Abnormal neuronal function in the cerebral cortex, hypothalamus or medulla oblongata is probably involved in the pathophysiology of clinical entities such as the hypertensive diencephalic syndrome or the Cushing's reflex. The syndromes of orthostatic intolerance, which are quite common, could also encompass such mechanisms. These are characterized by variable changes in standing blood pressure, pronounced orthostatic tachycardia, symptoms compatible with pre-syncope and rarely syncope, especially during changes in gravitational forces. We have identified a subset of subjects with orthostatic intolerance in whom hemodynamic instability is associated with marked increases in sympathetic tone, characterized by high resting levels of muscle, skin, and cardiac sympathetic activity and by extreme increases in plasma norepinephrine and muscle sympathetic nerve activity during the upright posture. Most of these patients also experience symptoms such as extreme anxiety, fatigue, inability to concentrate, and changes in personality. We hypothesize that a primary central disorder is present in these patients and results in a hyperadrenergic condition. In the present proposal we will test this hypothesis by experiments that (a) determine whether there is an enhancement of neural sympathetic outflow, (b) investigate whether sympathetic regulation by central structures (i.e., cerebral cortex) is affected in these patients (this will be documented by studies changing cortical function with mental stress, barbiturates, and by investigating sympathetic function during sleep), (c) localization of potential central sites affected by study of brain glucose metabolism at rest and during hypotension using Positron Emission Tomography, (d) by pharmacological manipulation of sympathetic tone, (e) by testing whether reducing sympathetic outflow can normalize hemodynamics and symptoms in patients and whether increasing sympathetic outflow in healthy subjects can replicate the symptomatic and cardiovascular abnormalities of hyperadrenergic subjects.
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