BIOCHEMICAL EVALUATION OF ADRENERGIC FUNCTION--RESPONSES TO STRESS & DISEASE

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The main objectives of this project are (1) to determine the physiologic significance of alterations in plasma levels and urinary excretion rates of the catecholamines, their metabolites and their precursor, DOPA; (2) to develop in animals and humans clinically useful methods for assessing catecholaminergic function; and (3) to apply these methods to examine function of catecholaminergic neurons in the peripheral sympathetic nervous system and in brain. Changes in tissue or plasma levels or urinary excretion rates of catecholamines and their metabolites, and tissue tyrosine hydroxylase levels are evaluated, during and after stress, in response to pharmacologic treatments, or in disease states in animals, in normal subjects, and in patients with various neurologic or related disorders (autonomic dysfunction, Parkinson's disease, hypertension, etc). Use of 18-F labelled dopamine has been developed for imaging by positron emission tomography (PET) peripheral sympathetic activity in vivo in dogs and is awaiting application to humans. In rats, plasma levels of DOPA parallel pharmacologic or stress-induced enhancement of norepinephrine release, even after adrenalmedullectomy. Tyrosine hydroxylase levels in tissues do not reflect the rate of catecholamine production, indicating that tyrosine hydroxylation, can be regulated independently of the levels of tyrosine hydroxylase. Chronic elevation of plasma glucocorticoid levels elevates rat blood pressure but depresses plasma norepinephrine levels. Baroreceptor sensitivity is unaltered and pressor responses to phenylephrine are normal. There is, however, an increase in the tachycardia induced by isoproterenol, indicating that cardiac beta-adrenoceptors are hyperresponsive. The mechanism of hypertension attending chronic elevation of corticosteriods differs from that in other forms of hypertension. Most patients with pure autonomic failure were found to have low plasma levels of DOPA as well as of norepinephrine, DHPG and DOPAC, consistent with loss of peripheral sympathetic neurons, whereas in most patients with multiple system atrophy, levels of DOPA, DHPG and DOPAC are generally normal; this is consistent with normal catecholamine biosynthesis in these patients who are believed to have intact peripheral sympathetic neurons but diminished nerve impulse traffic from the central nervous system.