Cardiovascular responses to intravenous administration of norepinephrine and the properties of alpha receptors on platelets were compared in normal human subjects and subjects with multiple system atrophy (MSA) and sympathetic degeneration. All the subjects with MSA had low plasma norepinephrine concentrations (in the supine position) (0.42 +/- 0.09 nM, normal 3.47 +/- 0.58 nM), which did not increase on tilt. The pressor sensitivity of subjects with MSA to norepinephrine infusion was increased 10- to 20-fold, demonstrating denervation supersensitivity to adrenergic agonists. Analysis of alpha receptors was by binding of [3H]dihydroergocryptine to platelets. Results are shown as mean +/- standard error of the mean. In the MSA subjects, the number of alpha receptors (1,712 +/- 699 fmol/10(8) platelets) was about sevenfold greater than in normal subjects (224 +/- 21 fmol/10(8) platelets), and the affinity, as measured by the equilibrium dissociation constant (Kd), was similar in both groups (MSA subjects, 9.6 +/- 4.3 nM; normal subjects, 4 +/- 0.5 nM). These observations suggest that an increase in alphaadrenergic receptor numbers may account for the denervation supersensitivity to infused norepinephrine in patients with sympathetic degeneration. All the subjects with MSA had low levels of the endogenous adrenergic transmitter norepinephrine: the simultaneous increase in alpha adrenergic receptors supports the theory of agonist regulation of receptor numbers.