Phenotypical evidence for a gender difference in cardiac norepinephrine transporter function

Schroeder, Christoph; Adams, Frauke; Boschmann, Michael; Tank, Jens; Haertter, Sebastian; Diedrich, André; Biaggioni, Italo; Luft, Friedrich C.; Jordan, Jens

doi:10.1152/ajpregu.00689.2003

Cited by 37 publications

(32 citation statements)

References 32 publications

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“…In contrast, the tachycardic response to hypergravitation was substantially augmented with NET inhibition. This mismatch between cardiac and vascular responses to NET inhibition has been observed earlier during orthostatic stimulation (2,16,18). Systemic norepinephrine concentrations did not change with NET inhibition, which further supports the idea of a differential sympathetic response between tissues.…”

Section: Discussionsupporting

confidence: 77%

Norepinephrine transporter inhibition alters the hemodynamic response to hypergravitation

Strempel

Schroeder²,

Hemmersbach³

et al. 2008

Journal of Applied Physiology

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transporter inhibition alters the hemodynamic response to hypergravitation. J Appl Physiol 104: 756-760, 2008. First published January 10, 2008 doi:10.1152/japplphysiol.01128.2007.-Sympathetically mediated tachycardia and vasoconstriction maintain blood pressure during hypergravitational stress, thereby preventing gravitation-induced loss of consciousness. Norepinephrine transporter (NET) inhibition prevents neurally mediated (pre)syncope during gravitational stress imposed by head-up tilt testing. Thus it seems reasonable that NET inhibition could increase tolerance to hypergravitational stress. We performed a double-blind, randomized, placebo-controlled crossover study in 11 healthy men (26 Ϯ 1 yr, body mass index 24 Ϯ 1 kg/m 2 ), who ingested the selective NET inhibitor reboxetine (4 mg) or matching placebo 25, 13, and 1 h before testing on separate days. We monitored heart rate, blood pressure, and thoracic impedance in three different body positions (supine, seated, standing) and during a graded centrifuge run (incremental steps of 0.5 g for 3 min each, up to a maximal vertical acceleration load of 3 g). NET inhibition increased supine blood pressure and heart rate. With placebo, blood pressure increased in the seated position and was well maintained during standing. However, with NET inhibition, blood pressure decreased in the seated and standing position. During hypergravitation, blood pressure increased in a graded fashion with placebo. With NET inhibition, the increase in blood pressure during hypergravitation was profoundly diminished. Conversely, the tachycardic responses to sitting, standing, and hypergravitation all were greatly increased with NET inhibition. In contrast to our expectation, short-term NET inhibition did not improve tolerance to hypergravitation. Redistribution of sympathetic activity to the heart or changes in baroreflex responses could explain the excessive tachycardia that we observed. norepinephrine reuptake transporter; cardiovascular regulation; autonomic nervous system; human HYPERGRAVITATION INDUCED BY rapid flight maneuvers or centrifugation challenges the cardiovascular system through increased venous pooling and plasma extravasation into the dependent parts of the body. In addition, hypergravitation elicits considerable psychological stress and engages the vestibular system (1, 23). In this setting, the ability of the cardiovascular system to maintain cerebral perfusion determines gravity (G) tolerance. Once the physiological challenge imposed by hypergravitation overwhelms the adjustment mechanisms, gravitation-induced loss of consciousness (G-LOC) ensues (19). Sympathetic nervous system activation, which is modulated by the vestibular system (23), is a crucial mechanism to maintain cerebral perfusion pressure (3, 24). Sympathetic cardiovascular responses are mediated by norepinephrine acting on adrenergic receptors (6). The synaptic norepinephrine concentration is regulated through norepinephrine release and norepinephrine re-uptake by the neuronal norepinephrine transp...

