These studies will define basic mechanisms of circulatory control in two clinical syndromes of chronic orthostatic hypertension. These patients are often severely incapacitated; therapy is only partially effective and is attended by significant side effects. Both sympathotonic orthostatic hypotension (SOH), which overlaps clinically with "vasoregulatory" or "neurocirculatory" asthenia and a portion of the mitral valve prolapse population, and dysautonomic orthostatic hypotension (DOH), including patients with idiopathic orthostatic hypotension (IOH) and multiple system atrophy (MSA), exhibit faulty cardiovascular control. These studies will not only provide information about these abnormalities of control, but also have the potential to improve therapy. We will compare patients with SOH and concomitantly studied controls, using multiple techniques to study the contribution of a number of aspects of circulatory control to the orthostatic intolerance of these patients. We will define the density, affinity and regulation of alpha- and beta-adrenoreceptors on circulating blood cells with radioligand binding, examining in particular responses to physiologic maneuvers. We will measure forearm blood flow, resistance and capacitance to study the responses of vascular smooth muscle to adrenergic and non-adrenergic agonists. Microneurographic techniques will allow us to measure precisely the peripheral sympathetic outflow response to baroreceptor stimulation. Finally, we will critically assess intravascular volume during controlled sodium intake and the responses of renin, angiotension and atrial natriuretic factor to volume manipulation. In patients with DOH, we will utilize a number of pharmacologic methods to manipulate neurotransmitter levels to enhance sympathetic outflow and orthostatic tolerance. We will use acetylcholinestnese inhibition to elevate peripheral and central levels of ACh, defining potential enhancement of sympathetic tone with microneurography and hemodynamic responses. The addition of a peripherally-acting muscarinic antagonist enhance the sympathetic effect. We will employ central alpha2-adrenoreceptor blockade to enhance sympathetic outflow, and then "protect" the increased norepinephrine levels with an MAO inhibitor. A final step will be the combination of central alpha2-blockade with MAO and cholinesterase inhibition. We will use similar methods to explore the role of central alpha2-adrenoreceptors in the orthostatic hypotension produced by levodopa therapy.