Synergistic effect of norepinephrine transporter blockade and α-2 antagonism on blood pressure in autonomic failure

Abstract

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<0.001 and P=0.016, respectively) in a synergistic manner. The maximal increase in seated systolic blood pressure seen with the combination was 31±33 mm Hg at 60 minutes postdrug. Only the combination showed a significant improvement in orthostatic symptoms. In conclusion, the combination of yohimbine and atomoxetine had a synergistic effect on blood pressure and orthostatic tolerance in peripheral autonomic failure, which may be explained by an increased release of norepinephrine in peripheral sympathetic neurons by α-2 antagonism combined with a reduced norepinephrine clearance by norepinephrine transporter blockade. Safety studies are required to address the clinical usefulness of this pharmacological approach.

Trial registration: ClinicalTrials.gov NCT00223691.

Figure 1

Changes from baseline in seated SBP (ΔSBP) during 1 hour after drug administration (A), and at 60 minutes post-drug (B). The combination significantly increased SBP at 60 minutes compared to each drug alone. There was no significant difference between placebo vs. atomoxetine, and placebo vs. yohimbine. Values are expressed as mean±SEM. The P values were generated by comparing the mean of log seated SBP 60 minutes after drug administration using random effects model. * Comparisons between placebo vs. atomoxetine and placebo vs. yohimbine (P>0.05 by random effects model).

Figure 2

Changes from baseline in seated SBP (ΔSBP) at 60 minutes post-drug. The increase in SBP with the combination was significantly greater than the sum of the pressor effects produced by the two drugs individually. Values are expressed as mean±SEM. The P value was generated by comparing the mean of log seated SBP 60 minutes after the combination with the sum effects of those during the two drugs alone using random effects model.

Figure 3

Changes from baseline in areas under the curve of standing SBP (Δ AUC_SBP) at 60 minutes post-drug. The combination significantly increased AUC_SBP at 60 minutes compared to each drug alone. There was no significant difference between placebo vs. atomoxetine, and placebo vs. yohimbine. Values are expressed as mean±SEM. The P values were generated by comparing the mean of log AUC_SBP 60 minutes after drug administration using random effects model. * Comparisons between placebo vs. atomoxetine and placebo vs. yohimbine (P>0.05 by random effects model).

Figure 4

Orthostatic symptom score at baseline (pre) and after 1 hour of drug administration (post). The total score ranges from 0-60, with lower scores reflecting lower symptom burden. Values are expressed as mean±SEM. The P values were generated by Wilcoxon signed-rank test.