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Keywords:

  • renin-angiotensin system;
  • angiotensin II receptor types;
  • AT1 receptors;
  • paraventricular nucleus;
  • restraint stress;
  • isolation stress;
  • stress disorders

Abstract: The presence of a brain Angiotensin II (Ang II) system, separated from and physiologically integrated with the peripheral, circulating renin-angiotensin system, is firmly established. Ang II is made in the brain and activates specific brain AT1 receptors to regulate thirst and fluid metabolism. Some AT1 receptors are located outside the blood-brain barrier and are sensitive to brain and circulating Ang II. Other AT1 receptors, located inside the blood-brain barrier, respond to stimulation by Ang II of brain origin. AT1 receptors in the subfornical organ, the hypothalamic paraventricular nucleus (PVN), and the median eminence are involved in the regulation of the stress response. In particular, AT1 receptors in the PVN are under glucocorticoid control and regulate corticotrophin-releasing hormone (CRH) formation and release. In the PVN, restraint elicits a fast increase in AT1 receptor mRNA expression. The expression of paraventricular AT1 receptors is increased during repeated restraint and after 24 h of isolation stress, and their stimulation is essential for the hypothalamic-pituitary-adrenal axis activation, the hallmark of the stress response. Peripheral administration of an AT1 receptor antagonist blocks peripheral and brain AT1 receptors, prevents the sympathoadrenal and hormonal response to isolation stress, and prevents the gastric stress ulcers that are a characteristic consequence of cold-restraint stress. This evidence indicates that pharmacologic inhibition of the peripheral and brain Ang II system by AT1 receptor blockade has a place in the prevention and treatment of stress-related disorders.