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NEUROHUMORAL CONTROL OF CIRCULATION AND HYPERTENSION

Phenotypical evidence for a gender difference in cardiac norepinephrine transporter function

¹Medical Faculty of the Charité, Franz Volhard Clinical Research Center, Helios Klinikum-Berlin and Max Delbrück Center for Molecular Medicine, 13125 Berlin; ²Neurochemical Laboratory, University of Mainz, 55101 Mainz, Germany; and ³Autonomic Dysfunction Service, Vanderbilt University, Nashville, Tennessee 37221

Submitted 2 December 2003 ; accepted in final form 9 January 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 beats/min 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 sensitive 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.

autonomic nervous system

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