| Research Focus De ´ ja ` vu: angiotensin and stress Ferenc A. Antoni and Christopher J. Kenyon Division of Neuroscience and Molecular Endocrinology Unit, University of Edinburgh, Edinburgh, UK In the 21st century we wish to believe that the inter- action of our genetic background with the stress of life underlies most of our health problems, especially those associated with cardiovascular disease. Doubtless, there are many interrelated connections. A recent study provides evidence of a direct link between the neuro- endocrine stress response and the renin – angiotensin – aldosterone system, the major blood-pressure control system of the body. Angiotensin is a hormone with a mission in mammals: its numerous actions in multiple organ systems are geared to retaining sufficient water and salt in the body to keep the systemic circulation of blood going. It works in concert with the hypothalamic neuropeptide vasopres- sin (antidiuretic hormone) and aldosterone, the major mineralocorticoid synthesized by the zona glomerulosa of the adrenal cortex. The regulation of these hormones is connected to the CNS through the neuroendocrine and autonomic nervous systems, and as such is responsible for one of the major woes of Western post- industrial society – hypertension. Recently published studies [1] have compared the levels of angiotensin (AT) receptor mRNAs (Box 1) in various organs of Wistar Kyoto rats (WKY) with those in spontaneously hypertensive rats (SHR). The main findings were higher levels of AT 1A receptor mRNA in the pituitary and adrenal glands of SHR. In parallel, the plasma adrenocorticotrophic hormone (ACTH) and corticosterone responses to intra-arterial angiotensin II (AII; Box 2) were enhanced in the SHR, whereas the plasma levels of aldosterone were identical in the WKY and SHR animals. Because AT 1A receptor mRNA is normally barely detectable in the pituitary gland, its appearance, accompanied by a reduction in AT 1B receptor mRNA levels, is all the more remarkable. The implication of the data is that enhanced expression of AT 1A receptors augments the stress response in SHR. Various methodological issues notwithstanding, these observations have several previous correlates and as such are a useful piece of the jigsaw puzzle that needs to be assembled for understanding the connection between behavioural traits, neuroendocrine control mechanisms and genetically determined hypertension. A fundamental question for the interpretation of such data is what constitutes a good control group for SHRs? Typically, WKY are used, but studies of the hypothalmus– pituitary–adrenal (HPA) axis of inbred rat strains [2–4] show that WKYanimals fall into the ‘stress hyporesponsive’ category and by comparison SHR show a tendency for an exaggerated HPA response. However, the response is not highly exaggerated and it is not consistent at all levels of the axis [2–4]. Indeed it is important to look carefully at the experimental variables used, the way the animals are brought to the experimenters’ laboratory, as well as the conditions of rearing. Data in the literature show that perinatal events could determine a lifetime ‘programme’ of developing hypertension [5,6] and abnormal pituitary–adrenal responsiveness [7]. By using immobilization and electric shocks to the tail as the stressor, it was concluded that the differences in HPA function in five inbred rat strains (including WKY as well as SHR) were largely manifested by the adrenal cortex [3,4]. Although in vitro studies of adrenocortical cells agree with this [8], monitoring of early-immediate genes as well as other stress-induced genes has indicated that responses in the hypothalamic paraven- tricular nuclei of SHR are greater than in WKY [9]. Moreover, behavioural analyses have claimed that WKY have traits indicative of mild depression, whereas SHR are ‘hyper’ – possibly a rat model of Box 1. Angiotensin receptors Four angiotensin (AT) receptor genes have been isolated in rodents, AT 1A , AT 1B , AT 2 and AT 4 . Although coded for by distinct genes, AT 1A and AT 1B are similar in function and, depending on the target tissue, jointly mediate many effects, including stimulation of aldosterone synthesis by the adrenal gland, thirst mechanisms in the brain, maintenance of vascular tone and regulation of renal function. AT 2 receptors are distributed widely in the fetus but have a narrower distribution by adulthood (e.g. forebrain and adrenal medulla) and function broadly in opposition to AT 1 receptors. AT 1A receptors are highly expressed at vascular, renal and adreno- cortical sites, whereas AT 1B receptors feature predominantly in the pituitary and adrenal glands. Despite a common mechanism of action, an almost identical amino acid sequence and overlapping patterns of expression, AT 1A and AT 1B receptors do have subtly different properties. This is exemplified by the phenotypes of AT 1A and AT 1B null mice. In vivo and in vitro studies have shown that the synthetic glucocorticoid hormone dexamethasone reduces angiotensin receptor protein levels, an effect that in vitro studies suggest is because of a selective decrease in AT 1B expression. This negative effect of dexametha- sone contrasts markedly with effects on tissues that predomi- nantly express the AT 1A subtype. In cardiac and smooth muscle cells, AT 1A , but not AT 1B mRNA is increased by dexamethasone. The molecular basis for this differential response appears to depend on the activity of putative glucocorticoid response elements within the promoter of each gene. For more details of AT receptors, see Refs [17,18]. Corresponding author: F.A. Antoni (ferenc.antoni@ed.ac.uk). Update TRENDS in Endocrinology and Metabolism Vol.14 No.6 August 2003 249 http://tem.trends.com