title: Angiotensin II AT1 blockade reduces the lipopolysaccharide-induced innate immune response in rat spleen.
abstract: ANG II AT(1) receptor blockade reduces inflammation in hypertension. To determine whether ANG II AT(1) receptor blockers (ARBs) influence the innate immune inflammatory response in normotensive rats, we studied rat plasma and spleen after a 3-day subcutaneous pretreatment with the ARB candesartan followed by a single dose of the bacterial endotoxin LPS (50 microg/kg ip). Peripheral administration of LPS to rodents produced a generalized inflammatory response with increased release of TNF-alpha, IL-1beta, and IL-6 into the circulation. Candesartan pretreatment reduced the LPS-induced release of TNF-alpha, IL-1beta, and IL-6 into the circulation. The red pulp of rat spleen expressed large numbers of AT(1) receptors and the LPS receptors Toll-like receptor 4 and CD14. Candesartan administration significantly blocked AT(1) receptors. The ARB reduced the LPS-induced upregulation of CD14 gene expression; expression of TNF-alpha and IL-6 mRNA and protein; expression of IL-1beta and IkappaB-alpha mRNA; COX-2 mRNA and protein expression and PGE(2) concentration; inducible nitric oxide synthase (iNOS) gene and protein expression and iNOS activity; and Nox2 gene expression and 8-isoprostane levels. In addition, candesartan reduced the CD14 protein expression in saline- and LPS-treated rats. Our results suggest that AT(1) receptors are essential for the development of the full innate immune response to bacterial endotoxin. The ARB decreased the general peripheral inflammatory reaction to LPS and partially decreased the inflammatory response in the spleen. An unrestricted innate immune response to the bacterial endotoxin may have deleterious effects for the organism and may lead to development of chronic inflammatory disease. We postulate that ARBs may have therapeutic effects on inflammatory conditions.
authors.affiliation: Section on Pharmacology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA. sancheze@mail.nih.gov
authors.forename: Enrique
authors.initials: E
authors.lastname: Sánchez-Lemus
authors.forename: Julius
authors.initials: J
authors.lastname: Benicky
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Pavel
authors.forename: Ignacio M
authors.initials: IM
authors.lastname: Larrayoz
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.forename: Martina
authors.initials: M
authors.lastname: Baliova
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nishioku
authors.forename: Juan M
authors.initials: JM
authors.lastname: Saavedra
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D015232:Dinoprostone / Q000097:blood; D004195:Disease Models, Animal; D007113:Immunity, Innate / Q000187:drug effects* / Q000502:physiology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects; D013154:Spleen / Q000187:drug effects* / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D015232:Dinoprostone; C081643:candesartan