Norepinephrine Transporter Blockade With Atomoxetine Induces Hypertension in Patients With Impaired Autonomic Function

Abstract

Abstract-Atomoxetine, a selective norepinephrine transporter blocker, could increase blood pressure by elevating norepinephrine concentration in peripheral sympathetic neurons. This effect may be masked in healthy subjects by central sympatholytic mechanisms. To test this hypothesis we studied the pressor effect of 18 mg of atomoxetine (pediatric dose) in 21 patients with damage of the central (10 subjects) and peripheral (11 subjects) autonomic nervous system. Atomoxetine was administered in a randomized, crossover, placebo-controlled fashion, and blood pressure and heart rate were measured at baseline and for 60 minutes after drug intake. Atomoxetine acutely increased seated and standing systolic blood pressure in patients with central autonomic failure by 54Ϯ26 (meanϮstandard deviation; Pϭ0.004) and 45Ϯ23 mm Hg (Pϭ0.016), respectively, as compared with placebo. At the end of the observation period the mean seated systolic blood pressure in the atomoxetine group was in the hypertensive range (149Ϯ26, range 113 to 209 mm Hg). However, in patients with peripheral autonomic failure, atomoxetine did not elicit a pressor response; seated and standing systolic blood pressure increased by 4Ϯ18 mm Hg (Pϭ0.695) and 0.6Ϯ8 mm Hg (Pϭ0.546) with atomoxetine as compared with placebo. In conclusion, atomoxetine induces a dramatic increase in blood pressure in patients with central autonomic failure even at very low doses. These findings suggest that a functional central sympatholytic pathway is essential to avoid hypertension in patients treated with this drug. Caution should be exercised when this medication is used in patients with milder form of autonomic impairment. Key Words: atomoxetine Ⅲ norepinephrine transporter protein Ⅲ hypertension Ⅲ autonomic nervous system diseases Ⅲ multiple system atrophy

Norepinephrine transporter function and human cardiovascular disease

“…In contrast, in patients with low sympathetic activity, sympathetic activity cannot be decreased further, such that the peripheral NET inhibitor action prevails. In accordance with this concept, selective NET blockade with atomoxetine induced a substantial increase in blood pressure in patients with central autonomic failure (119). In this condition, peripheral adrenergic neurons are disconnected from brain stem input (117) such that the peripheral stimulatory effect of NET inhibition is unmasked.…”

Pure Autonomic Failure

“…It is FDA-approved for the treatment of attention deficit hyperactivity disorder [67]. In neurogenic orthostatic hypotension, atomoxetine has been shown to be most helpful in increasing orthostatic blood pressure in a central autonomic disorder such as MSA, whereas the effect on a peripheral autonomic disorder such as PAF is not significant [68]. The role of atomoxetine is, therefore, in treating orthostatic hypotension refractory to more common medications in a central autonomic disorder [64].…”

Research highlights from the literature

“…Another study by the same group [3] gives new insight into norepinephrine transporter physiology. The norepinephrine transporter reclaims approximately 80-90% of norepinephrine released from adrenergic neurons.…”

“…Perhaps, the central sympatholytic effect prevents a pressor response in patients who are treated with medications inhibiting the norepinephrine transporter. Shibao et al [3] reasoned that norepinephrine transporter inhibition in patients with different lesions of the autonomic nervous system may provide more insight.…”