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

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Abstract
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; PP−/− mice (565±5 versus 551±3 bpm; PP−/− 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.