Neuropeptides/Biogenic Amines: Stress and Brain Ischemia

National Institute Of Mental Health

Investigators

Linked publications & trials

Abstract

Our laboratory studies the central functions of the hormone and brain modulator Angiotensin II and in particular its role in the regulation of the cerebral circulation and the reaction to stress. We have earlier discovered that pre-treating spontaneously (genetic) hypertensive rats (SHR) with an inhibitor of the peripheral, cerebrovascular and brain Angiotensin II AT1 receptors, candesartan, protected against subsequent brain ischemia resulting from occlusion of a major cerebral artery, reversed the hypertension-induced shifts in cerebral blood flow autoregulation, preserves blood flow above a critical threshold at the periphery of the ischemic zone, reversed the pathological cerebrovascular remodeling characteristic of hypertension, and thus normalized cerebrovascular compliance. We now report that inhibition of the Angiotensin II system by AT1 receptor blockade antagonizes Angiotensin II-induced cerebrovascular growth and inflammation. The AT1 receptor blocker, when administered peripherally, decreased iNOS, increased eNOS and decreased ICAM-1 in cerebrovascular beds, eliminated macrophage infiltration and reduced inflammation in cerebral arteries. AT1 receptor antagonists are superior, in its therapeutic potential for brain ischemia and stroke, when compared to other anti-hypertension medications. We now are attempting to clarify the mechanisms of such protection and reduction of ischemia. We constructed a large database, with the use of Gene Chip Expression Analysis, of changes in gene expression in microvessels of hypertensive and normotensive rats, treated with the AT1 receptor antagonist or vehicle. We found that the AT1 receptor blockade increases the expression of the AT2 receptor, an Angiotensin II receptor type that may counteract the growth-promoting and inflammatory effects of AT1 receptor stimulation. In addition, a large number of heat shock protein genes upregulated in microvessels from hypertensive rats, and are in turn down regulated by AT1 receptor antagonism. Thus, AT1 receptors control the expression of heat shock proteins during inflammation. Important mechanisms are emerging to explain the protective effect of AT1 receptor antagonism. AT1 receptors regulate eNOS and iNOS, restoring the equilibrium between these two isoenzymes, endothelial NO production and vasodilatation; AT1 receptor inhibition promotes expression of the AT2 receptor, and heat shock proteins play important roles in the process of protection from ischemia. A role of AT1 receptor inhibition in the protection from brain ischemia, beyond its effects in blood pressure control, begins to emerge. In addition, there may be a role for AT1 antagonists to prevent or reverse inflammatory conditions of the brain. Our studies continue with the analysis of specific groups of genes selected on the basis of carefully researched specific questions, and the results obtained with the microarrays are carefully controlled and confirmed by means of RT-PCR for gene expression, Western blot for protein expression and immunohistochemistry, to localize the regulated proteins to specific cell types. AT1 receptor antagonists can be proposed to be elective first class antihypertensive medications with additional properties to protect from brain ischemia and inflammation. We have earlier found that in addition to its vasoconstrictive, pro-hypertensive, pro-ischemic properties, Angiotensin II is an important stress hormone, and that pretreatment with a peripheral and central AT1 receptor antagonist completely prevents the sympathoadrenal response to isolation stress, including a modulation of TH transcription through regulation of transcription factors and including an interaction with AT2 receptors. We asked the question whether AT1 receptor antagonism could prevent a stress-induced illness, and we found that blockade of AT1 receptors completely prevented the production of stress-induced gastric ulcers in the rat dduring cold-restraint. We then found that multiple mechanisms were responsible for this effect, including protection of local gastric blood flow, selective inhibition of the sympathetic response to stress, and anti-inflammatory effects including decrease in ICAM expression and neutrophil infiltration in the gastric mucosa. The anti-inflammatory effects of AT1 receptor antagonism were of great interest, and coincided with the anti-inflammatory effects earlier described in the brain vasculature. Prevention of gastric ulcer formation, predominantly through anti-inflammatory effects, is a new finding of potentially important clinical implications. Our experiments continue to clarify our initial findings that in rodents, AT1 receptor blockade has an anxiolytic effect, as determined by behavioral studies using the Plus Maze. We propose that the anxiolytic effects are related to the modulation of AT1 receptor antagonists of brain CRH and GABAA receptor expression. This may indicate that AT1 receptor antagonists may be considered as a possible novel class of anti-anxiety medications. Because these compounds are devoid of addictive properties, development of new compounds of this class may result in anti-anxiety medications of great therapeutic potential. In addition, we have completed a two-and-a half year study to determine if life-long administration of the AT1 receptor antagonist affected rodent life span and if so, to determine the mechanisms of this effect. We chose Spontaneously Hypertensive Rats, and compared them with normotensive controls. We found a very significant extension of the life span of hypertensive animals, in parallel with cardiac and renal protection. We are in the process to determine if such end organ protection extends to the brain, and to clarify the mechanisms. 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, protect against stress-related disorders, exert important peripheral and central anti-inflammatory effects, and may be useful compounds to develop effective and non-addictive anti-anxiety and anti-stress drugs. We are planning to propose the first clinical study to determine if such compounds could be effectively used in the clinic to treat anxiety and stress-related disorders, and we continue our efforts to further clarify their mechanisms of action. The study of the complementary effects of AT2 receptor agonism and antagonism is another important direction in our current search for new and effective compounds of psychiatric interest.