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, regulat es pituitary hormones and autonomic activity. We have administered the insu rmountable 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 Candesart an (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-depend ently 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, periph eral treatment with Candesattan does not affect AT(1A) receptor mRNA, the p redominant receptor subtype expressed in these areas, or Angiotensin II bin ding to AT(1) receptors in the locus coeruleus or inferior olive,Our result s 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 th e AT(1) antagonist Candesartan. (C) 2000 Elsevier Science B.V. All rights r eserved.