Influences of Norepinephrine Transporter Function on the Distribution of Sympathetic Activity in Humans

Abstract

Abstract-Previous studies suggest that neuronal norepinephrine transporter function may regulate the distribution of sympathetic activity among blood vessels, heart, and kidney; we tested the functional relevance in humans. Sixteen healthy men (26Ϯ1 years) ingested 8 mg of the selective norepinephrine reuptake transporter inhibitor reboxetine or a matching placebo on 2 separate days in a double-blind, randomized, crossover fashion. We monitored heart rate, thoracic bioimpedance, blood pressure, glomerular filtration rate, and renal blood flow. Ninety minutes after ingestion of the test medication, subjects were tilted to a 45°head-up position, where they remained for an additional 30 minutes. Reboxetine increased supine systolic blood pressure through an increase in cardiac output whereas systemic vascular resistance decreased. Furthermore, reboxetine increased heart rate, particularly with a head-up tilt. Supine plasma renin activity was 0.71Ϯ0.15 ng angiotensin (Ang)/L per mL/h with placebo and 0.36Ϯ0.07 ngAng/L per mL/h with reboxetine (PϽ0.01). Supine plasma Ang II concentrations were also decreased with reboxetine. Both plasma renin activity and Ang II concentrations remained suppressed during head-up tilt. On placebo, renal vascular resistance increased with head-up tilt. The response was abolished with norepinephrine reuptake inhibition. We conclude that norepinephrine reuptake function profoundly influences the distribution of sympathetic activity between the heart, vasculature, and kidney in humans. All of these changes are physiologically relevant because they lead to corresponding changes in organ function. (Hypertension. 2006;48:120-126.)Key Words: sympathetic nervous system Ⅲ norepinephrine Ⅲ renal circulation Ⅲ renin-angiotensin system S ympathetic activity is not evenly distributed among the blood vessels, heart, and kidney. Discordant sympathetic activation of the heart and the kidney may be relevant to common cardiovascular disorders. For example, the postural tachycardia syndrome (POTS) is associated with excessive cardiac sympathetic activity. 1 Decreased renal sympathetic activity in POTS is suggested by hypovolemia together with inappropriately low renin-angiotensin system activity. 2 In contrast, in obese subjects, renal norepinephrine spillover is increased. 3 Sympathetic traffic to the vasculature may also be increased, at least in a subgroup of obese patients. 4,5 Cardiac sympathetic activity is suppressed in obese normotensive persons and is within the normal range in obese hypertensive patients. 6 Yet, the mechanisms regulating sympathetic distribution between the heart and kidney are poorly understood. Norepinephrine reuptake transporter (NET) function may be important in this regard. Acute pharmacological NET blockade reduces sympathetic vasomotor tone 7 and renal norepinephrine spillover in humans. 8 In contrast, cardiac norepinephrine spillover 8 and upright heart rate are substantially increased. 9 Similarly, upright heart rate is increased in patients with genetic NET deficiency....

Altered Sympathetic Nervous Reactivity and Norepinephrine Transporter Expression in Patients With Postural Tachycardia Syndrome

“…However, selective NET inhibition by reboxetine did not alter NE plasma concentration in the supine and upright positions in another study. 24 The mismatch between NET abundance and NE spillover to plasma in patients with POTS may reflect profound changes in NE content within adrenergic nerves or abnormalities in NE release, although this remains to be demonstrated. Indeed, Jacob et al 22 found that sympathetic challenge induced by the cold pressor test, sodium nitroprusside infusion, and tyramine infusion increased NE spillover in the arms to a similar extent in the POTS and control groups, although the increases in the legs were smaller in the patients with POTS than in the normal subjects.…”

Ganglion-Specific Impairment of the Norepinephrine Transporter in the Hypertensive Rat

“…4,28 Increased activity in the sympathetic nervous system has been widely implicated in hypertension, [1][2][3][4] and it is conceivable that a part of this response is related to impaired NET activity, resulting in increased junctional NE concentrations. 3,10,[12][13][14][15] Studies investigating defective NET activity in hypertension have been inconclusive. We observed that stellate sympathetic neurons had a significant reduction in NET activity in the SHR compared with WKY; however, no difference in NET rate was observed when comparing age-matched SHR and WKY cells isolated from the SCG or the CG/SMG.…”

“…9 However, enhanced transmission may also result from impaired NE reuptake by the norepinephrine uptake transporter (NET; uptake-1) system, although evidence in support of this hypothesis is far from conclusive. 3,[10][11][12][13] In the SHR, NET has been shown to be either downregulated, 12 unaffected, 14,15 or upregulated. 15,16 Similarly in human hypertension, the putative role of NET has been reported to be either reduced 3,10 or unaltered 17 when comparing hypertensive and normotensive subjects.…”

Norepinephrine transporter inhibition alters the hemodynamic response to hypergravitation

“…NET, norepinephrine transporter; NS, not significant. (7,13). Predominant cardiac sympathetic stimulation with NET inhibition may be explained by ultrastructural or functional differences in cardiac adrenergic nerve terminals (6).…”