Sustaining excessive nitric oxide upregulates protein expression of nitric oxide synthase via soluble guanylyl cyclase: an in vivo study in rats.
The aim of this study was to elucidate whether upregulation of the endothelial NO synthase (eNOS)/nitric oxide (NO) pathway is associated with downregulation of the NO/soluble guanylyl cyclase (sGC) pathway. To produce acutely or chronically excessive NO, lipopolysaccharide (LPS) was administered intraperitoneally to rats in a single dose of 4 mg/kg (LPS-single group) or in stepwise doses of 0.5, 1.0, and 2.0 mg/kg every other day (LPS-repeated group). At 24 hours after the treatment, in the thoracic aorta from the LPS-single group, both relaxations in response to sodium nitroprus-side (SNP), an NO donor, and acetylcholine (ACh) and protein levels of sGC and eNOS remained unchanged. In contrast, in the LPS-repeated group, the SNP-induced relaxation and sGC protein expression significantly decreased, while the ACh-induced relaxation and eNOS protein expression significantly increased compared with the non-treated control. All these changes in the relaxations and protein levels were restored by treatment with NOX-100, an NO scavenger. Furthermore, similar alteration in vascular function observed in the LPS-repeated group occurred in rats receiving SNP via subcutaneous using osmotic pumps (0.4 mg/h). These results indicate that persistent excessive NO exposure induces upregulation of the eNOS/NO pathway in the endothelium together with downregulation of the NO/sGC pathway.
Kagota
Satomi
S
Department of Pharmacology, School of Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Japan. skagota@mwu.mukogawa-u.ac.jp
Yamaguchi
Yu
Y
Nakamura
Kazuki
K
Shinozuka
Kazumasa
K
Kunitomo
Masaru
M
D000818:Animals; D015153:Blotting, Western; D006162:Guanylate Cyclase / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D009569:Nitric Oxide / Q000097:blood / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects
D008070:Lipopolysaccharides; D009599:Nitroprusside; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase