- Okamoto LE, Shibao C, Gamboa A, Choi L, Diedrich A, Raj SR, Black BK, Robertson D, Biaggioni I. Synergistic effect of norepinephrine transporter blockade and α-2 antagonism on blood pressure in autonomic failure. Hypertension. 2012 Mar;59(3). 650-6. PMID: 22311903 [PubMed]. PMCID: PMC3312003. NIHMSID: NIHMS356219.
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 atomoxetine significantly increased seated systolic blood pressure or orthostatic tolerance compared with placebo. The combination, however, significantly increased seated systolic blood pressure and orthostatic tolerance (P