Observations from the literature suggest that the SNS affects leukocyte endothelial interaction through at least four pathways: 1) circulating leukocyte cell adhesion molecule expression, particularly, increased CD11a expression; 2) elevated endothelial cell adhesion molecule expression (as indexed by elevated circulating levels of sCD54); 3) increased formation of leukocyte-platelet aggregates, which in turn enhance leukocyte adhesion to the endothelium; and 4) increased production of proinflammatory cytokines, particularly IL-6 and TNF-alpha, that in turn enhance the expression of leukocyte and endothelial cell adhesion molecules. The potential disease implications of these findings are not well understood. We have also gathered preliminary data suggesting that subjects with hypertension, as compared to subjects with normal blood pressure, exhibit exaggerated responses in each of these four pathways. Hypertensives show: 1) increased density of lymphocyte CD11a at rest and in response to stressors; 2) elevated resting and stressor-induced levels of circulating soluble sCD54; 3) increased SNS-induced formation of leukocyte-platelet aggregates in circulation; and 4) increased production of proinflammatory cytokines. This project will examine these pathways, particularly the effect of sCD54 on in vitro leukocyte adhesion in hypertension, the effects of platelet activation on leukocyte adhesion in hypertension, and the potential role of adhesion molecule-inducing proinflammatory cytokines on increased adhesion in hypertension. We propose to study 40 hypertensive and 40 normotensive women and men prior to and following an exhaustive exercise task and an infusion of the beta-adrenergic agonist isoproterenol. The overarching hypothesis of the proposal is that hypertension combined with sympathetic activation results in enhanced effects on leukocyte, platelet and endothelial adhesion that are of likely clinical significance.
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