Abnormal norepinephrine clearance and adrenergic receptor sensitivity in idiopathic orthostatic intolerance

Background-Chronic orthostatic intolerance (Ol)is characterized by symptoms of inadequate cerebral perfusion with standing, in the absence of signific ant orthostatic hypotension. A heart rate increase of greater than or equal to 30 bpm is typical. Possible underlying pathophysiologies include hypovo lemia, partial dysautonomia, or a primary hyperadrenergic state. We tested the hypothesis that patients with OI have functional abnormalities in auton omic neurons regulating cardiovascular responses. Methods and Results-Thirteen patients with chronic OI and 10 control subjec ts underwent a battery of autonomic tests. Systemic norepinephrine (NE) kin etics were determined with the patients supine and standing before and afte r tyramine administration. In addition, baroreflex sensitivity, hemodynamic responses to bolus injections of adrenergic agonists, and intrinsic heart rate were det:ermined. Resting supine NE spillover and clearance were simil ar in both groups. With standing, patients had a greater decrease in NE cle arance, than control subjects (55+/-5% versus 30+/-7%, P<0.02). After tyram ine, NE spillover did not change significantly in patients but increased 50 +/-10% in control subjects (P<0.001). The dose of isoproterenol required to increase heart rate 25 bpm was lower in patients than in control subjects (0.5+/-0.05 versus 1.0+/-0.1 mu g, P<0.005), and the dose of phenylephrine required to increase systolic blood pressure 25 mm Hg was lower in patients than control subjects (105+/-11 versus 210+/-12 mu g, P<0.001). Baroreflex sensitivity was lower in patients (12+/-1 versus 18+/-2 ms/mm Hg, P<0.02), but the intrinsic heart rare was similar in both groups. Conclusions-The decreased NE clearance with standing, resistance to the NE- releasing effect of tyramine, and increased sensitivity to adrenergic agoni sts demonstrate dramatically disordered sympathetic cardiovascular regulati on in patients with chronic OI.