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1 Franz Volhard Clinical Research Center, Medical Faculty of the Charite, Berlin, Germany
2 Neurochemical Laboratory, University of Mainz, Mainz, Germany
3 Autonomic Dysfunction Service, Vanderbilt University, Nashville, TN, USA
* To whom correspondence should be addressed. E-mail: jordan{at}fvk.charite-buch.de.
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 8 men and in 8 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 increase cardiac output. The orthostatic heart rate increase during NET inhibition was greater in men than women (56±5 bpm in men, 42±4 bpm in women, p<0.001). In contrast, NET inhibition resulted in a similar suppression in the cold pressor and handgrip response, low frequency blood pressure oscillations, and venous norepinephrine in the supine position. Men and women were similarly hypersensitive to the lipolytic effect of isoproterenol and tyramine. We conclude that NET inhibition results in more pronounced changes in cardiac regulation in men than women. Our observations suggest that the NET contribution to cardiac norepinephrine turnover may be decreased in women. The gender difference in NET function may not be expressed in tissues that are less NET-dependent than the heart.
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