Norepinephrine transporter-deficient mice exhibit excessive tachycardia and elevated blood pressure with wakefulness and activity.
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.


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.
Keller
Nancy R
NR
Autonomic Dysfunction Center, Department of Medicine, Nashville, TN 37232-2195, USA.
Diedrich
André
A
Appalsamy
Martin
M
Tuntrakool
Sunti
S
Lonce
Suzanna
S
Finney
Charlene
C
Caron
Marc G
MG
Robertson
David
D
D000818:Animals; D023181:Antimicrobial Cationic Peptides; D002940:Circadian Rhythm; D004298:Dopamine / Q000097:blood; D004837:Epinephrine / Q000097:blood; D006973:Hypertension / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology*; D009638:Norepinephrine / Q000097:blood; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D012119:Respiration; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D013610:Tachycardia / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D013686:Telemetry; D014851:Wakefulness / Q000502:physiology*
D023181:Antimicrobial Cationic Peptides; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493228:Slc6a2 protein, mouse; C072212:PR 39; D008734:Methoxyhydroxyphenylglycol; C010117:3,4-dihydroxyphenylglycol; D004298:Dopamine; D009638:Norepinephrine; D004837:Epinephrine