Endothelin-1 inhibits induction of nitric oxide synthase and GTP cyclohydrolase I in rat mesangial cells.
To investigate the interaction between endothelin (ET) and the nitric oxide system, we examined the effects of ET-1 and ET-3 on the induction of inducible nitric oxide synthase (iNOS) and guanosine triphosphate cyclohydrolase I (GTP:CHI), the rate-limiting enzyme of de novo synthesis of the cofactor tetrahydrobiopterin (BH4), in rat mesangial cells. ET-1 inhibited the nitrite accumulation induced by a combination of interleukin-1 beta, tumor necrosis factor-alpha, and lipopolysaccharide in a concentration-dependent manner. The inhibitory effect of ET-3 was less potent than that of ET-1. A selective ETA antagonist, BQ-485, and an ETA and ETB antagonist, TAK-044, abolished the inhibitory effects of ET-1, whereas the selective ETB antagonist BQ-788 had no effect on the inhibition produced by ET-1. These observations indicate that ET-1 inhibits cytokine-stimulated nitrite accumulation through the ETA receptor. Western blot analysis showed that the suppression of nitrite accumulation was accompanied by a decrease in iNOS protein. Northern blot analysis showed that ET-1 inhibited the expression of both iNOS and GTP:CHI mRNA. In conclusion, ET-1 inhibits cytokine-stimulated nitric oxide production through the ETA receptor by suppressing the expression of iNOS and GTP:CHI mRNA in rat mesangial cells.
Hirahashi
J
J
Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Nakaki
T
T
Hishikawa
K
K
Marumo
T
T
Yasumori
T
T
Hayashi
M
M
Suzuki
H
H
Saruta
T
T
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D006136:GTP Cyclohydrolase / Q000096:biosynthesis*; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D009573:Nitrites / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
D000975:Antioxidants; D001381:Azepines; D016207:Cytokines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009573:Nitrites; D009842:Oligopeptides; D012333:RNA, Messenger; C083116:BQ 485; D001708:Biopterins; D019001:Nitric Oxide Synthase; D006136:GTP Cyclohydrolase; C003402:sapropterin