Published Online
on August 30, 2004

A more recent version of this article appeared on September 7, 2004

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Submitted on April 15, 2004
Revised on June 30, 2004
Accepted on July 8, 2004

Norepinephrine Transporter-Deficient Mice Exhibit Excessive Tachycardia and Elevated Blood Pressure With Wakefulness and Activity

Nancy R. Keller PhD, André Diedrich MD, PhD, Martin Appalsamy , Sunti Tuntrakool BS, Suzanna Lonce BS, Charlene Finney , Marc G. Caron PhD, and David Robertson MD^*

From the Autonomic Dysfunction Center, Department of Medicine (N.R.K., A.D., M.A., S.L., C.F., D.R.), and Departments of Neurology and Pharmacology and the Center for Molecular Neuroscience (D.R.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Electrical Engineering, Vanderbilt University, Nashville, Tenn (S.T.); and Howard Hughes Medical Institute Laboratories, Departments of Cell Biology and Medicine, Duke University Medical Center, Durham, NC (M.G.C.).

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

Background--Norepinephrine (NE) is a primary neurotransmitter of central autonomic regulation and sympathetic nerve conduction, and the norepinephrine transporter (NET) is crucial in limiting catecholaminergic signaling. NET is sensitive to antidepressants, cocaine, and amphetamine. NET blockade often is associated with cardiovascular side effects, and NET deficiency is linked to tachycardia in familial orthostatic intolerance.

Methods and Results--We telemetrically monitored NET-deficient (NET^-/-) mice to determine the cardiovascular effects of reduced NE reuptake. Mean arterial pressure was elevated in resting NET^-/- mice compared with NET^+/+ controls (103±0.6 versus 99±0.4 mm Hg; P<0.01), and corresponding pressures increased to 122±0.3 and 116±0.3 mm Hg (P<0.0001) with activity. Heart rate was also greater in resting NET^-/- mice (565±5 versus 551±3 bpm; P<0.05), and genotypic differences were highly significant during the active phase (640±5 versus 607±3 bpm; P<0.0001). Conversely, the respiratory rate of resting NET^-/- mice was dramatically reduced, whereas increases after the day/night shift surpassed those of controls. Plasma catecholamines in NET^-/- and NET^+/+ mice were as follows: NE, 69±8 and 32±7; dihydroxyphenylglycol, 2+0.4 and 17±3; epinephrine, 15±3 and 4±0.6; and dopamine, 13±4 and 4±1 pmol/mL. Catechols in urine, brain, and heart also were determined.

Conclusions--Resting mean arterial pressure and heart rate are maintained at nearly normal levels in NET-deficient mice, most likely as a result of increased central sympathoinhibition. However, sympathetic activation with wakefulness and activity apparently overwhelms central modulation, amplifying peripheral catecholaminergic signaling, particularly in the heart.

Key words: norepinephrine • tachycardia • blood pressure • nervous system, autonomic • physiology

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