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.


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 degrees 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 degrees 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.
Schroeder
Christoph
C
Clinical Research Center, HELIOS Klinkum-Berlin, Germany. jordan@fvk-berlin.de
Tank
Jens
J
Boschmann
Michael
M
Diedrich
Andre
A
Sharma
Arya M
AM
Biaggioni
Italo
I
Luft
Friedrich C
FC
Jordan
Jens
J
D000322:Adrenergic Agonists / Q000494:pharmacology; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000328:Adult; D001341:Autonomic Nervous System / Q000502:physiology; D017704:Baroreflex; D001692:Biological Transport; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D011187:Posture; D000077593:Reboxetine; D012018:Reflex; D013577:Syndrome; D013610:Tachycardia / Q000209:etiology*; D018667:Tilt-Table Test
D000322:Adrenergic Agonists; D018759:Adrenergic Uptake Inhibitors; D009025:Morpholines; D010656:Phenylephrine; D000077593:Reboxetine; D007545:Isoproterenol; D009638:Norepinephrine