title: Multiple system atrophy: using clinical pharmacology to reveal pathophysiology.
abstract: Despite similarities in their clinical presentation, patients with multiple system atrophy (MSA) have residual sympathetic tone and intact post-ganglionic noradrenergic fibers, whereas patients with pure autonomic failure (PAF) and Parkinson disease have efferent post-ganglionic autonomic denervation. These differences are apparent biochemically, as well as in neurophysiological testing, with near normal plasma norephrine in MSA but very low levels in PAF. These differences are also reflected in the response patients have to drugs that interact with the autonomic nervous system. For example, the ganglionic blocker trimethaphan reduces residual sympathetic tone and lowers blood pressure in MSA, but less so in PAF. Conversely, the α2-antagonist yohimbine produces a greater increase in blood pressure in MSA compared to PAF, although significant overlap exists. In normal subjects, the norepinephrine reuptake (NET) inhibitor atomoxetine has little effect on blood pressure because the peripheral effects of NET inhibition that result in noradrenergic vasoconstriction are counteracted by the increase in brain norepinephrine, which reduces sympathetic outflow (a clonidine-like effect). In patients with autonomic failure and intact peripheral noradrenergic fibers, only the peripheral vasoconstriction is apparent. This translates to a significant pressor effect of atomoxetine in MSA, but not in PAF patients. Thus, pharmacological probes can be used to understand the pathophysiology of the different forms of autonomic failure, assist in the diagnosis, and aid in the management of orthostatic hypotension.
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany, Jordan.Jens@mh-hannover.de.
authors.forename: Jens
authors.initials: J
authors.lastname: Jordan
authors.forename: Cyndya
authors.initials: C
authors.lastname: Shibao
authors.forename: Italo
authors.initials: I
authors.lastname: Biaggioni
mesh_terms: D000069445:Atomoxetine Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use; D001341:Autonomic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D003000:Clonidine / Q000494:pharmacology / Q000627:therapeutic use; D003937:Diagnosis, Differential; D004358:Drug Therapy / Q000379:methods* / Q000639:trends*; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology / Q000627:therapeutic use; D019578:Multiple System Atrophy / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology*; D010300:Parkinson Disease / Q000175:diagnosis / Q000188:drug therapy / Q000503:physiopathology; D054970:Pure Autonomic Failure / Q000175:diagnosis / Q000188:drug therapy / Q000503:physiopathology; D011729:Pyridostigmine Bromide / Q000494:pharmacology / Q000627:therapeutic use; D014294:Trimethaphan / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D026121:Indole Alkaloids; C000602209:yohimbane; D000069445:Atomoxetine Hydrochloride; D014294:Trimethaphan; D011729:Pyridostigmine Bromide; D003000:Clonidine