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The norepinephrine transporter deserves more attention

Jordan, Jensa,b; Grassi, Guidoc,d

doi: 10.1097/HJH.0000000000001757
Editorial Commentaries

aInstitute for Aerospace Medicine, German Aerospace Center (DLR)

bAerospace Medicine, University of Cologne, Cologne, Germany

cClinica Medica, University of Milano-Bicocca

dIRCCS Multimedica, Sesto Sangiovanni, Milan, Italy

Correspondence to Jens Jordan, MD, Institute for Aerospace Medicine, German Aerospace Center (DLR), Linder Hoehe, 51147 Cologne, Germany. Tel: +49 2203 601 3115; fax: +49 2203 695 211; e-mail: jens.jordan@dlr.de

Norepinephrine released from adrenergic nerve terminals in heart, kidney, and vasculature is crucial for blood pressure (BP) regulation. Both, too little and too much norepinephrine perturbs cardiovascular regulation. Life without norepinephrine is miserable as exemplified by patients with genetic dopamine-beta-hydroxylase deficiency [1]. These rare patients lack the enzyme required for dopamine to norepinephrine conversion and suffer from profound orthostatic hypotension among other hypoadrenergic symptoms. Conversely, excess norepinephrine action can contribute to arterial hypertension (AH) and predisposes to cardiovascular and renal damage. The hyperadrenergic state may be particularly pronounced in patients with treatment-resistant AH [2]. These mechanism provide the pathophysiological rational for using adrenoreceptor blockers, sympatholytics, and interventions targeting the sympathetic nervous system in hypertension management. Yet, adrenergic contributions to hypertension vary between patients, thus, explaining the heterogeneous response to antiadrenergic treatments. Given the important role of norepinephrine in BP regulation, mechanisms regulating its availability deserve our attention.

Theoretically, increases in peripheral norepinephrine availability could be explained by increased sympathetic nerve traffic and norepinephrine release from adrenergic nerves, reduction in norepinephrine degradation, or both mechanisms combined. Much of the hypertension research in the last decades has focused on sympathetic nerve traffic and norepinephrine release. Norepinephrine uptake and metabolism has been neglected. The neuronal norepinephrine transporter reclaims much of the norepinephrine from the synaptic cleft. Then, norepinephrine can be either recycled or degraded by monoamine oxidases. Reduced norepinephrine transporter function could conceivably contribute to AH [3].

In this issue, Eikelis et al. [4], report data from a smaller scale study suggesting that a common single nucleotide polymorphism in the gene encoding the norepinephrine transporter (SLC6A2) may be associated with increased BP in 92 patients with treatment-resistant AH. Careful physiological and biochemical phenotyping including recordings of sympathetic nerve traffic and catechol measurements is a strength of the study. The polymorphism (rs7194256) assessed in this study is located in a noncoding region. Thus, mRNA and amino acid sequence of the norepinephrine transporter protein remain unchanged. The authors previously suggested that compared with the C allele, the T allele of the polymorphism attenuate norepinephrine transporter function indirectly through a microRNA-mediated mechanism. Yet, the role of the polymorphism in norepinephrine transporter regulation is not fully understood. In any event compared with patients homozygous for the C allele, heterozygous or homozygous T allele carriers featured increased ambulatory SBP measurements. SBP was increased 8 mmHg over 24 h and 10 mmHg during nighttime. However, diastolic ambulatory BP measurements and office BP did not differ between groups. The same was true for heart rate (HR).

Although, efferent sympathetic nerve traffic was not increased in T allele carriers, plasma norepinephrine concentrations were substantially raised. Moreover, T allele carriers showed reductions in the ratio between dihydroxyphenylglycol and norepinephrine plasma concentrations. Both findings would be expected in a patient with reduced norepinephrine transporter function. However, the study has some methodological limitations. The statistical analysis was not adjusted for multiple testing. None of the associations would be significant following adjustment. Furthermore, the findings were not replicated in an independent cohort. Despite these issues, the study provides an impetus revisiting the role of the norepinephrine transporter in hypertension.

Perusal of previous genetic and pharmacological studies may help gauging norepinephrine transporter influences on BP. Two previous association studies illustrate the difficulties in relating norepinephrine transporter genetics to BP or AH. In almost 2000 Japanese persons, carriers of the rs168924 polymorphism minor G allele exhibited increased hypertension risk [5]. In another study conducted in whites, presence of the minor G allele was associated with lower SBP measurements [6]. Whether the discrepancy results from ethnic-specific influences of norepinephrine transporter genetics on the cardiovascular system or simply mirror a chance finding is unknown. In any event, the norepinephrine transporter gene did not pop up in large-scale genome-wide association studies [7].

Rare patients with familial norepinephrine transporter dysfunction, which has been identified in one family so far, may provide more insight compared with association studies [8]. Affected family members were heterozygous for a previously unknown norepinephrine transporter gene mutation (g237c). The g237c mutation is associated with an alanin to prolin (A457P) amino acid exchange. The mutated norepinephrine transporter oligomerizes with the wild type, thereby profoundly decreasing its cell surface expression [9]. Phenotypically, patients with familial norepinephrine transporter dysfunction exhibit increased upright HR and plasma norepinephrine measurements. We did not observe obvious differences in BP between affected and nonaffected family members. In homozygous norepinephrine transporter knockout mice, mean BP assessed through telemetry was increased by 4 mmHg at rest and by 6 mmHg during the active phase [10].

Medications inhibiting norepinephrine transporter are commonly prescribed for the treatment of depression and neuropathic pain among other indications. In healthy patients, short-term pharmacological norepinephrine transporter inhibition increases resting BP and HR [11]. However, the striking feature is a profound increase in upright HR. Paradoxically, the pressor response to sympathetic stimuli, such as the cold pressor test, is decreased with norepinephrine transporter inhibition. Moreover, systemic norepinephrine transporter inhibition reduces supine venous norepinephrine concentrations and systemic norepinephrine spillover [12].

Apparently, reduced norepinephrine transporter function can attenuate as well as augment sympathetic responses. Although norepinephrine transporter inhibition in peripheral tissues tends to increase norepinephrine availability, norepinephrine transporter inhibition in the brain elicits a ‘clonidine-like’ sympatholytic response profoundly reducing efferent sympathetic nerve traffic activity [12,13]. The net result of systemic changes in norepinephrine transporter function results from interaction of peripheral decreases in norepinephrine clearance and central nervous reductions in sympathetic activity. Counterintuitively, norepinephrine transporter inhibition appears to raise BP less or not at all in individuals with increased sympathetic activity [14]. Norepinephrine transporter inhibition redistributes sympathetic activity from vasculature and kidney toward the heart [12,15]. In the Sibutramine Cardiovascular Outcome Trial, overweight or obese patients with type 2 diabetes mellitus and/or a medical history of cardiovascular disease were randomized to treatment with the serotonin and norepinephrine transporter inhibitor sibutramine or placebo [16]. The increased risk for nonfatal heart attack and stroke with sibutramine, led to market withdrawal in Europe.

Overall, genetic and pharmacological reductions in norepinephrine transporter function profoundly affect cardiovascular regulation. HR regulation appears to be affected more compared with BP. Previous studies suggested that HR does not always go in parallel with other adrenergic markers making it a pale albeit easily measurable index of adrenergic tone [17,18]. Nevertheless, reductions in norepinephrine transporter function may modestly raise BP and could contribute to cardiovascular organ damage. Although the jury is still out whether the rs7194256 predisposes to treatment resistant AH, there is no doubt in our mind that the norepinephrine transporter deserves more attention in the hypertension community for scientific and for clinical reasons. From a scientific point of view, the research on norepinephrine transporter function reveals a fascinating interaction between brain and peripheral tissues in cardiovascular control. Clinically, millions patients with or without AH regularly take medications inhibiting the norepinephrine transporter with unclear implications for cardiovascular health.

