title: Serelaxin reduces oxidative stress and asymmetric dimethylarginine in angiotensin II-induced hypertension.
abstract: Recent findings suggest the therapeutic action of relaxin during hypertension is dependent on nitric oxide synthase (NOS) activation; however, the mechanisms underlying the beneficial effects of relaxin on the NOS system have not been fully elucidated. We hypothesized that the protective effects of relaxin include reducing both oxidative stress and the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA). We examined the effect of Serelaxin [human recombinant relaxin-2 (RLX)] in male Sprague-Dawley rats given high-dose angiotensin (ANG) II (400 ng·kg(-1)·min(-1) sc) for 6 wk or shams. RLX was administered (4 μg/h sc) to half of the rats in each group after 2 wk of ANG II for the remaining 4 wk. ANG II induced hypertension and proteinuria, reduced NO oxidation products (NOx), and increased oxidative stress (NADPH oxidase activity, thiobarbituric acid-reactive substances, and 8-isoprostane excretion) and plasma ADMA. While RLX had no effect on sham rats, RLX attenuated the ANG II-dependent hypertension (165 ± 5 vs. 135 ± 13 mmHg, P < 0.05) and proteinuria at 6 wk (62 ± 6 vs. 41 ± 4 mg·day(-1)·100 g(-1), P < 0.05) and normalized oxidative stress and circulating ADMA, in association with restored NOx excretion and kidney cortex NOx. We found that RLX had no impact on the ADMA-regulatory enzymes protein arginine methyltransferase and dimethylarginine-dimethylaminohydrolase (DDAH). Furthermore, RLX treatment did not increase DDAH activity in kidney cortex or liver. These data suggest that benefits of RLX treatment include reduced ADMA levels and increased NO bioavailability, possibly due to its antioxidant effects.
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida; and jsasser@umc.edu.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Sasser
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida; and.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Cunningham
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida; and Department of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Chris
authors.initials: C
authors.lastname: Baylis
mesh_terms: D000804:Angiotensin II; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D062186:Arterial Pressure / Q000187:drug effects; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D007279:Injections, Subcutaneous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011507:Proteinuria / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012065:Relaxin / Q000008:administration & dosage / Q000494:pharmacology*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D000975:Antioxidants; D011994:Recombinant Proteins; D017392:Thiobarbituric Acid Reactive Substances; C577649:serelaxin protein, human; D000804:Angiotensin II; C075750:8-epi-prostaglandin F2alpha; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D012065:Relaxin; D001120:Arginine; D015237:Dinoprost; D019255:NADPH Oxidases
keywords: NADPH oxidase; dimethylarginine dimethylaminohydrolase; nitric oxide; protein arginine methyltransferase-1