Mechanisms of autonomic nervous system dysfunction in uremia

Transcription

1 Kidney Interntionl, Vol. 2 (1981), pp Mechnisms of utonomic nervous system dysfunction in uremi VITO M. CMPESE, MRK S. ROMOFF, DNIEL LEVITN, KENNETH LNE, nd SHUL G. MSSRY Division of Nephrology nd the Deprtment of Medicine, The University of Southern Cliforni School of Medicine, Los ngeles, Cliforni Mechnisms of utonomic nervous system dysfunction in uremi. utonomic nervous system (NS) function ws evluted in 6 norml subjects, 21 predilysis ptients, 16 dilysis ptients, nd 15 ptients with chronic illnesses nd norml renl function by Vlslv rtio, hnd-grip exercise, nd response to orthostsis. Blood levels of norepinephrine (NE) nd the response to NE infusion were lso evluted. Vlslv rtio ws norml in ptients with chronic illness nd significntly reduced (P <.1) in both dilysis nd predilysis ptients; this bnormlity ws more mrked in the ltter. During upright posture, men blood pressure (MBP) decresed significntly in predilysis but not in dilysis ptients. During hnd-grip exercise, the increment of hert rte ws significntly reduced (P <.1) in the ptients with uremi nd this bnormlity ppered relted to the disturbnce in Vlslv rtio. Plsm NE in predilysis ( ng/dl) ws higher (P <.1) thn it ws in dilysis ptients (24 3 ng/dl), norml subjects (21 1 ngldl) nd in those with chronic illness (21 3 ngldl). The mgnitude of rise in plsm NE in response to orthostsis ws greter (P <.1) in predilysis (6 7 ng/dl) thn it ws in dilysis ptients (3 5 ng/dl) nd norml subjects (28 2 ng/dl). NE infusion produced smller (P <.5) chnges in MBP nd hert rte in predilysis thn it did in dilysis ptients nd in normls. These dt indicte tht disturbnces of NS function re common in uremi nd tht they re more extensive in predilysis thn in dilysis ptients. Tken together, the results re consistent with the notion tht the mechnisms for these derngements re multifctonl. Reduced end-orgn response to NE ppers to be mjor fctor underlying these bnormlities in predilysis ptients; derngements in the prsympthetic nervous system nd! or disturbnces in crdic function my lso be involved. Mécnismes du dysfonctionnement du système nerveux utonome u cours de I'uremie. Le fonctionnement du système nerveux utonome (NS) étè évlué chez 6 sujets normux, 21 mldes vnt l'institution de I dilyse, 16 mldes en dilyse et 15 mldes tteints d'ffections chroniques mis vec une fonction rénle normle, pr le rpport de Vlslv, l'epreuve du serrement de min et I réponse l'orthosttisme. Les concentrtions plsmtiques de norépinephrine (NE) et I réponse I perfusion de NE ont ussi été évluées. Le rpport de Vlslv Ctit norml chez les mldes tteints d'ffections chroniques et significtivement réduit (P <,1) chez les mldes dilyses et vnt I dilyse. L'nomlie étit plus importnte chez ces derniers. u cours de I position debout, I pression snguine moyenne (MBP) diminué de fcon significtive chez les mldes vnt I dilyse, mis ps chez les mldes dilyses. u cours de l'épreuve du serrement de min l'ugmenttion du rythme crdique été significtivement diminuée (P <,1) chez les mldes urémiques et cette Received for publiction ugust 11, 198 nd in revised form November 25, /81/2-246 $ by the Interntionl Society of Nephrology nomlie prit en rpport vec I modifiction du rpport de Vlslv. L NE plsmtique étit plus élevée (P <,1) chez les mldes vnt I phse de dilyse (35 3,6ng!dl) que chez les mldes dilyses (24 3 ng/dl), les sujets normux (21 1 ng/dl) et les sujets tteints d'ffections chroniques (21 3 ng/dl). L'mplitude de l'ugmenttion de NE du plsm en réponse l'orthosttisme étit plus importnte (P <,1) chez les mldes vnt dilyse (6 7 ng/dl) que chez les mldes dilyses (3 5 ng/dl) et les sujets normux (28 2 ng/dl). L perfusion de NE produit des modifictions plus fibles (P <,5) de MBP et du rythme crdique chez les mldes vnt dilyse que chez les mldes dilyses et les sujets normux. Ces résultts indiquent que les dcsordres de fonctionnement de NS sont frequents dns l'urémie et qu'ils sont plus importnts chez les mldes I phse prédilytique que chez les mldes dilyses. Dns leur ensemble ces rcsultts sont en ccord vec I notion selon lquelle les mécnismes de ces désordres sont multifonctionnels. L diminution de I réponse NE de l'orgne cible prit ètre un fcteur mjeur de ces nomlies chez les mldes vnt I dilyse. Des ltertions du système prsympthique et/ou des désordres de I fonction crdique pourrient ussi ètre impliqucs. 246 Severl bnormlities of utonomic nervous system (NS) function hve been noted in ptients with end-stge renl filure, nd these include defective function of swet glnds [1, 21, bnorml response to the Vlslv mneuver 13, 4], reduced broreceptor sensitivity [5, 6], reduced elevtion in blood pressure in response to sustined hnd-grip exercise [4], nd nonvolume responsive hypotension during hemodilysis 171. The pthogenesis of these disturbnces nd the locliztion of the lesion responsible for them long the broreceptor reflex rc re, s yet, not cler, however. Some investigtors [8] postulted, on the bsis of n bnorml myl nitrte inhltion test ( functionl index of the entire broreceptor reflex rc) nd of norml cold pressor test ( proposed index of the efferent pthwy) tht the lesion my reside in the broreceptors. Others, hve found, on the other hnd, tht plsm norepinephrine (NE) levels re elevted in ptients with renl filure. The ssocition of elevted levels of NE nd NS dysfunction could suggest end-orgn resistnce to the ction of NE. In ddition, ptients with dvnced renl filure hve mrked nemi nd suffer from stte of chronic illness; the role of these fctors in the genesis of NS dysfunction in uremi hve not been exmined. The present study ws undertken in 138 subjects in n ttempt to investigte the fctors responsible for the genesis of the dysfunction of the NS in ptients with dvnced chronic renl filure.

