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.
Similar content being viewed by others
References
Bannister R, Boylston AW, Davies IB, Mathias CJ, Sever PS, Sudera D (1981) Beta-receptor numbers and thermodynamics in denervation supersensitivity. J Physiol 319:369–377
Biaggioni I (2008) Clinical pharmacology of autonomic failure. In: Low PA (ed) Clinical autonomic disorders. Lippincott Williams & Wilkins, Philadelphia, PA, pp p307–p316
Braune S, Reinhardt M, Schnitzer R, Riedel A, Lucking CH (1999) Cardiac uptake of [123I] MIBG separates Parkinson’s disease from multiple system atrophy. Neurology 53:1020–1025
Davies B, Sudera D, Sagnella G, Marchesi-Saviotti E, Mathias C, Bannister R, Sever P (1982) Increased numbers of alpha receptors in sympathetic denervation supersensitivity in man. J Clin Invest 69:779–784
Diedrich A, Jordan J, Tank J, Shannon JR, Robertson RM, Luft FC, Robertson D, Biaggioni I (2003) The sympathetic nervous system in hypertension. Assessment by blood pressure variability and ganglionic blockade. J Hypertens 21:1677–1686
Goldberg MR, Hollister AS, Robertson D (1983) Influence of yohimbine on blood pressure, autonomic reflexes and plasma catecholamines in humans. Hypertension 5:772–778
Goldstein DS, Holmes C, Cannon RO, Eisenhofer G, Kopin IJ (1997) Sympathetic cardioneuropathy in dysautonomias. N Engl J Med 336:696–702
Goldstein DS, Polinsky RJ, Garty M, Robertson D, Brown RT, Biaggioni I, Stull R, Kopin IJ (1989) Patterns of plasma levels of catechols in neurogenic orthostatic hypotension. Ann Neurol 26:558–563
Grossman E, Rea RF, Hoffman A, Goldstein DS (1991) Yohimbine increases sympathetic nerve activity and norepinephrine spillover in normal volunteers. Am J Physiol 260:R142–R147
Heusser K, Tank J, Diedrich A, Engeli S, Klaua S, Kruger N, Strauss A, Stoffels G, Luft FC, Jordan J (2006) Influence of sibutramine treatment on sympathetic vasomotor tone in obese subjects. Clin Pharmacol Ther 79:500–508
Hui KKP, Conolly ME (1981) Increased numbers of beta receptors in orthostatic hypotension due to autonomic dysfunction. N Engl J Med 304:1473–1476
Jordan J, Lipp A, Tank J, Schroder C, Stoffels M, Franke G, Diedrich A, Arnold G, Goldstein DS, Sharma AM, Luft FC (2002) Catechol-o-methyltransferase and blood pressure in humans. Circulation 106:460–465
Jordan J, Shannon JR, Biaggioni I, Norman R, Black BK, Robertson D (1998) Contrasting actions of pressor agents in severe autonomic failure. AJM 105:116–124
Jordan J, Shannon JR, Black BK, Lance RH, Squillante MD, Costa F, Robertson D (1998) N(N)-nicotinic blockade as an acute human model of autonomic failure. Hypertension 31:1178–1184
Jordan J, Tank J, Shannon JR, Diedrich A, Lipp A, Schroder C, Arnold G, Sharma AM, Biaggioni I, Robertson D, Luft FC (2002) Baroreflex buffering and susceptibility to vasoactive drugs. Circulation 105:1459–1464
Kaufmann H, Oribe E, Miller M, Knott P, Wiltshire-Clement M, Yahr MD (1992) Hypotension-induced vasopressin release distinguishes between pure autonomic failure and multiple system atrophy with autonomic failure. Neurology 42:590–593
Kimber JR, Watson L, Mathias CJ (1997) Distinction of idiopathic Parkinson’s disease from multiple-system atrophy by stimulation of growth-hormone release with clonidine. Lancet 349:1877–1881
Onrot J, Goldberg MR, Biaggioni I, Wiley R, Hollister AS, Robertson D (1987) Oral yohimbine in human autonomic failure. Neurology 37:215–220
Ramirez CE, Okamoto LE, Arnold AC, Gamboa A, Diedrich A, Choi L, Raj SR, Robertson D, Biaggioni I, Shibao CA (2014) Efficacy of atomoxetine versus midodrine for the treatment of orthostatic hypotension in autonomic failure. Hypertension 64:1235–1240
Robertson D, Goldberg MR, Hollister AS, Wade D, Robertson RM (1983) Clonidine raises blood pressure in idiopathic orthostatic hypotension. AJM 74:193–199
Robertson D, Goldberg MR, Onrot J, Hollister AS, Thompson JC, Wiley R, Robertson RM (1986) Isolated failure of autonomic noradrenergic neurotransmission: evidence for impaired beta-hydroxylation of dopamine. N Engl J Med 314:1494–1497
Schroeder C, Birkenfeld AL, Mayer AF, Tank J, Diedrich A, Luft FC, Jordan J (2006) Norepinephrine transporter inhibition prevents tilt-induced pre-syncope. J Am Coll Cardiol 48:516–522
Schroeder C, Jordan J, Kaufmann H (2013) Management of neurogenic orthostatic hypotension in patients with autonomic failure. Drugs 73:1267–1279
Shannon JR, Jordan J, Diedrich A, Pohar B, Black BK, Robertson D, Biaggioni I (2000) Sympathetically mediated hypertension in autonomic failure. Circulation 101:2710–2715
Shibao C, Gamboa A, Abraham R, Raj SR, Diedrich A, Black B, Robertson D, Biaggioni I (2006) Clonidine for the treatment of supine hypertension and pressure natriuresis in autonomic failure. Hypertension 47:522–526
Shibao C, Okamoto L, Biaggioni I (2012) Pharmacotherapy of autonomic failure. Pharmacol Ther 134:279–286
Shibao C, Okamoto LE, Gamboa A, Yu C, Diedrich A, Raj SR, Robertson D, Biaggioni I (2010) Comparative efficacy of yohimbine against pyridostigmine for the treatment of orthostatic hypotension in autonomic failure. Hypertension 56:847–851
Shibao C, Raj SR, Gamboa A, Diedrich A, Choi L, Black BK, Robertson D, Biaggioni I (2007) Norepinephrine transporter blockade with atomoxetine induces hypertension in patients with impaired autonomic function. Hypertension 50:47–53
Singer W, Opfer-Gehrking TL, McPhee BR, Hilz MJ, Bharucha AE, Low PA (2003) Acetylcholinesterase inhibition: a novel approach in the treatment of neurogenic orthostatic hypotension. J Neurol Neurosurg Psychiatry 74:1294–1298
Tank J, Schroeder C, Diedrich A, Szczech E, Haertter S, Sharma AM, Luft FC, Jordan J (2003) Selective impairment in sympathetic vasomotor control with norepinephrine transporter inhibition. Circulation 107:2949–2954
Wang N, Gibbons CH, Lafo J, Freeman R (2013) α-Synuclein in cutaneous autonomic nerves. Neurology 81:1604–1610
Watanabe H, Saito Y, Terao S, Ando T, Kachi T, Mukai E, Aiba I, Abe Y, Tamakoshi A, Doyu M, Hirayama M, Sobue G (2002) Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients. Brain 125:1070–1083
Young TM, Asahina M, Watson L, Mathias CJ (2006) Hemodynamic effects of clonidine in two contrasting models of autonomic failure: multiple system atrophy and pure autonomic failure. Mov Disord Off J Mov Disord Soc 21:609–615
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jordan, J., Shibao, C. & Biaggioni, I. Multiple system atrophy: Using clinical pharmacology to reveal pathophysiology. Clin Auton Res 25, 53–59 (2015). https://doi.org/10.1007/s10286-015-0271-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10286-015-0271-4