title: Aminoguanidine attenuates hypertension, whereas 7-nitroindazole exacerbates kidney damage in spontaneously hypertensive rats: the role of nitric oxide.
abstract: Nitric oxide (NO) deficiency contributes to hypertension and end-organ damage. Three nitric oxide synthase (NOS) isoforms have been identified: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). Whether selective nNOS or iNOS inhibition exacerbates kidney damage in spontaneously hypertensive rats (SHRs) remains unclear. Seven-week-old SHRs were randomly assigned to 4 groups (n=8 for each group): group 1, SHRs receiving no treatment; group 2 (SHR+7-NI), SHRs given 7-nitroindazole (7-NI, nNOS inhibitor) in their drinking water (10mg/kg/day); group 3 (SHR+salt), SHRs given 1% NaCl; and group 4 (SHR+AG), SHRs given 0.1% aminoguanidine (AG; iNOS inhibitor) in drinking water. The mean arterial pressure of SHRs treated with salt was significantly elevated compared with untreated controls. While AG caused a decrease of mean arterial pressure at 8 and 12 weeks of age in SHRs, both 7-NI and salt exacerbated kidney injury. In addition, AG significantly increased l-arginine levels and the l-arginine-to-asymmetric dimethylarginine (ADMA) ratio in the kidney. Salt treatment decreased renal nNOS-α protein levels and reduced dimethylarginine dimethylaminohydrolase (DDAH) activity. Salt and AG treatment increased nNOS-β and l-citrulline levels in SHR kidneys. AG attenuates hypertension development by upregulation of l-citrulline-to- l-arginine conversion and an increase in the l-arginine-to-ADMA ratio in SHR kidneys. 7-NI impairs renal function but has no effect on blood pressure, suggesting reno-protective role for the nNOS. Salt exacerbates kidney damage mainly through decreasing renal nNOS-α protein levels and DDAH activity. Our findings highlight the protective role of the nNOS/NO pathway in the development of kidney damage in SHRs.
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Huang
authors.forename: Chien-Ning
authors.initials: CN
authors.lastname: Hsu
authors.forename: Shao-Ju
authors.initials: SJ
authors.lastname: Chien
authors.forename: Ying-Jui
authors.initials: YJ
authors.lastname: Lin
authors.forename: Li-Tung
authors.initials: LT
authors.lastname: Huang
authors.forename: You-Lin
authors.initials: YL
authors.lastname: Tain
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002956:Citrulline / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy*; D007191:Indazoles / Q000494:pharmacology* / Q000633:toxicity; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017673:Sodium Chloride, Dietary / Q000633:toxicity; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D006146:Guanidines; D007191:Indazoles; D017673:Sodium Chloride, Dietary; D002956:Citrulline; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D052248:Nitric Oxide Synthase Type I; D000581:Amidohydrolases; C059999:dimethylargininase; C004479:pimagedine; C080122:7-nitroindazole