dra. Anti-inflammatory effects of angiotensin II AT 1 receptor antagonism prevent stress-induced gastric injury. Am J Physiol Gastrointest Liver Physiol 285: G414-G423, 2003. First published April 9, 2003 10.1152/ajpgi.00058.2003.-Stress reduces gastric blood flow and produces acute gastric mucosal lesions. We studied the role of angiotensin II in gastric blood flow and gastric ulceration during stress. Spontaneously hypertensive rats were pretreated for 14 days with the AT 1 receptor antagonist candesartan before cold-restraint stress. AT 1 receptors were localized in the endothelium of arteries in the gastric mucosa and in all gastric layers. AT 1 blockade increased gastric blood flow by 40-50%, prevented gastric ulcer formation by 70-80% after coldrestraint stress, reduced the increase in adrenomedullary epinephrine and tyrosine hydroxylase mRNA without preventing the stress-induced increase in adrenal corticosterone, decreased the stress-induced expression of TNF-␣ and that of the adhesion protein ICAM-1 in arterial endothelium, decreased the neutrophil infiltration in the gastric mucosa, and decreased the gastric content of PGE 2. AT1 receptor blockers prevent stress-induced ulcerations by a combination of gastric blood flow protection, decreased sympathoadrenal activation, and anti-inflammatory effects (with reduction in TNF-␣ and ICAM-1 expression leading to reduced neutrophil infiltration) while maintaining the protective glucocorticoid effects and PGE 2 release. Angiotensin II has a crucial role, through stimulation of AT 1 receptors, in the production and progression of stress-induced gastric injury, and AT 1 receptor antagonists could be of therapeutic benefit. gastric blood flow; prostaglandins; tumor necrosis factor STRESS INDUCES ACUTE GASTRIC mucosal lesions (33) by complex psychological factors influencing individual vulnerability, stimulation of specific brain pathways regulating autonomic function, decreased blood flow to the mucosa, increase in muscular contractility, mast cell degranulation, leukocyte activation, and increased free radical generation resulting in increased lipid peroxidation (2, 33, 49, 55).Cold-restraint stress is a commonly used and clinically relevant experimental model for acute gastric damage (44). A sudden blood flow reduction to the gastric mucosa and increased free radical formation play fundamental roles in ulcer production (49). Maintenance of gastric blood flow is important to protect the mucosa from endogenous and exogenous damage factors.Angiotensin II (ANG II) is a stress hormone (40), the levels of which dramatically increase in plasma and tissues, including stomach, during stress (10, 54). ANG II not only regulates vascular tone in resistance arteries (16) and in the brain (31) but also constricts the gastric vasculature through AT 1 receptor stimulation (19). In addition, ANG II generates reactive oxygen species with cellular damage and inflammation (36). The mucosal vasoconstriction and proinflammatory effects of ANG II could contribute to the production of...

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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 AT(1) receptors to regulate thirst and fluid metabolism. Some AT(1) receptors are located outside the blood-brain barrier and are sensitive to brain and circulating Ang II. Other AT(1) receptors, located inside the blood-brain barrier, respond to stimulation by Ang II of brain origin. AT(1) 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, AT(1) 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 AT(1) receptor mRNA expression. The expression of paraventricular AT(1) 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 AT(1) receptor antagonist blocks peripheral and brain AT(1) 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 AT(1) receptor blockade has a place in the prevention and treatment of stress-related disorders.

