Oral administration of an AT1 receptor antagonist prevents the central effects of angiotensin II in spontaneously hypertensive rats.
Peripheral and brain angiotensin II AT(1) receptor blockade decreases high blood pressure, stress, and neuronal injury. To clarify the effects of long-term brain Ang II receptor blockade, the AT(1) blocker, candesartan, was orally administered to spontaneously hypertensive rats (SHRs) for 40 days, followed by intraventricular injection of 25 ng of Ang II. Before Ang II injection, AT(1) receptor blockade normalized blood pressure and decreased plasma adrenocorticotropic hormone (ACTH) and corticosterone. After central administration of excess Ang II, the reduction of ACTH and corticosterone release induced by AT(1) receptor blockade no longer occurred. Central Ang II administration to vehicle-treated SHRs further increased blood pressure, provoked drinking, increased tyrosine hydroxylase (TH) mRNA expression in the locus coeruleus, and stimulated sympathoadrenal catecholamine release. Pretreatment with the AT(1) receptor antagonist eliminated Ang II-induced increases in blood pressure, water intake, and sympathoadrenal catecholamine release; inhibited peripheral and brain AT(1) receptors; increased AT(2) receptor binding in the locus coeruleus, inferior olive, and adrenal cortex; and decreased AT(2) receptor binding in the adrenal medulla. Inhibition of brain AT(1) receptors correlated with decreased TH transcription in the locus coeruleus, indicating a decreased central sympathetic drive. This, and the diminished adrenomedullary AT(1) and AT(2) receptor stimulation, result in decreased sympathoadrenomedullary stimulation. Oral administration of AT(1) antagonists can effectively block central actions of Ang II, regulating blood pressure and reaction to stress, and selectively and differentially modulating sympathoadrenal response and the hypothalamic-pituitary-adrenal stimulation produced by brain Ang II--effects of potential therapeutic importance.
Seltzer
Alicia
A
Section on Pharmacology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bldg 10, Rm 2D57, 10 Center Dr, MSC-1514, Bethesda, MD 20892, USA.
Bregonzio
Claudia
C
Armando
Inés
I
Baiardi
Gustavo
G
Saavedra
Juan M
JM
D000284:Administration, Oral; D000311:Adrenal Glands / Q000187:drug effects; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000704:Analysis of Variance; D000804:Angiotensin II / Q000008:administration & dosage*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects*; D002396:Catechols / Q000097:blood; D003345:Corticosterone / Q000097:blood; D004334:Drug Administration Schedule; D004347:Drug Interactions; D007276:Injections, Intraventricular; D008125:Locus Coeruleus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000502:physiology; D013777:Tetrazoles / Q000008:administration & dosage*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002396:Catechols; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; D000324:Adrenocorticotropic Hormone; D014446:Tyrosine 3-Monooxygenase; C081643:candesartan; D003345:Corticosterone