Chronic peripheral administration of the angiotensin II AT1 receptor antagonist Candesartan blocks brain AT1 receptors

Nishimura, Yasuaki; Ito, Takeshi; Hoe, Kwang Lae; Saavedra, Juan M.

doi:10.1016/s0006-8993(00)02377-5

Cited by 133 publications

(103 citation statements)

References 23 publications

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“…We confirmed that subcutaneous administration of the insurmountable and selective AT 1 receptor antagonist candesartan blocked brain AT 1 receptors, demonstrating that the compound crossed the blood-brain barrier and is an effective agent to antagonize the effects of brain Ang II (Nishimura et al, 2000;Seltzer et al, 2004). Pretreatment with the AT 1 antagonist, by preventing the hormonal response to isolation, prevented the glucocorticoid-induced increase in receptor transcription (Armando et al, 2001;Leong et al, 2002;present results) and the corresponding increase in expression of AT 1 receptors in the PVN (Armando et al, 2001).…”

Section: Discussionsupporting

confidence: 62%

“…We demonstrated that long-term treatment with candesartan, an insurmountable AT 1 antagonist that, when administered peripherally, readily inhibits not only peripheral but also central AT 1 receptors (Nishimura et al, 2000), abolished the HPA axis and sympathoadrenal response to isolation in rats (Armando et al, 2001). Isolation is a clinically relevant model of emotional stress resulting from the restriction from freely regulating exposure to novel surroundings and access to familiar territory.…”

Section: Introductionmentioning

confidence: 95%

“…Groups of animals received minipumps containing vehicle or candesartan (ASTRA, Mölndal, Sweden) dissolved in 1 mol/l sodium carbonate and further diluted in isotonic saline, at a final pH of 7.5-8.0, to be delivered at a rate of 0.5 mg/kg/day. The dose of 0.5 mg/kg/day was selected because it produced a very significant decrease in binding to brain AT 1 receptors (Nishimura et al, 2000) and was effective in blocking the sympathoadrenal and hormonal response to isolation stress (Armando et al, 2001). After minipump implantation, the rats were kept in their cages in groups of 3-4 for 13 days.…”

Section: Experiments 1 Determination Of Ang II Receptor Binding and Tmentioning

confidence: 99%

“…The binding to AT 2 receptors was not affected by the treatment (Table 1). The significant reduction in binding to AT 1 receptors in grouped, nonstressed animals very likely represents insurmountable binding of candesartan (Nishimura et al, 2000;Armando et al, 2001).…”

Section: Effect Of Isolation and At 1 Antagonism On Expression Of Angmentioning

confidence: 99%

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A Centrally Acting, Anxiolytic Angiotensin II AT1 Receptor Antagonist Prevents the Isolation Stress-Induced Decrease in Cortical CRF1 Receptor and Benzodiazepine Binding

Saavedra

Armando

Bregonzio

et al. 2005

Neuropsychopharmacol

102

100

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Long-term pretreatment with an angiotensin II AT 1 antagonist blocks angiotensin II effects in brain and peripheral organs and abolishes the sympathoadrenal and hypothalamic-pituitary-adrenal responses to isolation stress. We determined whether AT 1 receptors were also important for the stress response of higher regulatory centers. We studied angiotensin II and corticotropin-releasing factor (CRF) receptors and benzodiazepine binding sites in brains of Wistar Hannover rats. Animals were pretreated for 13 days with vehicle or a central and peripheral AT 1 antagonist (candesartan, 0.5 mg/kg/day) via osmotic minipumps followed by 24 h of isolation in metabolic cages, or kept grouped throughout the study (grouped controls). In another study, we determined the influence of a similar treatment with candesartan on performance in an elevated plus-maze. AT 1 receptor blockade prevented the isolation-induced increase in brain AT 1 receptors and decrease in AT 2 binding in the locus coeruleus. AT 1 receptor antagonism also prevented the increase in tyrosine hydroxylase mRNA in the locus coeruleus. Pretreatment with the AT 1 receptor antagonist completely prevented the decrease in cortical CRF 1 receptor and benzodiazepine binding produced by isolation stress. In addition, pretreatment with candesartan increased the time spent in and the number of entries to open arms of the elevated plus-maze, measure of decreased anxiety. Our results implicate a modulation of upstream neurotransmission processes regulating cortical CRF 1 receptors and the GABA A complex as molecular mechanisms responsible for the anti-anxiety effect of centrally acting AT 1 receptor antagonists. We propose that AT 1 receptor antagonists can be considered as compounds with possible therapeutic anti-stress and anti-anxiety properties.