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Section: Discussionsupporting

confidence: 77%

Norepinephrine transporter inhibition alters the hemodynamic response to hypergravitation

Strempel

Schroeder²,

Hemmersbach³

et al. 2008

Journal of Applied Physiology

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“…However, NET inhibition has a gender-specific effect on the cardiovascular system. 27 Thus, our findings cannot be simply extrapolated to women. Finally, we cannot exclude completely that reboxetine directly interfered with some of our laboratory measurements.…”

Section: Discussionmentioning

confidence: 89%

“…Higher reboxetine plasma concentrations and higher tilt angles in previous studies may account for this discrepancy. 9,27 We only studied men. However, NET inhibition has a gender-specific effect on the cardiovascular system.…”

mentioning

confidence: 99%

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

et al. 2006

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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....

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“…44,45 Another possible explanation is a gender difference in norepinephrine transporter function. 46 Norepinephrine transporter function strongly influences baroreflex distribution between tissues. 9,10 …”

Section: Perspectivementioning

confidence: 99%

Baroreflex Regulation of Heart Rate and Sympathetic Vasomotor Tone in Women and Men

et al. 2005

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Abstract-Gender has been reported to influence baroreflex heart rate regulation and baroreflex blood pressure buffering.We tested the hypothesis that gender influences baroreflex regulation of heart rate and sympathetic vasomotor tone. We recruited 32 normal-weight healthy subjects (17 men and 15 women). ECGs for heart rate, brachial and finger blood pressure, and muscle sympathetic nerve activity (MSNA) were measured. Baroreflex heart rate and MSNA regulation were assessed using incremental phenylephrine and nitroprusside infusions. Baseline blood pressure was similar in men and women. MSNA was 21Ϯ2.5 bursts/min in women and 19Ϯ2.8 bursts/min in men (NS). The gain of the baroreflex MSNA curves was similar in women and men (Ϫ1.9Ϯ0.2 bursts/min per mm Hg in men and Ϫ2.0Ϯ0.3 bursts/min per mm Hg in women). Baroreflex gain for heart rate regulation was 17Ϯ3.2 ms/mm Hg in women and 19Ϯ1.9 ms/mm Hg in men (NS). We conclude that baroreflex gains for heart rate and sympathetic MSNA regulation are similar in women and men. However, the probability for congruence between men and women in terms of the MSNA baroreflex curves was 0.06% for burst rate, 0.4% for burst incidence, and 0.01% for burst area. In women, the MSNA baroreflex curve may be shifted to slightly lower blood pressure such that at a given blood pressure MSNA tends to be lower. Key Words: autonomic nervous system Ⅲ baroreflex Ⅲ gender Ⅲ nervous system, sympathetic T he autonomic nervous system influences blood pressure and heart rate through adjustments in parasympathetic and sympathetic activity. Parasympathetic and sympathetic activities are tightly regulated through baroreflex mechanisms. Therefore, baroreflexes have a pivotal role in shortterm cardiovascular regulation and buffer-excessive blood pressure swings. 1,2 Among numerous other variables, baroreflexes are also involved in long-term blood pressure maintenance. [3][4][5] Even when overall blood pressure regulation is functioning properly, the balance between baroreflex regulation of heart rate and vascular tone may be perturbed. Imbalance between sympathetic activation of the heart and the vasculature has been described in heart failure patients, 6 postural tachycardia syndrome patients, 7,8 and in healthy subjects treated with norepinephrine transporter inhibitors. 9,10 Factors influencing baroreflex function may have an important bearing on human cardiovascular disease. Gender may be such a variable. Previous studies suggest that baroreflex blood pressure buffering is less effective in women than in men. 11 The balance between baroreflex-mediated heart rate and muscle sympathetic nerve activity (MSNA) changes may also be influenced by gender. The idea is supported by the observation that resting sympathetic vasomotor tone tends to be decreased in women, 12,13 whereas resting heart rate is increased. 14 -16 Furthermore, with standing, women showed an exaggerated heart rate and an attenuated sympathetic vasomotor response. 17 Moreover, previous studies suggested that baroreflex heart rate regulati...

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Phenotypical evidence for a gender difference in cardiac norepinephrine transporter function

Cited by 37 publications

References 32 publications

Norepinephrine transporter inhibition alters the hemodynamic response to hypergravitation

Norepinephrine transporter inhibition alters the hemodynamic response to hypergravitation

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

Baroreflex Regulation of Heart Rate and Sympathetic Vasomotor Tone in Women and Men

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