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Background: Impaired autonomic control of postural homeostasis results in orthostatic intolerance. However, the role of neurohormones in orthostatic intolerance has not been explained., Methods: Six-hundred-and-seventy-one patients (299 males; 55 ± 22 years) with unexplained syncope underwent head-up tilt (HUT) with serial blood sampling. Systolic blood pressure (SBP) and heart rate (HR) supine, after 3 min, and lowest BP/highest HR during HUT were recorded. Plasma levels of epinephrine, norepinephrine, renin, C-terminal-pro-arginine-vasopressin (CT-proAVP), C-terminal- endothelin-1 (CT-proET-1), and mid-regional-fragment of pro-atrial-natriuretic-peptide (MR-proANP) were determined at supine and 3 min of HUT. Multivariate-adjusted logistic regression model was applied to compare 1st (reference) with 4th quartile of 3 min and maximal ΔSBP/ΔHR (i.e. pronounced hypotension or tachycardia) vs. changes in neuroendocrine biomarkers, respectively., Results: Higher resting CT-proET-1 predicted BP fall at 3 min (Odds ratio (OR) per 1 SD: 1.62, 95%CI 1.18-2.22; p = 0.003), and max BP fall during HUT (1.82, 1.28-2.61; p = 0.001). Higher resting CT-proAVP predicted BP fall at 3 min (1.33, 1.03-1.73; p = 0.03), which was also associated with increase in CT-proAVP (1.86, 1.38-2.51; p = 0.00005) and epinephrine (1.47, 1.12-1.92; p = 0.05) during HUT. Lower resting MR-proANP predicted tachycardia at 3 min (0.37, 0.24-0.59; p = 0.00003), and max tachycardia during HUT (0.47, 0.29-0.77; p = 0.002). Further, tachycardia during HUT was associated with increase in epinephrine (1.60, 1.15-2.21; p = 0.005), and norepinephrine (1.87, 1.38-2.53; p = 0.005)., Conclusions: Resting CT-proET-1 and CT-proAVP are increased in orthostatic hypotension, while resting MR-proANP is decreased in postural tachycardia. Moreover, early BP fall during orthostasis evokes increase in CT-proAVP and epinephrine, while postural tachycardia is associated with increase in norepinephrine and epinephrine.