Chronic peripheral administration of the angiotensin II AT(1) receptor antagonist candesartan blocks brain AT(1) receptors.
Brain Angiotensin II, through stimulation of brain AT(1) receptors, regulates pituitary hormones and autonomic activity. We have administered the insurmountable AT(1) antagonist Candesartan, s.c. via osmotic minipumps for 14 days, to determine whether peripheral chronic AT(1) blockade affects AT(1) receptor binding and mRNA in the brain. Peripherally administered Candesartan (0.1, 0.5 or 1.0 mg/kg per day) inhibits AT(1) binding in adrenal gland zona glomerulosa and kidney glomeruli. In addition, Candesartan dose-dependently decreases AT(1) binding in brain areas outside (subfornical organ and area postrema) and inside (paraventricular nucleus of the hypothalamus and nucleus of the solitary tract) the blood-brain barrier. Conversely, peripheral treatment with Candesartan does not affect AT(1A) receptor mRNA, the predominant receptor subtype expressed in these areas, or Angiotensin II binding to AT(2) receptors in the locus coeruleus or inferior olive. Our results demonstrate that chronic peripheral treatment with selective, potent AT(1) antagonists not only inhibits peripheral but also brain AT(1) receptors. These central effects may play a role in the antihypertensive effects of the AT(1) antagonist Candesartan.
Nishimura
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Section on Pharmacology, IRP, NIMH, 10 Center Drive, Bldg. 10, Room 2D-57, 20892, Bethesda, MD, USA.
Ito
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Hoe
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Saavedra
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D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001345:Autoradiography; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007263:Infusions, Parenteral; D007678:Kidney Glomerulus / Q000187:drug effects / Q000502:physiology; D008297:Male; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics / Q000502:physiology*; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D015384:Zona Glomerulosa / Q000187:drug effects / Q000502:physiology
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C081643:candesartan