Angiotensin II type 1 receptor-mediated inhibition of cytokine-stimulated inducible nitric oxide synthase expression in vascular smooth muscle cells.
In vascular smooth muscle cells (VSMC), inflammatory cytokines such as interleukin 1 (IL1) and tumour necrosis factor alpha (TNF alpha) stimulate nitric oxide (NO) production via the expression of an inducible type of NO synthase (iNOS). This study was performed to determine whether angiotensin II (AII) affected NO production in cultured VSMC. AII by itself did not stimulate the production of nitrite, a stable metabolite of NO, but dose-dependently inhibited IL1 beta-induced nitrite production. This inhibitory effect of AII was blocked by the AII type 1 (AT1) receptor antagonist, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylic acid (CV-11974), but not by the AII type 2 (AT2) receptor antagonist, (S)-1-[[4-(di-methylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl++ +- 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (PD-123319). In parallel with the decrease in nitrite production, AII suppressed IL1 beta-induced increases in iNOS mRNA and protein levels, as measured by Northern blotting using an iNOS cDNA probe and by immunoblotting using an anti-iNOS antibody, respectively. AII also inhibited the increases in nitrite production and iNOS mRNA and protein levels caused by TNF alpha. These results indicate that AII inhibits cytokine-induced NO production in VSMC by blocking iNOS expression through the AT1 receptor; this suggests that the AT1 receptor antagonist may modulate the development of atherosclerotic and postangioplastic lesions by blocking this inhibitory effect of AII.
Nakayama
I
I
Department of Internal Medicine (First Division), Kobe University School of Medicine, Japan.
Kawahara
Y
Y
Okuda
M
M
Yokoyama
M
M
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis* / Q000187:drug effects*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004347:Drug Interactions; D004790:Enzyme Induction; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D011945:Receptors, Angiotensin / Q000187:drug effects* / Q000502:physiology*; D013268:Stimulation, Chemical; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology*
D007375:Interleukin-1; D009573:Nitrites; D011945:Receptors, Angiotensin; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases