application) The hypertensive syndrome is accompanied by a broad range of microvascular dysfunctions. The mechanisms responsible for development of cardiovascular complications in hypertension, however, have remained speculative. The applicant's hypothesis is that in addition to the definitive elevation of the blood pressure a key feature of hypertension is a shift in free radical formation at the tissue level which involves an adrenal/renal pathway. An oxidative stress on one hand leads to elevation of the arteriolar resistance while on the other hand it triggers a multitude of pathophysiological consequence, especially at the level of the microcirculation. Introduction of advanced microvascular techniques has enabled the investigators to identify higher levels of free radical production in-vivo in several models of hypertension together with a shift in the state of activation and interaction of cells in the circulation. The objective of this study is to investigate the mechanisms for the enhanced free radical production and outline its consequences for adjustments of microvascular function. In specific terms, the investigators propose to examine (I) the role of adrenal glucocorticoids and specific oxidases in free radical production, (II) mechanisms by which cell death, including apoptosis, are induced by oxidative stress relative to microvascular rarefaction (a loss of the smallest terminal arterioles and selected capillaries) and its modulation through the involvement of adrenal glucocorticoids, free radical production, and nitric oxide suppression, (III) the modification in the shear stress response of circulating leukocytes and endothelial cells in hypertensives as a consequence of glucocorticoids, and (IV) the basis for the reduced capacity of circulating leukocytes in hypertensives to respond to chemotactic stimuli, reduced adhesion to microvascular endothelium and the consequences for the migratory response. Several well-documented hypertensive models (spontaneously hypertensive rat, Dahl genetic salt-dependent hypertensive model, nitric oxide synthase gene knockout mouse) will be examined in a specific context in order to bring to light common pathophysiological pathways which undermine the microcirculation in various forms of hypertension. Such a program will serve to clarify the pathogenesis of hypertension and is expected to stimulate the design of novel approaches for interventions.
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