Amphetamine‐induced neuroadaptations involve vascular damage, neuroinflammation, a hypo‐functioning prefrontal cortex (PFC), and cognitive alterations. Brain angiotensin II, through angiotensin type 1 receptor (AT1‐R), mediates oxidative/inflammatory responses, promoting endothelial dysfunction, neuronal oxidative damage and glial reactivity. The present work aims to unmask the role of AT1‐R in the development of amphetamine‐induced changes over glial and vascular components within PFC and hippocampus. Attention deficit was evaluated as a behavioral neuroadaptation induced by amphetamine. Brain microvessels were isolated to further evaluate vascular alterations after amphetamine exposure. Male Wistar rats were administered with AT1‐R antagonist, candesartan, followed by repeated amphetamine. After one week drug‐off period, animals received a saline or amphetamine challenge and were evaluated in behavioral tests. Afterward, their brains were processed for cresyl violet staining, CD11b (microglia marker), GFAP (astrocyte marker) or von Willebrand factor (vascular marker) immunohistochemistry, and oxidative/cellular stress determinations in brain microvessels. Statistical analysis was performed by using factorial ANOVA followed by Bonferroni or Tukey tests. Repeated amphetamine administration increased astroglial and microglial markers immunoreactivity, increased apoptotic cells, and promoted vascular network rearrangement at the PFC concomitantly with an attention deficit. Although the amphetamine challenge improved the attentional performance, it triggers detrimental effects probably because of the exacerbated malondialdehyde levels and increased heat shock protein 70 expression in microvessels. All observed amphetamine‐induced alterations were prevented by the AT1‐R blockade. Our results support the AT1‐R involvement in the development of oxidative/inflammatory conditions triggered by amphetamine exposure, affecting cortical areas and increasing vascular susceptibility to future challenges.

The use of psychostimulants, such as amphetamine (Amph), is associated with inflammatory processes, involving glia and vasculature alterations. Brain Angiotensin II (Ang II), through AT -receptors (AT -R), modulates neurotransmission and plays a crucial role in inflammatory responses in brain vasculature and glia. Our aim for the present work was to evaluate the role of AT -R in long-term alterations induced by repeated exposure to Amph. Astrocyte reactivity, neuronal survival and brain microvascular network were analysed at the somatosensory cortex. Thermal nociception was evaluated as a physiological outcome of this brain area. Male Wistar rats (250-320 g) were administered with AT -R antagonist Candesartan/vehicle (3 mg/kg p.o., days 1-5) and Amph/saline (2.5 mg/kg i.p., days 6-10). The four experimental groups were: Veh-Sal, CV-Sal, Veh-Amph, CV-Amph. On day 17, the animals were sacrificed and their brains were processed for Nissl staining and immunohistochemistry against glial fibrillary acidic protein (GFAP) and von Willebrand factor. In another group of animals, thermal nociception was evaluated using hot plate test, in the four experimental groups, on day 17. Data were analysed with two-way anova followed by Bonferroni test. Our results indicate that Amph exposure induces an increase in: neuronal apoptosis, astrocyte reactivity and microvascular network, evaluated as an augmented occupied area by vessels, branching points and their tortuosity. Moreover, Amph exposure decreased the thermal nociception threshold. Pretreatment with the AT -R blocker prevented the described alterations induced by this psychostimulant. The decreased thermal nociception and the structural changes in somatosensory cortex could be considered as extended neuroadaptative responses to Amph, involving AT -R activation.

OBJECTIVE: To evaluate the relationship between insulin, the renin-aldosterone system and blood pressure in obese subjects. DESIGN AND METHODS: A cross sectional study of a group of severely obese normotensive subjects who were surgical candidates (n 39; mean BMI: 47.8 AE 1.4) and a group of hypertensive patients (n 57; mean BMI: 28.0 AE 0.7) twenty-nine of whom had BMI b 27. All subjects were studied after 15 days on a balanced diet. Insulin, plasma renin activity and aldosterone were measured. RESULTS: Fasting insulin, plasma renin activity and aldosterone were higher in severely obese normotensive subjects than in hypertensive subjects (respectively 32.3 AE 3.0 vs 13.1 AE 1.0 mUal, P 0.0001; 1.34 AE 0.22 vs 0.88 AE 0.12 ngamlah, P 0.04; 137.2 AE 16.2 vs 87.9 AE 12.1 pgaml, P 0.015). Insulin was related to BMI and to aldosterone both in normotensive and in hypertensive patients. CONCLUSION: Hyperinsulinemia itself does not determine hypertension; in some people it could play a vasodilator role in opposition to the renin-aldosterone system.