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‘A woman's gentle heart, but not acquainted with shifting change…’William Shakespeare, Sonnet 20
Elevated sympathetic activity, expressed as an increased release of cardioactive neurotransmitters such as norepinephrine (NE) and epinephrine, provides inotropic support to the heart and peripheral vasoconstriction, adapting cardiac performance to increased workload. Over time, however, the persistent and growing sympathetic efferent firing rate contributes to the adversities of cardiac remodelling, transitioning from compensation to heart failure (HF). Combined with defective neuronal catecholamine reuptake,1 this neurohormonal overdrive favours accumulation of large amounts of NE (and other monoamines) in the cardiac sympathetic neuroeffector junctions. Neuronal membrane transporters, such as NE transporter (NET), that display high affinity for NE recapture these mediators into the sympathetic terminals. In control subjects, the NET removes more than 90% of NE from the junction, while the remainder is cleared via extraneuronal carriers and circulatory dissipation.2 NET centrality is attested by the fact that animal1 or human3 HF is characterised by a loss in its function, leading to decreased NE stores,2 4 almost a doubling of NE extraneuronal clearance, and contractile impairment. Furthermore, NET−/− mice display excessive tachycardia and raised blood pressure with wakefulness and physical activity.5
Gender often imparts divergent autonomic nervous modulation to heart function. Women have greater parasympathetic tone and less sympathetic control of heart rate (HR), but with higher HR at rest. Men have increased catecholamine response and higher systolic and mean arterial pressure in response to exercise.6 After strenuous exercise, male triathletes have attenuated chronotropic/inotropic response to β-adrenergic stimulation compared with female triathletes,7 suggesting a greater reduction in cardiac β-receptor responsiveness in males. As a key carrier associated with sympathetic activity, NET is not immune from gender-sensitive issues. Testing the effects of NET inhibition with reboxetine in 12 healthy men and …