Published Online
on June 7, 2004

A more recent version of this article appeared on June 29, 2004

This Article Full Text (PDF) All Versions of this Article: 109/25/3202    most recent 01.CIR.0000130847.18666.39v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vincent, S. Articles by Robertson, D. Search for Related Content PubMed PubMed Citation Articles by Vincent, S. Articles by Robertson, D. Related Collections Cardiovascular Pharmacology Clinical Studies Autonomic, reflex, and neurohumoral control of circulation

Submitted on June 23, 2003
Revised on March 9, 2004
Accepted on March 16, 2004

Clinical Assessment of Norepinephrine Transporter Blockade Through Biochemical and Pharmacological Profiles

Simi Vincent MD, PhD, Peter R. Bieck MD, PhD, Emily M. Garland PhD, Corina Loghin MD, Frank P. Bymaster MS, Bonnie K. Black RN, NP, Celedon Gonzales MS, William Z. Potter MD, PhD, and David Robertson MD^*

From the Autonomic Dysfunction Center, Departments of Medicine, Pharmacology, and Neurology, Vanderbilt University, Nashville, Tenn (S.V., E.M.G., B.K.B., D.R.); and Lilly Research Laboratories, Indianapolis, Ind (P.R.B., C.L., F.P.B., C.G., W.Z.P.).

^* To whom correspondence should be addressed. E-mail: david.robertson{at}vanderbilt.edu.

Background--To assess the sensitivity of biochemical, physiological, and pharmacological markers of peripheral norepinephrine (NE) transporter (NET) function, we chronically antagonized NET by a range of doses of duloxetine [(+)-N-methyl-3-(1-naphthalenyloxy)-2 thiophenepropanamine], which blocks the NE reuptake process.

Methods and Results--Duloxetine was administered in a randomized, placebo-controlled study in 15 healthy volunteers. Plasma from duloxetine-treated subjects (ex vivo effect) dose-dependently decreased radioligand binding to human NET (maximum inhibition was 60%) (P=0.02). The dose of intravenous tyramine required to raise systolic blood pressure by 30 mm Hg (PD₃₀) increased dose-dependently with duloxetine and was significant at the end of the 120-mg/d dosage (P<0.001). The plasma dihydoxyphenylglycol to NE (DHPG/NE) ratio was reduced significantly at 2 weeks of treatment with 80 mg/d duloxetine (11.3 at baseline, 3.4 at 240 mg/d, P<0.001). Plasma NE was significantly increased starting at 120 mg/d duloxetine. Urine results (corrected for 24-hour creatinine excretion) showed a dose-dependent change from the baseline urinary excretion for NE, DHPG, and the DHPG/NE ratio. The most sensitive measure, the DHPG/NE ratio, was significant at the 80-mg dose. Urinary NE excretion was significantly raised after 2 weeks of treatment with 80 mg/d duloxetine (P<0.001), the lowest dose used in the study.

Conclusions--These findings suggest that the degree of NET blockade can be assessed with the plasma or urine DHPG/NE ratio and the pressor effect of tyramine. Also, the DHPG/NE ratio is more sensitive at the lower end of NET inhibition, whereas tyramine exhibits a linear relation, with NET inhibition commencing at a higher dose.

Key words: norepinephrine • blood pressure • plasma • drugs • catecholamines

This article has been cited by other articles:

				S. R. Raj, C. M. Stein, P. J. Saavedra, and D. M. Roden Cardiovascular Effects of Noncardiovascular Drugs Circulation, September 22, 2009; 120(12): 1123 - 1132. [Full Text] [PDF]

				V Raj, K L Haman, S R Raj, D Byrne, R D Blakely, I Biaggioni, D Robertson, and R C Shelton Psychiatric profile and attention deficits in postural tachycardia syndrome J. Neurol. Neurosurg. Psychiatry, March 1, 2009; 80(3): 339 - 344. [Abstract] [Full Text] [PDF]

				P. Blier Resiliency of monoaminergic systems: the 80% rule and its relevance to drug development J Psychopharmacol, August 1, 2008; 22(6): 587 - 589. [PDF]

				E. Lambert, N. Eikelis, M. Esler, T. Dawood, M. Schlaich, R. Bayles, F. Socratous, A. Agrotis, G. Jennings, G. Lambert, et al. Altered Sympathetic Nervous Reactivity and Norepinephrine Transporter Expression in Patients With Postural Tachycardia Syndrome Circ Arrhythm Electrophysiol, June 1, 2008; 1(2): 103 - 109. [Abstract] [Full Text] [PDF]

				I. Moldovanova, C. Schroeder, G. Jacob, C. Hiemke, A. Diedrich, F. C. Luft, and J. Jordan Hormonal Influences on Cardiovascular Norepinephrine Transporter Responses in Healthy Women Hypertension, April 1, 2008; 51(4): 1203 - 1209. [Abstract] [Full Text] [PDF]

				L. K. Gilliam, J. P. Palmer, and G. J. Taborsky Jr. Tyramine-Mediated Activation of Sympathetic Nerves Inhibits Insulin Secretion in Humans J. Clin. Endocrinol. Metab., October 1, 2007; 92(10): 4035 - 4038. [Abstract] [Full Text] [PDF]

				A K Agarwal, R Garg, A Ritch, and P Sarkar Postural orthostatic tachycardia syndrome Postgrad. Med. J., July 1, 2007; 83(981): 478 - 480. [Abstract] [Full Text] [PDF]

				C. Shibao, S. R. Raj, A. Gamboa, A. Diedrich, L. Choi, B. K. Black, D. Robertson, and I. Biaggioni Norepinephrine Transporter Blockade With Atomoxetine Induces Hypertension in Patients With Impaired Autonomic Function Hypertension, July 1, 2007; 50(1): 47 - 53. [Abstract] [Full Text] [PDF]

				E. Hazen and M. Fava Successful treatment with duloxetine in a case of treatment refractory bulimia nervosa: a case report J Psychopharmacol, September 1, 2006; 20(5): 723 - 724. [Abstract] [PDF]

				T. O. Mundinger, D. E. Cummings, and G. J. Taborsky Jr Direct Stimulation of Ghrelin Secretion by Sympathetic Nerves Endocrinology, June 1, 2006; 147(6): 2893 - 2901. [Abstract] [Full Text] [PDF]

				N. R. Keller, A. Diedrich, M. Appalsamy, S. Tuntrakool, S. Lonce, C. Finney, M. G. Caron, and D. Robertson Norepinephrine Transporter-Deficient Mice Exhibit Excessive Tachycardia and Elevated Blood Pressure With Wakefulness and Activity Circulation, September 7, 2004; 110(10): 1191 - 1196. [Abstract] [Full Text] [PDF]