| Synergistic Effect of Norepinephrine Transporter Blockade and α-2 Antagonism on Blood Pressure in Autonomic Failure. | |
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MedLine Citation:
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PMID: 22311903 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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Luis E Okamoto; Cyndya Shibao; Alfredo Gamboa; Leena Choi; André Diedrich; Satish R Raj; Bonnie K Black; David Robertson; Italo Biaggioni |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-2-6 |
Journal Detail:
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Title: Hypertension Volume: - ISSN: 1524-4563 ISO Abbreviation: - Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-2-7 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7906255 Medline TA: Hypertension Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Vanderbilt Autonomic Dysfunction Center, Division of Clinical Pharmacology, and Departments of Medicine, Pharmacology, Neurology, Biomedical Engineering, and Biostatistics, Vanderbilt University School of Medicine, Nashville, TN. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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