Norepinephrine transporter function and tolerance to hypergravitational stress: A pilot study (original) (raw)
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Journal of applied physiology (Bethesda, Md. : 1985), 2002
Orthostatic intolerance is a debilitating syndrome characterized by tachycardia on assumption of upright posture. The norepinephrine (NE) transporter (NET) has been implicated in a genetic form of the disorder. We assessed the combined central and peripheral effects of pharmacological NET blockade on cardiovascular regulation and baroreflex sensitivity in rats. NE reuptake was blocked chronically in female Sprague-Dawley rats by the NET antagonist desipramine (DMI). Treated animals demonstrated an elevated supine heart rate, reduced tyramine responsiveness, and a reduced plasma ratio of the intraneuronal NE metabolite dihydroxyphenylglycol relative to NE, all of which are consistent with observations in human NET deficiency. Spectral analysis revealed a dramatic decrease in low-frequency spectral power after DMI that was consistent with decreased sympathetic outflow. Stimulation of the baroreflex with the vasodilator nitroprusside revealed an attenuated tachycardia in DMI-treated an...
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.
Norepinephrine and Epinephrine Responses during Orthostatic Intolerance in Healthy Elderly Men
The Japanese Journal of Physiology, 2000
When humans assume the upright posture (orthostasis), a significant volume of blood is displaced from the central circulation into the veins of the legs [1, 2]. The rapid reduction in central blood volume results in a fall in central venous pressure, stroke volume and cardiac output [1-3]. In an attempt to maintain arterial pressure (AP), the arterial baroreceptors, (located in the carotid sinus and aortic arch), reduce their firing rates, resulting in a reflex increase in heart rate (HR) and total peripheral resistance [4, 5]. Despite the falling cardiac output, AP is either maintained or elevated, due largely to the increase in sympathetically mediated vasoconstriction [6]. However, while some humans may tolerate the reduced cardiac output, others are unable to compensate for the falling atrial and ventricular filling pressures, resulting in orthostatic intolerance [2, 3]. Normotensive orthostatic stress evokes significant increases in muscle sympathetic nerve activity and norepinephrine (NE) concentrations and non-significant rises in epinephrine (EPI) concentrations [7-10]. However, in young individuals, orthostatic intolerance is associated with a sudden cessation of sympathetic outflow and the inhibition of vasoconstrictor impulses
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 ± ...
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
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...
Journal of Investigative Medicine, 2006
Background: Exposure to microgravity induces cardiovascular deconditioning, manifested by orthostatic intolerance (OI). We assessed the renal, cardioendocrine, and cardiovascular responses of women and men to simulated microgravity to examine the impact of gender on OI. Methods: Fifteen healthy female and 14 healthy male subjects were given a constant diet for 3 to 5 days, after which they underwent a tilt-stand test (pre-TST) and began 14 to 16 days of head-down tilt bed rest (HDTB), followed by a repeat tilt-stand test (post-TST). Female subjects began HDTB so that the post-TST was at the same time in their menstrual cycle as their pre-TST. Twenty-four-hour urine collections (daily), hormonal measurements, plethysmography, and cardiovascular system identification were performed. Results: The times to presyncope were significantly different for men and women before (p = .005) and after HDTB (p = .001), with all of the women but only 50% of the men experiencing presyncope during the pre-TST (p = .002) and all of the women but only 64% of the men experiencing presyncope during the post-TST. At baseline, the following differences between women and men were observed: women had higher serum aldosterone levels (p = .02), higher parasympathetic responsiveness (p = .01), lower sympathetic responsiveness (p = .05), and lower venous compliance (p = .05). Several parameters changed with HDTB in both men and women. In a double-blinded randomized trial, midodrine (5 mg orally) or placebo given to female subjects 1 hour before post-TST was ineffective in preventing OI. Conclusion: In conclusion, the frequency of OI is higher in women than in men and is not modified by midodrine at the dose used. This increased susceptibility is likely secondary to intrinsic basal differences in the activity of volume-mediated parasympathetic and adrenergic systems and in venous tone. Thus, approaches to reduce OI in women are likely to differ from those effective in men.
Frontiers in Endocrinology
AimsEssential hypertension (EHT) is characterized by cardiovascular hyperreactivity to stress but underlying mechanism are not fully understood. Here, we investigated the role of α-adrenergic receptors (α-AR) in the cardiovascular reactivity to a norepinephrine (NE)-stress reactivity-mimicking NE-infusion in essential hypertensive individuals (HT) as compared to normotensive individuals (NT).Methods24 male HT and 24 male NT participated in three experimental trials on three separate days with a 1-min infusion followed by a 15-min infusion. Trials varied in infusion-substances: placebo saline (Sal)-infusions (trial-1:Sal+Sal), NE-infusion without (trial-2:Sal+NE) or with non-selective α-AR blockade by phentolamine (PHE) (trial-3:PHE+NE). NE-infusion dosage (5µg/ml/min) and duration were chosen to mimic duration and physiological effects of NE-release in reaction to established stress induction protocols. We repeatedly measured systolic (SBP) and diastolic blood pressure (DBP) as well...
Journal of the Autonomic Nervous System, 1995
Circulatory metabolic and cardiovascular responses to 1-h-long infusions of norepinephrine (NE) (approx. 0.2 and 0.4 nmol/kg body weight per min) were measured on two separate occasions in six subjects. The infusions increased circulating NE concentrations 6-and 13-fold, respectively. Blood flow to adipose tissue, measured with the ~33Xe clearance technique, increased from a basal value of about 3 ml/100 g per min, to about twice this value at 60 min with both doses of NE. In contrast muscle blood flow was unaffected. The higher dose of NE produced significant increments at 60 rain in whole body oxygen consumption (approx. 9%), and circulating concentrations of glucose (approx. 18%), non-esterified fatty acids (approx. 200%) and glycerol (approx. 32%)which were greater than those observed with the low-dose infusion. Changes in blood pressure, pulse and CO2 exchange were observed within 5-10 min after the start of the infusion, whilst changes in adipose tissue blood flow were observed after 15-30 rain. It is concluded that in humans (i) a dose of NE as low as 0.2 nmol/kg per rain is sufficient to evoke both circulatory and metabolic responses; (ii) the pattern in the adipose tissue blood flow response to NE may help explain some of the conflicting reports about the haemodynamic effects of this hormone in adipose tissue; and (iii) blood flow and vascular resistance in different tissues may be affected in different ways by norepinephrine.