Autonomic control after blockade of the norepinephrine transporter: a model of orthostatic intolerance (original) (raw)
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Selective Norepinephrine Reuptake Inhibition as a Human Model of Orthostatic Intolerance
Circulation, 2002
Background-Observations in patients with functional mutations of the norepinephrine transporter (NET) gene suggest that impaired norepinephrine uptake may contribute to idiopathic orthostatic intolerance. Methods and Results-We studied the effect of the selective NET blocker reboxetine and placebo in a randomized, double-blind, crossover fashion on cardiovascular responses to cold pressor testing, handgrip testing, and a graded head-up tilt test (HUT) in 18 healthy subjects. In a subset, we determined isoproterenol and phenylephrine sensitivities. Subjects ingested 8 mg reboxetine or placebo 12 hours and 1 hour before testing. In the supine position, heart rate was 65Ϯ2 bpm with placebo and 71Ϯ3 bpm with reboxetine. At 75°HUT, heart rate was 84Ϯ3 and 119Ϯ4 bpm with placebo and with reboxetine (PϽ0.0001). Mean arterial pressure was 85Ϯ2 with placebo and 91Ϯ2 mm Hg with reboxetine while supine (PϽ0.01) and 88Ϯ2 mm Hg and 90Ϯ3 mm Hg at 75°HUT. Blood pressure responses to cold pressor and handgrip testing were attenuated with reboxetine. Reboxetine increased the sensitivity to the chronotropic effect of isoproterenol and the pressor effect of phenylephrine. Vasovagal reactions occurred in 9 subjects on placebo and in 1 subject on reboxetine. Conclusions-Selective NET blockade creates a phenotype that resembles idiopathic orthostatic intolerance. This observation supports the hypothesis that disordered norepinephrine uptake mechanisms can contribute to human cardiovascular disease. Our study also suggests that NET inhibition might be useful in preventing vasovagal reactions.
Selective Impairment in Sympathetic Vasomotor Control With Norepinephrine Transporter Inhibition
Circulation, 2003
attenuates the response to sympathetic stimuli. The phenomenon may be a result of impaired regulation of sympathetic vasomotor tone. Methods and Results-We studied the effects of the selective NET blocker reboxetine and placebo on baroreflex control of heart rate (HR) and sympathetic traffic in a randomized, double-blind, crossover manner in healthy subjects. Subjects ingested 8 mg reboxetine or placebo 12 hours and 1 hour before testing. ECGs were measured for HR, brachial and finger blood pressure (BP), and muscle sympathetic nerve activity (MSNA). Sympathetic and parasympathetic baroreflex slopes were determined by use of incremental phenylephrine and nitroprusside infusions. The dose to reach BP changes of 12.5 mm Hg was significantly lower during NET inhibition (0.25 versus 0.64 g · kg Ϫ1 · min Ϫ1 phenylephrine and 0.40 versus 1.10 g · kg Ϫ1 · min Ϫ1 nitroprusside, PϽ0.01). Baroreflex control of HR was similar (16 ms/mm Hg with placebo versus 14 ms/mm Hg with reboxetine) but reset to higher BP values. MSNA and sympathetically mediated low-frequency BP oscillations were profoundly reduced at baseline and failed to increase sufficiently during nitroprusside infusion. Reboxetine attenuated BP and MSNA responses to cold pressor testing.
Expert Reviews in Molecular Medicine, 2001
The norepinephrine transporter (NET) has a major role in terminating the neurochemical signal established by the neurotransmitter norepinephrine (NE) in the synaptic cleft. The NET is also the initial site of action for therapeutic antidepressants, and drugs such as cocaine and amphetamines. Polymorphisms in the NET gene have been identified, and associations with several disorders such as depression have been proposed but not established. However, evidence of a direct association between a genetic mutation of the NET and an autonomic clinical syndrome has recently emerged. A patient and her identical twin were evaluated for typical symptoms of orthostatic intolerance (OI), a disorder mainly characterised by elevated heart rate on standing, and both were found to have clinical and laboratory signs of abnormal uptake of NE. Sequence analysis of the patients' NET gene identified a mutation that resulted in more than 98% loss of function as compared with the wild-type gene. This ar...
Phenotypical evidence for a gender difference in cardiac norepinephrine transporter function
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2004
Norepinephrine transporter (NET) function has a central role in the regulation of synaptic norepinephrine concentrations. Clinical observations in orthostatic intolerance patients suggest a gender difference in NET function. We compared the cardiovascular response to selective NET inhibition with reboxetine between 12 healthy men and 12 age-matched women. Finger blood pressure, brachial blood pressure, and heart rate were measured. The subjects underwent cardiovascular autonomic reflex testing and a graded head-up tilt test. In a separate study, we applied incremental concentrations of tyramine and isoproterenol through subcutaneous microdialysis catheters in eight men and in eight women. NET inhibition elicited a threefold greater increase in supine blood pressure in men than women ( P < 0.05). The pressor response was driven by an increased cardiac output. The orthostatic heart rate increase during NET inhibition was greater in men than women (56 ± 5 beats/min in men, 42 ± 4 be...
