Abnormal norepinephrine clearance and adrenergic receptor sensitivity in idiopathic orthostatic intolerance

• Published in: Circulation (New York, N.Y.) Vol. 99; no. 13; pp. 1706 - 1712
• Main Authors: Jacob, G., Shannon, J. R., Costa, F., Furlan, R., Biaggioni, I., Mosqueda-Garcia, R., Robertson, R. M., Robertson, D.
• Format: Journal Article
• Language: English
• Published: Legacy CDMS Lippincott Williams & Wilkins 06-04-1999; American Heart Association, Inc
• Subjects: Adult; Aerospace Medicine; Autonomic Nervous System - drug effects; Autonomic Nervous System - physiopathology; Biological and medical sciences; Cranial nerves. Spinal roots. Peripheral nerves. Autonomic nervous system. Gustation. Olfaction; Female; Humans; Hypotension, Orthostatic - metabolism; Isoproterenol - administration & dosage; Male; Medical sciences; Nervous system (semeiology, syndromes); Neurology; Nitroprusside - administration & dosage; Norepinephrine - blood; Norepinephrine - pharmacokinetics; Phenylephrine - administration & dosage; Posture; Receptors, Adrenergic - physiology; Space life sciences; Supine Position; Tyramine - administration & dosage; Non-Nasa Center; Controlled Clinical Trial; Clinical Trial; Nasa Discipline Regulatory Physiology; Human; Intolerance; Nervous system diseases; Sensitivity; Pathogenesis; Diseases of the autonomic nervous system; Norepinephrine; Clearance; Orthostatism; Adrenergic receptor; NASA Discipline Regulatory Physiology; Non-NASA Center
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.99.13.1706

BACKGROUND: Chronic orthostatic intolerance (OI) is characterized by symptoms of inadequate cerebral perfusion with standing, in the absence of significant orthostatic hypotension. A heart rate increase of >/=30 bpm is typical. Possible underlying pathophysiologies include hypovolemia, partial dysautonomia, or a primary hyperadrenergic state. We tested the hypothesis that patients with OI have functional abnormalities in autonomic neurons regulating cardiovascular responses. METHODS AND RESULTS: Thirteen patients with chronic OI and 10 control subjects underwent a battery of autonomic tests. Systemic norepinephrine (NE) kinetics were determined with the patients supine and standing before and after tyramine administration. In addition, baroreflex sensitivity, hemodynamic responses to bolus injections of adrenergic agonists, and intrinsic heart rate were determined. Resting supine NE spillover and clearance were similar in both groups. With standing, patients had a greater decrease in NE clearance than control subjects (55+/-5% versus 30+/-7%, P<0.02). After tyramine, 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 microg, 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 microg, P<0.001). Baroreflex sensitivity was lower in patients (12+/-1 versus 18+/-2 ms/mm Hg, P<0.02), but the intrinsic heart rate 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 agonists demonstrate dramatically disordered sympathetic cardiovascular regulation in patients with chronic OI.