title: Metformin reduces asymmetric dimethylarginine and prevents hypertension in spontaneously hypertensive rats.
abstract: Elevated asymmetric dimethylarginine (ADMA) levels and nitric oxide (NO) deficiency are associated with the development of hypertension. Metformin, an antidiabetic agent, is a structural analog of ADMA. We examined whether metformin can prevent the development of hypertension in spontaneously hypertensive rats (SHRs) by restoration of ADMA-NO balance. SHRs and control normotensive Wistar-Kyoto (WKY) rats were assigned to 4 groups (N = 8 for each group): untreated SHRs and WKY rats, metformin-treated SHRs and WKY rats. Metformin-treated rats received metformin 500 mg/kg per day via oral gavage for 8 weeks. All rats were sacrificed at the age of 12 weeks. We found an increase in the blood pressure of SHRs was prevented by metformin. ADMA levels in the plasma and lung were elevated in SHRs, which metformin prevented. Lung dimethylarginine dimethylaminohydrolase (DDAH, ADMA-metabolizing enzyme) activity was lower in SHRs than WKY rats. Next, metformin had no effect on protein arginine methyltransferase 1 (ADMA-synthesizing enzyme), DDAH-1, DDAH-2, NO synthase enzymes, and DDAH activity in the kidney. Moreover, metformin increased the levels of NO in kidney. Conclusively, the observed antihypertensive effect of metformin in SHRs is because of the restoration of the ADMA-NO pathway. Our findings support the consideration of metformin as an antihypertensive agent for diabetic patients with prehypertension.
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Chang Gung University, College of Medicine, Taoyuan, Taiwan.
authors.forename: Chih-Min
authors.initials: CM
authors.lastname: Tsai
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Chang Gung University, College of Medicine, Taoyuan, Taiwan.
authors.forename: Hsuan-Chang
authors.initials: HC
authors.lastname: Kuo
authors.affiliation: Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chien-Ning
authors.initials: CN
authors.lastname: Hsu
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Chang Gung University, College of Medicine, Taoyuan, Taiwan.
authors.forename: Li-Tung
authors.initials: LT
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Chang Gung University, College of Medicine, Taoyuan, Taiwan; Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. Electronic address: tainyl@hotmail.com.
authors.forename: You-Lin
authors.initials: YL
authors.lastname: Tain
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000096:biosynthesis; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
chemical_list: D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D008687:Metformin; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase