Journal of Neurology, Neurosurgery, and Psychiatry 1991;54:807-812

Central and peripheral effects of arecoline inpatients with autonomic failure

Ronald J Polinsky, Robert T Brown, M Teresa Curras, Susan M Baser,Celeste E Baucom, Douglas R Hooper, AnnM Marini

AbstractIncreased plasma adrenalin (A) levelsfollowing arecoline in normal subjectsand patients with multiple system atro-phy (MSA) may result from nicotinicadrenal stimulation. Lack of this re-sponse in patients with pure autonomicfailure (PAF) is consistent with peri-pheral sympathetic dysfunction. Themechanisms underlying diminishedplasma corticotropin (ACTH) responsesto arecoline may differ in patients withautonomic failure. Hypothalamic, cho-linergic degeneration could prevent theresponse in MSA whereas patients withPAF do not manifest the normalincrease in A which may be requiredto elicit an ACTH response. Theappearance and exacerbation of tremor,vertigo, and pathological affect in theMSA group suggest that some centralcholinergic receptors remain functional.

ClinicalNeuropharmacologySection, ClinicalNeuroscience Branch,National Institute ofNeurologicalDisorders and Stroke,Bethesda, Maryland,USAR J PolinskyR T BrownM T CurrasS M BaserC E BaucomD R HooperA M Marini

Correspondence to:Dr Polinsky, Building 10,Room 5N262, NationalInstitutes of Health, 9000Rockville Pike, Bethesda,Maryland 20892, USAReceived 9 August 1988and in final revised form7 January 1991.Accepted 11 January 1991

Central and peripheral lesions of the auto-nomic nervous system result in failure toregulate vegetative functions in the body. Thebiochemical and pharmacological consequen-ces of autonomic failure differ according to thenature and site of the lesion(s).' Two clinicalsyndromes have been intensively investigated.Pure autonomic failure (PAF) occurs in theabsence of peripheral neuropathy or signs ofany central neurological disturbance.2 Lowplasma noradrenalin (NA) levels,3 noradre-nergic receptor supersensitivity,4 reducedneuronal NA stores,4 and diminished neuronaluptake of NA5 reflect the primary involvementof postganglionic sympathetic neurons inPAF. Multiple system atrophy (MSA) is a

degenerative neurological disorder character-ised clinically by autonomic failure, Parkin-sonism, cerebellar dysfunction and pyramidaltract involvement.6 Indices of peripheral sym-pathetic neuronal function are normal inMSA.' Several central nervous systemneurotransmitter systems, however, are affec-ted by the degenerative process.7"9Hypoglycaemia is an effective stimulus for

releasing an array of neurotransmitters, hor-mones, and peptides. Corticotropin (ACTH)and fl-endorphin levels in plasma do notincrease normally during hypoglycaemia inpatients with MSA."' Since release of ACTHis stimulated by centrally active cholinergicagonists such as arecoline," the diminishedACTH response to hypoglycaemia in MSAmay reflect a hypothalamic cholinergic defect.

Alternatively, the mechanisms may beseparate. In this study we measured cate-cholamine and ACTH responses to arecolineafter glycopyrrolate administration in patientswith autonomic failure and normal subjects toassess peripheral and central effects of cholin-ergic stimulation.

Materials and methodsSubjects. All subjects were admitted to theClinical Center, National Institutes of Health(NIH), for the study. Medical history,neurological examination, electrocardiogramand blood studies were performed before theinfusion test. A clinical diagnosis of MSA wasmade as described previously.4 Ten controlsubjects (seven men, three women) volun-teered through the NIH normal volunteerprogramme. The mean (SEM) age for controlsubjects [58-5 (4) years] did not differ from the15 patients (eight men, seven women) withMSA [57-9 (1-8) years] or those (two men,four women) with PAF [52 3 (1 8) years].Medications were discontinued for at least oneweek before the study. There were no dietaryrestrictions. All subjects gave informed con-sent according to NIH guidelines.

Arecoline Test. All studies were performedin the moming following an overnight fast.An intravenous needle was inserted into a veinof one arm for sampling blood; a catheterplaced in a vein of the opposite arm was keptpatent with an infusion of normal saline.Subjects remained in the supine positionthroughout the test which was performedas previously described." Glycopyrrolate(0-2 mg) was given intravenously to blockperipheral muscarinic effects. After a 20minute baseline period, subjects receivedarecoline hydrobromide (3 mg of base)intravenously over 10 minutes. Blood samplesfor measurement of catecholamines andACTH were drawn just before arecolineadministration, and at 10 minute intervals forthe next hour. All samples were kept on iceand centrifuged immediately following thetest. The plasma was removed and kept frozenat -700C until the time of assay. Blood pres-sure was measured every 10 minutes with aDinamapX Vital Signs Monitor (Critikon,Tampa, FL).

Catecholamine Assay. Blood was drawn intotubes containing heparin. The catecholamineswere partially purified and concentrated fromplasma using alumina adsorption. Plasmaadrenalin (A) and noradrenalin (NA) levelswere determined using high-performance

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liquid chromatography (HPLC) with electro-chemical detection. After thawing and cen-

trifugation, 1 ml of plasma was added to400 pl ofTris-EDTA buffer, pH 8&6; 0 5 ng ofdihydroxybenzylamine was added as an inter-nal standard. Approximately 10 mg of acid-washed alumina was added; the tubes were

centrifuged and the supernatants removedfollowing 20 minutes of mixing. After thealumina was twice washed with water, cate-cholamines were eluted by vortexing thealumina with 200 pui of 0-2 N acetic acid.

Catecholamines were separated in the eluateusing a Microbondapak C18 reverse-phasecolumn (Waters Associates, Milford, MA).The mobile phase consisted of sodium acetate,EDTA, heptanesulfonic acid, and acetonitrile;a flow rate of 1 ml/min was employed. Poten-tials of 0 3, 0-3, and - 0 3 V were appliedrespectively to the guard cell and two flow-through glassy carbon electrodes connected inseries. The coulometric detector was set at a

gain of 8000. Plasma NA and A levels were

calculated from peak height after correctionfor recovery (approximately 70%). Approxi-mately 15 pg/ml of plasma catecholaminescould be detected easily with this method.Interassay variation was less than 12%.Measurement of ACTH. Blood (2 ml) was

collected into chilled tubes containing potas-sium EDTA (10-5 mg) and aprotinin(1000 KIU). The plasma was removed aftercentrifugation and frozen at - 70°C untilperformance of the ACTH assay with a

radioimmunoassay kit (Incstar, Stillwater,MN). Samples and standards were firstthawed on crushed ice; then 200 ,u of eachwas incubated in polystyrene tubes for 24hours at 4°C with 200 pi of rabbit anti-ACTHserum. After addition of 100 ,ul of '25I-ACTH,samples were incubated an additional 24hours at 4°C. Goat anti-rabbit precipitatingcomplex (500 jp) was then added, and incuba-tion for 20 minutes at 22°C was performed.Tubes were finally centrifuged using 760 g at4°C, the supernatant was aspirated and theprecipitates were counted in a gamma coun-

ter. Standards were assayed in triplicate, andsamples in duplicate. This procedure yieldeda lower limit of detection (95% B/BO) of7-3 pg/ml with an interassay variation ofapproximately 13%.Data Analysis. The plasma ACTH and

catecholamine responses were calculated foreach subject by subtracting the baseline fromthe levels at each time point. Mean bloodpressure (MBP) was calculated as diastolic BPplus one-third of pulse pressure. Comparisonbetween control subjects and patients with

E 240- /

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Arecoline

Figure I Plasma adrenalin and ACTH responses toarecoline administration in normal subjects.

autonomic failure was performed by analysisof variance with appropriate follow up tests.The relationship between ACTH and cate-cholamines was assessed by linear regression.A 2 x 2 Chi squared test of homogeneity was

used to compare the frequency of occurrence

of various signs and symptoms.

ResultsBaseline ACTH levels did not differ among

the three groups of subjects. As shownpreviously,34 the supine plasma NA level was

significantly (p < 0-05) lower in patients withPAF than in normal subjeCts or MSA patients.Although glycopyrrolate did not affect baselineplasma levels of ACTH or NA, the drug didsignificantly (p < 0 01) increase plasmaA in all

Table 1 The effect ofglycopyrrolate on plasma catecholamines and ACTH in normal subjects and patients withautonomic failure. Mean (SEM)

Noradrenaline (pg/ml) Adrenalin (pg/ml) ACTH (pg/ml)

Diagnosis Baseline Glycopyrrolate Baseline Glycopyrrolate Baseline Glycopyrrolate

CON 225-3 (21-1) 3313 (53 3) 20 126-9 (15-3)t 19 9 (4 1) 21 5 (4 3)MSA 305-1 (92 8) 267-8 (55 3) 20 117-7 (31-8)$ 17 1 (2-6) 19 8 (2 0)PAF 72-4 (20.4)* 200 1 (70-0) 20 66-6 (5 0)f 13-1 (2-1) 16 2 (3 0)

*p < 0-05, compared to control subjects; tP < 0-005, compared to baseline; lp < 0-01, compared to baseline.

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Central and peripheral effects of arecoline in patients with autonomicfailure

Figure 2 Plasma ACTHresponses to arecoline innormal subjects andpatients with autonomicfailure.

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groups (table 1). We have previously observedan increase in plasma A levels beginning 10minutes after glycopyrrolate administration;the increment in plasma A levels remainedconstant and was sustained for approximately150 minutes after which the levels return tobaseline (unpublished observations). In nor-mal subjects, arecoline administration wasfollowed by increases in plasma A and ACTHwhich were maximal at 10 and 20 minutesrespectively (fig 1). The plasma ACTH re-sponse was virtually absent in MSA; a slightincrease was observed in patients with PAF.However, the maximal increment in plasma

Figure 3 Mean (SEM)baseline and maximumplasma catecholaminelevels following arecolineadministration in normalsubjects and patients withMSA and PAF.

CD

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EQ0

E

0CON MSA PAF

(n = 10) (n = 1 5) (n = 6)

Table 2 Cardiovascular responses to arecoline in normalsubjects and patients with autonomic failure. Mean(SEM)

MBP increment HR incrementDiagnosis (mm Hg) (bpm)

CON 11-2 (3 0)* 28-9 (3-9)tMSA 11 3 (2 5)t 8-4 (1-7)tPAF 3-5 (8 5) 9 8 (6 2)

*p < 0005;tp < 0001.

ACTH was significantly (p < 0 01) lower thannormal in patients with MSA and PAF (fig 2).The magnitude of the plasma ACTH responsein MSA was not related to previous anticholi-nergic therapy.Plasma A levels were significantly (p < 0 02)

higher following arecoline only in normalsubjects and patients with MSA (fig 3). None ofthe groups manifested an increase in plasmaNA. There was a significant correlation(r = 0-61, p < 0 02) between the incrementsin plasma ACTH and A in response toarecoline in normal subjects and patients withPAF.MBP increased by 11 2 (3) and 11 3

(2 5) mm Hg in normal subjects and patientswith MSA; in PAF, there was not a significantchange in blood pressure (table 2). Con-comitant with the pressor response in normalsubjects was a significant elevation in heart rate.A smaller, significant increase in heart rateoccurred in the MSA patients. Although therewas a similar increase in PAF, the change wasnot statistically significant.Mild vertigo, nystagmus and nausea

occurred in several subjects in each group.Onset or exacerbation of tremor was observedin seven MSA patients, but in none of thecontrols or patients with PAF. Several subjectsin each group expressed a subjective alterationin mood but denied any emotional concomitantof their experience. In some patients withMSA, episodes of extreme, uncontrollablelaughing or crying developed. No similar sym-ptoms appeared during the baseline period orthe last 40 minutes of the test. Only tremor andpathological affective changes were significantly(p < 0-05) more frequent in patients withMSA. All symptoms resolved in all subjectswithin 10 minutes following cessation of drugadministration.

DiscussionThe ACTH response to cholinergic stimula-tion is impaired in patients with autonomicfailure. However, the mechanism underlyingthis neuroendocrine abnormality may differ inpatients with MSA and PAF. Release ofanterior pituitary hormones is primarily con-trolled by hypothalamic releasing factors.'2Several neurotransmitter systems alsomodulate pituitary responses to physiologicaland pharmacological stimuli. The cholinergicand noradrenergic systems are particularlyimportant with respect to ACTH release.Acetylcholine stimulates the release of cor-ticotropin releasing factor (CRF) from hypo-thalamic synaptosomes.'3 Although arecoline

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has muscarinic'4 and nicotinic"516 effects, thepresence of nicotinic receptors in the hypo-thalamus'7 suggests that a nicotinic mechanismmay be responsible for ACTH release.Nicotine administered into the third ventricleincreases ACTH. 8 Blockade ofthis effect with acentral but not peripheral nicotinic antagon-ist,'8 and the lack of CRF release followingadministration of bethanecol,'9 a pure mus-carinic agonist, add further support for a cen-tral nicotinic cholinergic pathway mediatingACTH release.Catecholamine effects on ACTH are more

complex. Although catecholamines canenhance the release ofACTH by CRF,20acetyl-choline-stimulated CRF activity is reduced byNA. Locus ceruleus activation also decreasesCRF release.2' In contrast, peripheral adminis-tration of isoproterenol causes ACTH levels torise, even in rats whose pituitary has beenseparated from the brain by stalk sectioning orlesioning of the median eminence.22 Release ofACTH during insulin-induced hypoglycaemiacan be blocked by propranolol.23 Thus itappears that adrenal medullary release of Amay be requ.red to elicit the ACTH response.However, normal ACTH and j3-endorphinresponses to hypoglycaemia occur in patientswith PAF who have adrenergic insufficiency.'"

In this studyACTH andNA did not increasenormally following arecoline administration inpatients with MSA and PAF, but plasma Aresponses differed in these disorders. Althoughplasma A levels increased following gly-copyrrolate administration to patients withPAF, the increment was less than in normalsubjects or patients with MSA. It is likely thatperipheral involvement in PAF is not com-plete, as indicated by the preservation of pres-sor and NA responses to tyramine.' Increasedplasma A levels to arecoline in normal subjectsand patients with MSA may result fromnicotinic stimulation of the adrenal medullasince muscarinic effects of the drug wereblocked by glycopyrrolate. Lack of this res-ponse and the low, resting plasma NA levels inPAF are also consistent with peripheral sym-pathetic involvement. These results differ fromthe ACTH and catecholamine responsesobserved during insulin-induced hypo-glycaemia in patients with autonomic failure.Most patients with MSA or PAF have deficientcatecholamine responses,24 whereas theincrement in ACTH and fl-endorphin is con-siderably diminished or absent only in thosewith MSA.'0 A lesion at any point in thesympathetic pathways can block the adrenalmedullary response to hypoglycaemia in con-trast to the effects of direct stimulation with acholinergic agonist which would only be affec-ted by peripheral dysfunction.The interaction between central and peri-

pheral cholinergic effects in mediating ACTHrelease provides a basis for formulating ahypothesis to explain the abnormal responsesin patients with autonomic failure. Arecolineincreases plasma f,-endorphin even when peri-pheral muscarinic effects are blocked;" atropineprevents the rise in fi-endorphin duringhypoglycaemia.25 Thus it appears that a central

cholinergic pathway effects these peptide re-sponses to hypoglycaemia. Studies in animalssuggest, however, that a peripheral cate-cholamine response, specifically secretion ofAfrom the adrenal medulla, also mediates releaseofACTH. Adrenalin can cross the blood-brainbarrier in the region of the hypothalamus incats.26 Failure of ACTH to rise in response tohypoglycaemia or arecoline in MSA probablyreflects dysfunction of cholinergic-stimulatedCRF release since the plasma A responses toarecoline were normal. Although an exag-gerated ACTH response might be anticipatedas a manifestation of central cholinergic super-sensitivity, this did not occur in patients withMSA.Itmay be that post-synaptic elements areaffected in a long-standing degenerative disor-der or supersensitivity results in depolarisationblockade leading to reduced ACITH secretion.Hypothalamic degeneration in MSA is atten-ded by a decrease in the level of cholineacetyltransferase,2 a marker of cholinergicneuronal integrity. We previously reported lowCSF levels of acetylcholinesterase in patientswith MSA,9 consistent with central cholinergicinvolvement. As discussed earlier, ACTHrelease is modulated through a variety ofmechanisms. Thus it is not surprising thatbasal levels are normal despite cholinergicdegeneration in MSA.ACTH levels do not increase following

arecoline administration in PAF, perhapsbecause they do not manifest the normalincrease in plasma A which may be required toelicit this response. The importance of thisadrenergic-cholinergic interaction is highligh-ted by the correlation between the incrementsin plasma ACTH and A following arecolineadministration. The catecholamine responsesto hypoglycaemia are not completely absent inPAF.'024 Normal ACTH and ,B-endorphin re-sponses to hypoglycaemia in PAF may occurbecause these patients develop a-' and f,-adrenergic2 2' receptor supersensitivity. TheACTH responses during hypoglycaemia mayalso be mediated through mechanisms that donot require substantial adrenal medullaryactivity.

Peripheral nicotinic stimulation of sympath-etic ganglia or the adrenal medulla could causethe elevation of MBP induced by arecoline innormal subjects and patients with MSA sinceperipheral muscarinic effects were blocked.'5Furthermore, a central action of arecoline is toproduce hypotension.30 An increase in circulat-ing A levels generally results in a mild pressoreffect since this catecholamine stimulates bothclasses of adrenergic receptors. The usual car-diovascular response to A administration ischaracterised by an increase in systolic, butdecrease in diastolic blood pressure; the sys-tolic change is usually greater than the effect ondiastolic so that the MBP increases slightly.Since the elevation ofMBP in these two groupswas nearly identical in this study, it appearsthat this dose of arecoline is much greater thanthe threshold dose required for this response.The lack of a significant change in MBP inpatients with PAF is consistent with theirabnormal A responses to arecoline. Inierpreta-

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Central and peripheral effects of arecoline in patients with autonomicfailure

tion of the arecoline effects on heart rate is morecomplex because there are direct cholinergiceffects that oppose the chronotropic effect of fi-adrenergic stimulation byA in addition to reflexchanges induced by alterations in MBP.Cardioaccelerator actions predominate in thenormal subjects; the increase observed in thepatient groups may be less since baroreflexfunction is compromised.

Vertigo, nausea, and nystagmus wereexperienced by a similar proportion of patientsand normal subjects. This combination ofsymptoms may represent a pharmacologicallyinduced sickness similar to that described forphysostigmine.3' Motion sickness may resultfrom a noradrenergic-cholinergic imbalance inthe vestibular nuclei3233 and the cholinergicreceptors involved are muscarinic.4 These sideeffects from arecoline could therefore result-from stimulation of muscarinic receptors in themedial vestibular nuclei. There is no reason tosuspect that this area is involved in thesedisorders. It is not surprising therefore that thesymptoms occurred with similar frequency inall groups.

Exacerbation or onset of tremor occurredonly in patients with MSA. Centrally activemuscarinic antagonists are effective in reducingtremor in Parkinson's disease, or that inducedby physostigmine.35 Hence, this arecoline effectmay result from an increase in striatal choliner-gic activity. Although the tremor was only seenin the MSA patients, this does not necessarilyimply cholinergic supersensitivity since deple-tion of striatal dopamine may also be a factor.

Affective changes have been previouslyreported in normal subjects given higher dosesof arecoline subcutaneously.36 In this study theappearance ofthis effect at a lower dose might bedue to the intravenous route of administration.Dramatic emotional manifestations wereobserved in seven of the MSA patients, four ofwhom specifically denied any feelings conson-ant with their outward appearance. It appearsthat arecoline may have precipitated episodesof pathological affect that often occur as part ofthe clinical picture in MSA. This syndrome ofpathological laughing or crying has been suc-cessfully treated in other diseases withlevodopa,37 38 or amantadine38 which would beconsistent with dopaminergic deficiency as thebasis for this phenomenon. Precipitation byarecoline and amelioration in other patients byamitriptyline,39 however, is also consistent witha role for relatively increased cholinergicactivity in producing this symptom in MSA.Since the predominant lesion in many cases ofpathological laughing and crying may involvethe neostriate grey matter of the left hemi-sphere,40 a dopaminergic-cholinergic balancemay therefore also exist in control of the motorsystem for emotional expression. The symp-toms could result from a relative cholinergicpredominance, analogous to the striatalimbalance in Parkinsonism.35

In summary, these results provide furtherdistinction between PAF and MSA. The lackofan increment in plasma A following arecolineadministration in patients with PAF suggeststhat adrenal medullary innervation is affected

by the peripheral involvement in this disorder.The resulting catecholamine deficiency mayprevent a normal ACTH response to arecolinein PAF. Decreased catecholamine responsesduring hypoglycaemia inMSA may result froma central lesion(s) since A levels rise in responseto stimulation by a cholinergic agonist. Thediminished ACTH response in MSA is consis-tent with a central abnormality involving anicotinic cholinergic pathway. Pulmonary,41vestibular and striatal responses during cholin-ergic stimulation suggest relative sparing ofmuscarinic receptors. This pattern of choliner-gic involvement is similar to that described inParkinson's disease.42

We are indebted to the many physicians in the United States whoallowed their patients to participate in this study. Ms Linda ENee provided valuable emotional support to many of thechronically ill patients. The staff of Ward 5-East, NIH ClinicalCenter, cared for the patients. Ms Jennifer R Spahn assisted inthe preparation of this manuscript.

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