg aliskiren. Renal cortical neuronal NOS-α and -β levels increased in SHRs fed with high-dose aliskiren. Early aliskiren treatment mitigates increases in ADMA, restores l-Arg-to-ADMA ratios, enhances neuronal NOS-α, prevents decreased nNOS-β levels in the kidney-which might restore NO bioavailability and contribute to the decrease of blood pressure in young SHRs. Our findings suggest that aliskiren is a therapeutic agent for prehypertension that regulates the ADMA/NO pathway.
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. tainyl@hotmail.com
authors.forename: You-Lin
authors.initials: YL
authors.lastname: Tain
authors.forename: Chien-Ning
authors.initials: CN
authors.lastname: Hsu
authors.forename: Ching-Yuang
authors.initials: CY
authors.lastname: Lin
authors.forename: Li-Tung
authors.initials: LT
authors.lastname: Huang
authors.forename: Ying-Tung
authors.initials: YT
authors.lastname: Lau
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005650:Fumarates / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006973:Hypertension / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D012083:Renin / Q000378:metabolism
chemical_list: D000577:Amides; D000959:Antihypertensive Agents; D005650:Fumarates; D009569:Nitric Oxide; C446481:aliskiren; C018524:N,N-dimethylarginine; D001120:Arginine; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D012083:Renin