Denervation supersensitivity to sympathomimetic amines was investigated in patients with sympathetic degeneration associated with multiple system atrophy (MSA, Shy Drager Syndrome). Sympathetic peripheral nerve degeneration was demonstrated by physiological and biochemical tests including measurements of plasma noradrenaline concentration which were lower in MSA than in normal subjects. Increased cardiovascular responses to intravenous noradrenaline, p-tyramine and isoprenaline showed supersensitivity of alpha and beta-adrenoceptors. Increased numbers but normal affinities of platelet alpha and lymphocyte beta-receptors were found in MSA compared with normal subjects; if these models reflect cardiovascular adrenoceptor status, the findings suggest that increased numbers of adrenoceptors may contribute to the denervation supersensitivity. All MSA patients had defective baroreflexes which probably contributed to supersensitivity. The role of baroreflexes was further studied in tetraplegics with complete cervical spinal cord transections, in whom sympathetic decentralization causes baroreflex dysfunction but peripheral sympathetic nerves are intact. , Tetraplegics were supersensitive to intravenous noradrenaline, but platelet alpha-receptors were normal suggesting that baroreflexes alone may produce supersensitivity. In patients with MSA fludrocortisone increased further the supersensitivity to noradrenaline and this may be important in the mechanism by which fludrocortisone benefits postural hypotension, a disabling feature of sympathetic degeneration in MSA. The sympathomimetic amines phenylephrine and ephedrine were also of benefit in the treatment of postural hypotension in patients with MSA. Decreased exposure to noradrenaline may cause increased adrenoceptor numbers in MSA for agonist concentrations appear to regulate receptor number. Therefore, the opposite situation was studied in patients with phaeochromocytomas in whom high plasma noradrenaline concentrations were associated with decreased pressor responses to noradrenaline (subsensitivity). Platelet alpha-receptor numbers were decreased in patients with phaeochromocytomas, but returned to normal after removal of the tumours. The apparent inverse relationship between alpha-receptors and noradrenaline concentration in MSA and phaeochromocytoma suggests that agonist concentration may regulate adrenoceptor number in man.