Selective Norepinephrine Reuptake Inhibition as a Human Model of Orthostatic Intolerance

Background—Observations in patients with functional mutations of the norepinephrine transporter (NET) gene suggest that impaired norepinephrine uptake may contribute to idiopathic orthostatic intolerance. Methods and Results—We studied the effect of the selective NET blocker reboxetine and placebo in a randomized, double-blind, crossover fashion on cardiovascular responses to cold pressor testing, handgrip testing, and a graded head-up tilt test (HUT) in 18 healthy subjects. In a subset, we determined isoproterenol and phenylephrine sensitivities. Subjects ingested 8 mg reboxetine or placebo 12 hours and 1 hour before testing. In the supine position, heart rate was 65±2 bpm with placebo and 71±3 bpm with reboxetine. At 75° HUT, heart rate was 84±3 and 119±4 bpm with placebo and with reboxetine (P <0.0001). Mean arterial pressure was 85±2 with placebo and 91±2 mm Hg with reboxetine while supine (P <0.01) and 88±2 mm Hg and 90±3 mm Hg at 75° HUT. Blood pressure responses to cold pressor and handgrip testing were attenuated with reboxetine. Reboxetine increased the sensitivity to the chronotropic effect of isoproterenol and the pressor effect of phenylephrine. Vasovagal reactions occurred in 9 subjects on placebo and in 1 subject on reboxetine. Conclusions—Selective NET blockade creates a phenotype that resembles idiopathic orthostatic intolerance. This observation supports the hypothesis that disordered norepinephrine uptake mechanisms can contribute to human cardiovascular disease. Our study also suggests that NET inhibition might be useful in preventing vasovagal reactions.

[1]  A. Diedrich,et al.  Genetic Influences on Baroreflex Function in Normal Twins , 2001, Hypertension.

[2]  Susan G. Amara,et al.  Reboxetine: a pharmacologically potent, selective, and specific norepinephrine reuptake inhibitor , 2000, Biological Psychiatry.

[3]  A. Porta,et al.  Oscillatory patterns in sympathetic neural discharge and cardiovascular variables during orthostatic stimulus. , 2000, Circulation.

[4]  R. Blakely,et al.  Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. , 2000, The New England journal of medicine.

[5]  A. Barsotti,et al.  Usefulness of a tilt training program for the prevention of refractory neurocardiogenic syncope in adolescents: A controlled study. , 1999, Circulation.

[6]  R. Furlan,et al.  Abnormal norepinephrine clearance and adrenergic receptor sensitivity in idiopathic orthostatic intolerance. , 1999, Circulation.

[7]  R. Furlan,et al.  Effects of standing on cerebrovascular resistance in patients with idiopathic orthostatic intolerance. , 1999, The American journal of medicine.

[8]  R Furlan,et al.  Chronic orthostatic intolerance: a disorder with discordant cardiac and vascular sympathetic control. , 1998, Circulation.

[9]  R. Furlan,et al.  Yohimbine in neurally mediated syncope. Pathophysiological implications. , 1998, The Journal of clinical investigation.

[10]  P. Novak,et al.  Hypocapnia and cerebral hypoperfusion in orthostatic intolerance. , 1998, Stroke.

[11]  J. Jordan,et al.  Uncoupling of the baroreflex by N(N)-cholinergic blockade in dissecting the components of cardiovascular regulation. , 1998, Hypertension.

[12]  T. Wein,et al.  Cerebrovascular and cardiovascular measurements during neurally mediated syncope induced by head-up tilt. , 1997, Stroke.

[13]  G. Jacob,et al.  Effects of volume loading and pressor agents in idiopathic orthostatic tachycardia. , 1997, Circulation.

[14]  J. Jordan,et al.  The physiological conundrum of hyperadrenergic orthostatic intolerance. , 1997, The Chinese journal of physiology.

[15]  C. Stein,et al.  Forearm beta adrenergic receptor-mediated vasodilation is impaired, without alteration of forearm norepinephrine spillover, in borderline hypertension. , 1995, The Journal of clinical investigation.

[16]  M. White,et al.  Aging and cardiovascular responsiveness to β‐agonist in humans: Role of changes in β‐receptor responses versus baroreflex activity , 1994 .

[17]  G. Ford,et al.  Effect of 'autonomic blockade' on cardiac beta-adrenergic chronotropic responsiveness in healthy young, healthy elderly and endurance-trained elderly subjects. , 1994, Clinical science.

[18]  P. Low,et al.  Idiopathic postural orthostatic tachycardia syndrome , 1993, Neurology.

[19]  R. Westerman,et al.  Effects of desipramine on sympathetic nerve firing and norepinephrine spillover to plasma in humans. , 1991, The American journal of physiology.

[20]  D. Streeten,et al.  Pathogenesis of hyperadrenergic orthostatic hypotension. Evidence of disordered venous innervation exclusively in the lower limbs. , 1990, The Journal of clinical investigation.

[21]  J. Fahrenberg,et al.  Methodological guidelines for impedance cardiography. , 1990, Psychophysiology.

[22]  M. Turiel,et al.  Power Spectral Analysis of Heart Rate and Arterial Pressure Variabilities as a Marker of Sympatho‐Vagal Interaction in Man and Conscious Dog , 1986, Circulation research.

[23]  R. Zimlichman,,et al.  Estimation of intrasynaptic norepinephrine concentrations in humans. , 1986, Hypertension.

[24]  J. J. Smith,et al.  The use of thoracic impedance for determining thoracic blood volume changes in man. , 1986, Aviation, space, and environmental medicine.

[25]  A Pedotti,et al.  A new approach to analysis of the arterial baroreflex. , 1985, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[26]  S. Z. Langer Presynaptic regulation of the release of catecholamines. , 1980, Pharmacological reviews.

[27]  G. Preiss,et al.  Patterns of sympathetic neuron activity associated with Mayer waves. , 1974, The American journal of physiology.

[28]  光夫 宮原,et al.  Hyperdynamic β-Adrenergic Circulatory Stateの1症例 , 1968 .

[29]  E. Frohlich,et al.  Hyperdynamic beta-adrenergic circulatory state. , 1966, Archives of internal medicine.