Norepinephrine Transporter Function and Autonomic Control of Metabolism
The Journal of Clinical Endocrinology & Metabolism, 2002
Genetic variability, numerous medications, and some illicit drugs influence norepinephrine transporter (NET) function; however, the metabolic consequences of NET inhibition are poorly understood. We performed a randomized, doubleblind, cross-over trial in 15 healthy subjects who ingested 8 mg of the selective NET inhibitor reboxetine or placebo. Energy expenditure and substrate oxidation rates were determined by indirect calorimetry before and during iv infusion of 0.25, 0.5, 1, and 2 g isoproterenol/min. Adipose tissue metabolism was studied by microdialysis before and during local isoproterenol perfusion. At rest, energy expenditure and substrate oxidation rates did not differ between reboxetine and placebo treatment. At 1 g/min isoproterenol, energy expenditure was significantly increased in men (؉15%) and women (؉20%) with both reboxetine and placebo treatment. However, carbohydrate oxidation rate was significantly higher with reboxetine compared with placebo. Baseline and isoproterenol-stimulated adipose tissue blood flow was about 2-fold higher with reboxetine vs. placebo. Furthermore, glucose supply and metabolism was significantly increased and lipid mobilization much more stimulated in adipose tissue under reboxetine when compared with placebo at all isoproterenol concentrations used. We conclude that acute NET inhibition increases adipose tissue glucose uptake and metabolism. While lipid mobilization is increased, overall lipid oxidation is decreased during -adrenergic stimulation. This effect cannot be explained by increased systemic or adipose tissue norepinephrine concentrations. Instead, NET inhibition may sensitize adipose tissue to -adrenergic stimulation.
2010
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 (261 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
Feedback effects of circulating norepinephrine on sympathetic outflow in healthy subjects
American Journal of Physiology-Heart and Circulatory Physiology, 2004
The amplitude of low-frequency (LF) oscillations of heart rate (HR) usually reflects the magnitude of sympathetic activity, but during some conditions, e.g., physical exercise, high sympathetic activity results in a paradoxical decrease of LF oscillations of HR. We tested the hypothesis that this phenomenon may result from a feedback inhibition of sympathetic outflow caused by circulating norepinephrine (NE). A physiological dose of NE (100 ng·kg−1·min−1) was infused into eight healthy subjects, and infusion was continued after α-adrenergic blockade [with phentolamine (Phe)]. Muscle sympathetic nervous activity (MSNA) from the peroneal nerve, LF (0.04–0.15 Hz) and high frequency (HF; 0.15–0.40 Hz) spectral components of HR variability, and systolic blood pressure variability were analyzed at baseline, during NE infusion, and during NE infusion after Phe administration. The NE infusion increased the mean blood pressure and decreased the average HR ( P < 0.01 for both). MSNA (10 ± ...
Effects of norepinephrine reuptake inhibition on postural tachycardia syndrome
Journal of the American Heart Association, 2013
Postural tachycardia syndrome (POTS) is a disorder of chronic orthostatic intolerance accompanied by excessive orthostatic tachycardia. Patients with POTS commonly have comorbid conditions such as attention deficit hyperactivity disorder, depression, or fibromyalgia that are treated with medications that inhibit the norepinephrine reuptake transporter (NRI). NRI medications can increase sympathetic nervous system tone, which may increase heart rate (HR) and worsen symptoms in POTS patients. We sought to determine whether NRI with atomoxetine increases standing tachycardia or worsens the symptom burden in POTS patients. Patients with POTS (n = 27) underwent an acute drug trial of atomoxetine 40 mg and placebo on separate mornings in a randomized, crossover design. Blood pressure (BP), HR, and symptoms were assessed while seated and after standing prior to and hourly for 4 hours following study drug administration. Atomoxetine significantly increased standing HR compared with placebo ...
Hypertension, 2012
Patients with autonomic failure have disabling orthostatic hypotension because of impaired sympathetic activity. Norepinephrine transporter blockade with atomoxetine raises blood pressure in autonomic failure by increasing synaptic norepinephrine concentrations in postganglionic sympathetic neurons. This effect requires tonic release of norepinephrine, which is decreased in patients with low sympathetic tone. We hypothesized that increasing residual sympathetic outflow with the α-2 antagonist yohimbine would potentiate the pressor effect of norepinephrine transporter blockade with atomoxetine and improve orthostatic tolerance in peripheral autonomic failure. Seventeen patients received a single oral dose of either placebo, yohimbine 5.4 mg or atomoxetine 18.0 mg, and the combination yohimbine and atomoxetine in a single blind, crossover study. Blood pressure was assessed while patients were seated and standing for ≤10 minutes before and 1 hour postdrug. Neither yohimbine nor atomoxe...