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Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 95%

Section: Experiments 1 Determination Of Ang II Receptor Binding and Tmentioning

confidence: 99%

Section: Effect Of Isolation and At 1 Antagonism On Expression Of Angmentioning

confidence: 99%

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A Centrally Acting, Anxiolytic Angiotensin II AT1 Receptor Antagonist Prevents the Isolation Stress-Induced Decrease in Cortical CRF1 Receptor and Benzodiazepine Binding

Saavedra

Armando

Bregonzio

et al. 2005

Neuropsychopharmacol

102

100

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“…16 Chronic systemic treatment with candesartan also dose-dependently decreased AT 1 binding in brain areas localised outside, as well as inside, the bloodbrain barrier. 17 The effective and long-lasting blockade of brain AT 1 receptors displayed by candesartan may be attributed to the insurmountable antagonism, characterised by tight binding and slow dissociation from the receptor. This suggests that systemically administered candesartan may exhibit a long duration of action in the brain.…”

Section: Angiotensin Receptors and Signal Transduction Pathwaysmentioning

confidence: 99%

The renin-angiotensin system in the brain: possible therapeutic implications for AT1-receptor blockers

et al. 2002

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Angiotensin II AT₁ receptor antagonists inhibit the angiotensin‐CRF‐AVP axis and are potentially useful for the treatment of stress‐related and mood disorders

Saavedra

Pavel

2005

Drug Development Research

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The corticotropin-releasing factor (CRF), arginine-vasopressin (AVP), atrial natriuretic peptide (ANP), and Angiotensin II (Ang II) interact, regulating the central sympathetic system, the hypothalamic-pituitary-adrenal (HPA) axis, and the central behavioral mechanisms involved in the response to stress and the development of mood disorders. Non-peptidic, orally active AVP V 1 , V 3 , or CRF 1 receptor antagonists reduce anxiety in animals. ANP is anxiolytic when administered to rodents and humans with anxiety disorders. These compounds are being developed for the therapy of anxiety and depression, but their clinical efficacy has not yet been established.Brain Ang II, a physiological ANP antagonist, promotes CRF and AVP release and stimulates the peripheral and central sympathetic systems. The degree of Ang II AT 1 receptor stimulation determines the response to stress. An orally active, non-peptidic Ang II AT 1 receptor antagonist blocks CRF and AVP release during stress, prevents the sympathoadrenal and hormonal stress reaction, the cortical CRF 1 and benzodiazepine receptor alterations, facilitates the effects of ANP, prevents stress-induced gastric ulcerations, and is anxiolytic in rodents. CRF, AVP, ANP, and the sympathetic system are intimately linked parts of a fundamental regulatory mechanism controlled by the brain Ang II system through AT 1 receptor stimulation, and should be studied together. Selective, safe antagonists of Ang II AT 1 receptors, with central effects after oral administration, have been actively used for the treatment of hypertension and should be considered also as potential anti-stress, anti-anxiety, and antidepressant compounds with properties similar or superior to the CRF and AVP antagonists or the ANP agonists under development. Drug Dev. Res. 65:237-269, 2005.

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Chronic peripheral administration of the angiotensin II AT1 receptor antagonist Candesartan blocks brain AT1 receptors

Cited by 133 publications

References 23 publications

A Centrally Acting, Anxiolytic Angiotensin II AT1 Receptor Antagonist Prevents the Isolation Stress-Induced Decrease in Cortical CRF1 Receptor and Benzodiazepine Binding

A Centrally Acting, Anxiolytic Angiotensin II AT1 Receptor Antagonist Prevents the Isolation Stress-Induced Decrease in Cortical CRF1 Receptor and Benzodiazepine Binding

The renin-angiotensin system in the brain: possible therapeutic implications for AT1-receptor blockers

Angiotensin II AT₁ receptor antagonists inhibit the angiotensin‐CRF‐AVP axis and are potentially useful for the treatment of stress‐related and mood disorders

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Chronic peripheral administration of the angiotensin II AT1 receptor antagonist Candesartan blocks brain AT1 receptors

Cited by 133 publications

References 23 publications

A Centrally Acting, Anxiolytic Angiotensin II AT1 Receptor Antagonist Prevents the Isolation Stress-Induced Decrease in Cortical CRF1 Receptor and Benzodiazepine Binding

A Centrally Acting, Anxiolytic Angiotensin II AT1 Receptor Antagonist Prevents the Isolation Stress-Induced Decrease in Cortical CRF1 Receptor and Benzodiazepine Binding

The renin-angiotensin system in the brain: possible therapeutic implications for AT1-receptor blockers

Angiotensin II AT1 receptor antagonists inhibit the angiotensin‐CRF‐AVP axis and are potentially useful for the treatment of stress‐related and mood disorders

Contact Info

Product

Resources

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Angiotensin II AT₁ receptor antagonists inhibit the angiotensin‐CRF‐AVP axis and are potentially useful for the treatment of stress‐related and mood disorders