In vivo Angiotensin II AT1 receptor blockade selectively inhibits LPS-induced innate immune response and ACTH release in rat pituitary gland.
Systemic lipopolysaccharide (LPS) administration induces an innate immune response and stimulates the hypothalamic-pituitary-adrenal axis. We studied Angiotensin II AT(1) receptor participation in the LPS effects with focus on the pituitary gland. LPS (50 microg/kg, i.p.) enhanced, 3h after administration, gene expression of pituitary CD14 and that of Angiotensin II AT(1A) receptors in pituitary and hypothalamic paraventricular nucleus (PVN); stimulated ACTH and corticosterone release; decreased pituitary CRF(1) receptor mRNA and increased all plasma and pituitary pro-inflammatory factors studied. The AT(1) receptor blocker (ARB) candesartan (1mg/kg/day, s.c. daily for 3 days before LPS) blocked pituitary and PVN AT(1) receptors, inhibited LPS-induced ACTH but not corticosterone secretion and decreased LPS-induced release of TNF-alpha, IL-1beta and IL-6 to the circulation. The ARB reduced LPS-induced pituitary gene expression of IL-6, LIF, iNOS, COX-2 and IkappaB-alpha; and prevented LPS-induced increase of nNOS/eNOS activity. The ARB did not affect LPS-induced TNF-alpha and IL-1beta gene expression, IL-6 or IL-1beta protein content or LPS-induced decrease of CRF(1) receptors. When administered alone, the ARB increased basal plasma corticosterone levels and basal PGE(2) mRNA in pituitary. Our results demonstrate that the pituitary gland is a target for systemically administered LPS. AT(1) receptor activity is necessary for the complete pituitary response to LPS and is limited to specific pro-inflammatory pathways. There is a complementary and complex influence of the PVN and circulating cytokines on the initial pituitary response to LPS. Our findings support the proposal that ARBs may be considered for the treatment of inflammatory conditions.
Sánchez-Lemus
Enrique
E
Section on Pharmacology, Division of Intramural Research Programs, Department of Health and Human Services, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. sancheze@mail.nih.gov
Benicky
Julius
J
Pavel
Jaroslav
J
Saavedra
Juan M
JM
D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism*; D000704:Analysis of Variance; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D016207:Cytokines / Q000097:blood* / Q000235:genetics; D015232:Dinoprostone / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D017403:In Situ Hybridization; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000633:toxicity; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000502:physiology; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000324:Adrenocorticotropic Hormone; D015232:Dinoprostone; C081643:candesartan; D003345:Corticosterone