Andrea Carranza

Peripheral Administration of an Angiotensin II AT1 Receptor Antagonist Decreases the Hypothalamic-Pituitary-Adrenal Response to Isolation Stress

Angiotensin II, which stimulates AT(1) receptors, is a brain and peripheral stress hormone. We pretreated rats with the AT(1) receptor antagonist candesartan for 13 d via sc-implanted osmotic minipumps, followed by 24-h isolation in individual metabolic cages. We measured angiotensin II receptor-type binding and mRNAs and tyrosine hydroxylase mRNA by quantitative autoradiography and in situ hybridization, catecholamines by HPLC, and hormones by RIA. Isolation increased AT(1) receptor binding in hypothalamic paraventricular nucleus as well as anterior pituitary ACTH, and decreased posterior pituitary AVP. Isolation stress also increased AT(1) receptor binding and AT(1B) mRNA in zona glomerulosa and AT(2) binding in adrenal medulla, adrenal catecholamines, tyrosine hydroxylase mRNA, aldosterone, and corticosterone. Candesartan blocked AT(1) binding in paraventricular nucleus and adrenal gland; prevented the isolation-induced alterations in pituitary ACTH and AVP and in adrenal corticosterone, aldosterone, and catecholamines; abolished the increase in AT(2) binding in adrenal medulla; and substantially decreased urinary AVP, corticosterone, aldosterone, and catecholamines during isolation. Peripheral pretreatment with an AT(1) receptor antagonist blocks brain and peripheral AT(1) receptors and inhibits the hypothalamic-pituitary-adrenal response to stress, suggesting a physiological role for peripheral and brain AT(1) receptors during stress and a possible beneficial effect of AT(1) antagonism in stress-related disorders.

Decreased Tubular Uptake of L-3,4-Dihydroxyphenylalanine in Streptozotocin-Induced Diabetic Rats

Background/Aims: This study determined alterations in renal dopamine production in streptozotocin-treated rats and explored the mechanisms underlying this alteration. Methods: Streptozotocin (65 mg/kg) or vehicle was administered to 3-month-old male Wistar rats. Treated animals had hyperglycemia, glycosuria and increased diuresis, natriuresis and excretion of L-dopa. Urinary dopamine and dihydroxyphenylacetic acid were similar to those in control animals. The production of dopamine by renal cortex slices from treated rats was significantly less than that from control animals. The addition of glucose (8.4–18.4 mM) to the incubation medium decreased about 40% the uptake of L-dopa by isolated proximal tubular cells. Scatchard analysis of the saturation curves obtained in this condition showed a decrease in the Vmax without changes in the Km. Results: Our results confirm previous studies suggesting a renal dopaminergic deficiency in insulin-dependent diabetes and provide evidence strongly suggesting that a decrease in the number of tubular L-dopa transport sites is the underlying defect of this deficiency. Conclusion: These results highlight the role of the uptake of dopa as an important modulator of renal dopamine synthesis.

The Role of Angiotensin II AT1 Receptors in the Sympathoadrenal Response to Stress

Angiotensin II (Ang II) is a hormone and brain neuropeptide implicated in the response of the hypothalamic-pituitary-adrenal axis to stress (Saavedra, 1992). Stress increases circulating Ang II (Xang et al., 1993) and the expression of Ang II receptors in brain areas such as the hypothalamic paraventricular nucleus (PVN) is crucial for central control of the stress reaction (Castren and Saavedra, 1988). Ang II stimulates CRH formation in the PVN during stress (Sumitomo et al., 1991; Aguilera et al., 1995) and this results in increased ACTH and adrenal corticoid release. Ang II has direct effects on adrenal function, stimulating aldosterone secretion from the zona glomerulosa and catecholamine release from the medulla (Aguilera, 1993; Livett et al., 1990). Ang II stimulates vasopressin (AVP) formation and release in the PVN (Saavedra, 1992). Released from the median eminence, AVP participates with CRH and enhances ACTH production (Antoni, 1993).

Candesartan decreases the sympatho-adrenal and hormonal response to isolation stress:

A change from group housing to isolation in unfamiliar metabolic cages represents, for rodents, a significant emotional stress. We studied the effect of candesartan, a peripheral and central angiotensin II AT1-receptor antagonist, on the hormonal and sympathetic response to acute isolation. We pretreated rats with 1 mg/kg/day candesartan for 13 days via subcutaneously implanted osmotic minipumps, followed by 24-hour isolation in individual metabolic cages. We measured brain, pituitary and adrenal angiotensin II (Ang II) receptor binding by quantitative autoradiography and adrenal hormones and catecholamines by RIA and HPLC. Isolation increased adrenal catecholamines, aldosterone and corticosterone, AT1-receptor binding in the zona glomerulosa and AT2-receptor binding in the adrenal medulla. Candesartan pretreatment decreased adrenal catecholamines, aldosterone and corticosterone, AT1-receptor binding in adrenal zona glomerulosa and medulla, pituitary gland and the hypothalamic paraventricular nucleus, and AT2-receptor binding in adrenal medulla, but increased AT2-receptor binding in zona glomerulosa. We conclude that peripheral and central AT1-receptor blockade with candesartan decreases the sympatho-adrenal and hormonal response to acute stress. Our results indicate that Ang II is an important stress hormone and suggest that blockade of the physiologically active AT 1-receptors could influence stress-related disorders.

Contents Vol. 55, 2001

W.F. Blum, Bad Homburg J.-P. Bourguignon, Liège H.G. Burger, Melbourne P.G. Chatelain, Lyon G. Chiumello, Milan P.E. Clayton, Manchester G. Copinschi, Brussels H.J. Degenhart, Rotterdam M.G. Forest, Lyon J. Girard, Basel P.D. Gluckman, Auckland A. Grüters, Berlin Z. Hochberg, Haifa R.P. Kelch, Iowa City, Iowa P.J. Keller, Zurich S.W.J. Lamberts, Rotterdam F. Leidenberger, Hamburg C.J. Migeon, Baltimore, Md. E. Milgrom, Bicêtre J. Müller, Copenhagen (Book Reviews) O.H. Pescovitz, Indianapolis, Ind. D.A. Price, Manchester R.G. Rosenfeld, Portland, Ohio G. Saggese, Pisa M.O. Savage, London S.M. Shalet, Manchester T. Tanaka, Tokyo G. Van Vliet, Montreal R.J. Voutilainen, Kuopio G.A. Werther, Parkville, Australia J.-M. Wit, Leiden M. Zachmann, Zurich