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ACKNOWLEDGEMENTS

J.J. served as consultant for Novartis, Novo-Nordisc, Boehringer-Ingelheim, Sanofi, Orexigen, Riemser, Theravance, Vivus; and is cofounder of Eternygen GmbH.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES

1. Robertson D, Goldberg MR, Onrot J, Hollister AS, Wiley R, Thompson JG Jr, et al. Isolated failure of autonomic noradrenergic neurotransmission: evidence of impaired b-hydroxylation of dopamine. N Engl J Med 1986; 314:1494–1497.
2. Grassi G, Seravalle G, Brambilla G, Pini C, Alimento M, Facchetti R, et al. Marked sympathetic activation and baroreflex dysfunction in true resistant hypertension. Int J Cardiol 2014; 177:1020–1025.
3. Schroeder C, Jordan J. Norepinephrine transporter function and human cardiovascular disease. Am J Physiol Heart Circ Physiol 2012; 303:H1273–H1282.
4. Eikelis N, Marques FZ, Hering D, Marusic P, Head GA, Walton AS, et al. A polymorphism in the noradrenaline transporter gene is associated with increased blood pressure in patients with resistant hypertension. J Hypertens 2018; 36:1571–1577.
5. Ono K, Iwanaga Y, Mannami T, Kokubo Y, Tomoike H, Komamura K, et al. Epidemiological evidence of an association between SLC6A2 gene polymorphism and hypertension. Hypertens Res 2003; 26:685–689.
6. Zolk O, Ott C, Fromm MF, Schmieder RE. Effect of the rs168924 single-nucleotide polymorphism in the SLC6A2 catecholamine transporter gene on blood pressure in Caucasians. J Clin Hypertens (Greenwich) 2012; 14:293–298.
7. Warren HR, Evangelou E, Cabrera CP, Gao H, Ren M, Mifsud B, et al. Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. Nat Genet 2017; 49:403–415.
8. Shannon JR, Flattem N, Jordan J, Jacob G, Black BK, Biaggioni I, et al. Orthostatic intolerance and tachycardia associated with norepinephrine transporter deficiency. N Engl J Med 2000; 342:541–549.
9. Hahn MK, Robertson D, Blakely RD. A mutation in the human norepinephrine transporter gene (SLC6A2) associated with orthostatic intolerance disrupts surface expression of mutant and wild-type transporters. J Neurosci 2003; 23:4470–4478.
10. Keller NR, Diedrich A, Appalsamy M, Tuntrakool S, Lonce S, Finney C, et al. Norepinephrine transporter-deficient mice exhibit excessive tachycardia and elevated blood pressure with wakefulness and activity. Circulation 2004; 110:1191–1196.
11. Schroeder C, Tank J, Boschmann M, Diedrich A, Sharma AM, Biaggioni I, et al. Selective norepinephrine reuptake inhibition as a human model of orthostatic intolerance. Circulation 2002; 105:347–353.
12. Esler MD, Wallin G, Dorward PK, Eisenhofer G, Westerman R, Meredith I, et al. Effects of desipramine on sympathetic nerve firing and norepinephrine spillover to plasma in humans. Am J Physiol 1991; 260 (4 Pt 2):R817–R823.
13. Tank J, Schroeder C, Diedrich A, Szczech E, Haertter S, Sharma AM, et al. Selective impairment in sympathetic vasomotor control with norepinephrine transporter inhibition. Circulation 2003; 107:2949–2954.
14. Heusser K, Engeli S, Tank J, Diedrich A, Wiesner S, Janke J, et al. Sympathetic vasomotor tone determines blood pressure response to long-term sibutramine treatment. J Clin Endocrinol Metab 2007; 92:1560–1563.
15. Mayer AF, Schroeder C, Heusser K, Tank J, Diedrich A, Schmieder RE, et al. Influences of norepinephrine transporter function on the distribution of sympathetic activity in humans. Hypertension 2006; 48:120–126.
16. James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 2010; 363:905–917.
17. Grassi G, Vailati S, Bertinieri G, Seravalle G, Stella ML, Dell’Oro R, et al. Heart rate as marker of sympathetic activity. J Hypertens 1998; 16:1635–1639.
18. Quarti Trevano F, Seravalle G, Macchiarulo M, Villa P, Valena C, Dell’Oro R, et al. Reliability of heart rate as neuroadrenergic marker in the metabolic syndrome. J Hypertens 2017; 35:1685–1690.
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