Our laboratory studies the central functions of the hormone and brain modulator Angiotensin II, the active principle of the Renin-Angiotensin System (RAS). Angiotensin II is involved in multiple functions besides its role in the control of blood pressure, through local RAS systems in most organs including the brain. In particular, our laboratory is focused on the study of the role of Angiotensin II in the regulation of brain circulation and ischemia, brain inflammation, and on its participation in the response to stress. Angiotensin II has an important role in the regulation of the reaction to stress through activation of its physiological receptors, the AT1 receptor type. Stress stimulates the expression and activity of brain AT1 receptors, in particular those located in the hypothalamic paraventricular nucleus. This results in increased corticotrophin-releasing factor (CRF) and vasopressin secretion and enhanced sympathoadrenal stimulation during stress. Our laboratory has earlier demonstrated that pretreatment with a peripheral and central AT1 receptor antagonist completely prevents the hormonal and sympathoadrenal response to isolation stress, including a modulation of tyrosine hydroxylase (TH) transcription through regulation of transcription factors and an interaction with AT2 receptors. We also found that AT1 receptor antagonism completely eliminated the production of stress-induced gastric ulcers in the rat during cold-restraint, preventing the stress-induced decrease in gastric blood flow and the acute inflammatory reaction of the gastric mucosa during stress. Prevention of stress-induced gastric ulcer formation by RAS blockade is a new finding with potentially important clinical implications. We continued our search for the central mechanisms involved in the role of Angiotensin II in the control of the stress reaction. We found that AT1 receptor blockade has an anxiolytic effect. Pretreatment with AT1 receptor antagonists with central effects prevents the decrease in CRF1 and benzodiazepine binding in the cerebral cortex produced by isolation stress. Thus, central inhibition of AT1 receptors counteracts the stimulation not only of the hypothalamic CRF system but of the cortical CRF system as well. Preservation of normal benzodiazepine binding during stress can be interpreted as protection of the cortical GABA-A system leading to decreased anxiety during stress. This may indicate that AT1 receptor antagonists should be considered as a novel class of anti-stress, anti-anxiety medications. Because these compounds, widely used to treat high blood pressure in humans, are safe and are devoid of addictive properties, development of new compounds of this class may result in medications of great therapeutic potential. We have recently started the first clinical protocol to evaluate the effects of AT1 receptor antagonists in the fear-startle response in human volunteers. The goal is to determine if AT1 receptor antagonists are effective in reducing anxiety and stress in humans. We earlier discovered that pre-treating spontaneously (genetic) hypertensive rats (SHR) with an inhibitor of the peripheral, cerebrovascular and brain Angiotensin II AT1 receptors protected against brain ischemia and inhibited cerebrovascular inflammation. To clarify the mechanisms of the beneficial effects of the AT1 receptor antagonists, we used Gene Chip Expression Analysis to construct a large database of changes in gene expression in cerebral microvessels of hypertensive and normotensive rats treated with the AT1 receptor antagonist or vehicle. We found alterations in gene expression of a number of systems, including the local cerebrovascular Renin-Angiotensin System (RAS), neurotransmitter systems and signal transduction factors, heat shock proteins and other markers of inflammation, transporter systems regulating the function of the blood brain barrier, and in many genes related to lipid and carbohydrate metabolism. We have confirmed some of the most important findings. Blockade of AT1 receptors inhibits the cerebrovascular heat shock protein response, restores the endothelial nitric oxide synthase (eNOS)/inducible nitric oxide synthase (iNOS) ratio, and reverses the chronic cerebrovascular inflammation characteristic of SHR. These facts indicate a role of AT1 receptor inhibition in protection from brain ischemia and inflammation beyond its effects in blood pressure control. We have also found that cerebral microvessels express all major RAS components including the newly discovered (pro) renin receptor. This indicates that Angiotensin II acting in the cerebral vasculature could have two origins: circulating, hormonal Angiotensin II and locally formed peptide. The central and peripheral anti-inflammatory effects of AT1 antagonists indicated that these compounds may prevent or reverse inflammatory conditions of the brain unrelated to hypertension. We chose a model of acute inflammation, the administration of lipopolysaccharide (LPS). We found that AT1 receptor blockade prevented the complete inflammatory response to LPS, in vivo in the rat spleen and the rat brain, and in human monocytes in culture. These findings demonstrate a role of Angiotensin II in the innate immune response, and reveal that AT1 receptor antagonists are effective anti-inflammatory compounds. Additional experiments demonstrate that there is a complete Renin-Angiotensin System in adipose tissue. Treatment with AT1 antagonists improves insulin sensitivity and increases the levels of adiponectin, a hormone released by adipose tissue and exerting anti-inflammatory effects in the vasculature. Some of these effects occur because of the adipocyte differentiation and lipolysis induced by the AT1 receptor antagonists. Our observations begin to elucidate some of the basic molecular mechanisms of the anti-inflammatory effect of AT1 receptor antagonists, and of the anti-diabetic properties of some of these compounds. In conclusion, our studies indicate that non-peptidic antagonists of the AT1 receptor with central effects may be considered among the drugs of choice in the treatment of cardiovascular disease and brain ischemia, to protect against stress-related disorders and diabetes, and to exert important peripheral and central anti-inflammatory effects. They may be useful compounds to develop effective and non-addictive anti-anxiety and anti-stress drugs. We continue our experiments to clarify: a) what is the mechanism of formation of Angiotensin II locally in the cerebral vasculature; b) what is the mechanism of anti-inflammatory effects of AT1 receptor antagonists; c) what are the central anti-ischemic, anti-inflammatory effects in animal models of inflammation; d) whether or not AT1 receptor antagonists can be considered as anti-anxiety, anti-stress therapeutic compounds in humans.
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