2 Methods totl of 112 subjects, including 6 norml volunteers, 37 ptients with chronic uremi, nd 15 ptients with chronic illness but norml renl function, were studied for evlution of NS function. Ptients with dibetes mellitus, congestive hert filure, nd those receiving mediction tht my ffect the utonomic nervous system were excluded from the study. Other studies were crried out in n dditionl 1 ptients with essentil hypertension for the evlution of pressor response to NE infusion nd in n dditionl 16 ptients on mintennce hemodilysis for the exmintion of the effect of dilysis procedure on blood levels of ctecholmines s detiled below. The nture of the reserch ws explined to ll prticipnts, nd n informed consent ws obtined prior to the study. mong the norml persons, there were 41 mles nd 19 femles, with their ges rnging between 18 nd 52 (35. 1) yers. They were selected from the medicl nd the prmedicl personnel of the Los ngeles unty-university of Southern Cliforni Medicl Center. The 37 uremic ptients were mde up of two groups: (1) 21 ptients with cretinine clernces of less thn 8 mi/mm nd who were not treted with dilysis (referred to herefter s "predilysis" ptients). mong them were 12 mles nd 9 femles (ge rnge, 19 to 62 [4 3] yers). These ptients were mbultory before dmission to the hospitl for evlution nd preprtion for dilysis. (2) The other group ws 16 ptients treted with chronic mintennce hemodilysis for.5 to 1 (4.5.9) yers. They received 4 to S hours of hemodilysis three times week. mong them were 11 mles nd 5 femles (ge rnge, 21 to 6 [38 31 yers). ll ptients were t home nd cme to the Center three times week for dilysis. The studies in the ptients were crried out on the dy when they did not receive dilysis therpy. The cuses of the renl filure in the 37 ptients were chronic glomerulonephritis in 11, mlignnt hypertension in 7, obstructive uropthy in 4, pyelonephritis in 3, polycystic kidney disese in 2, interstitil nephritis in 1, medullry cystic disese in I, nd the cuse ws unknown in 8 ptients. ll ptients with chronic uremi received diet contining 4 to 6 g of protein nd 1 meq of sodium per dy, nd ll ntihypertensive medictions were discontinued t lest 2 weeks prior to the study. The concentrtions of vrious compounds in the blood of predilysis nd dilysis ptients were: ure, nd 88 9 mgldl, P <.5; cretinine, nd mg/dl, P <.2; sodium nd meqfliter, NS; potssium, nd meq/liter, NS; clcium, 8..3 nd mg/dl, P <.5; phosphorus, nd 5..5 meq/iiter, NS; mgnesium, nd mg/di, NS, respectively. The 15 ptients with chronic illness nd norml renl function were ll mles, nd their ges rnged between 22 nd 63 (43 3) yers. Eleven were recruited from the medicl outptient clinic, nd 4 were t the hospitl t the time of the study. Cretinine utonomic nervous system in uremi 247 clernce ws 85 to 16 (113 57) mi/mm, nd hemtocrit ws 19. to 44.7% ( %). Four ptients hd rheumtoid rthritis, 5 Hodgkin's disese, 2 chronic obstructive pulmonry disese, I srcoidosis, I gout, 1 scleromyxedem, nd I chronic peptic ulcer. ll norml subjects nd those with chronic illness were sked to obtin complete urine collection during the 24 hours preceding the study for the mesurements of sodium excretion in order to judge their sodium intke. Both the norml subjects nd the ptients were sked to fst overnight nd to void coffee, te, coc-col, chocolte, nd smoking for t lest 12 hours before the study. In the morning of the study, the subjects remined in the supine position for 1 hour nd were connected to n electrocrdiogrph. Thirty minutes before the strt of the study, needle connected to heprin lock ws inserted into forerm vein. Blood pressure nd hert rte were mesured, nd blood smples were obtined for the determintion of plsm norepinephrine (NE), epinephrine (E) nd plsm renin ctivity (PR) fter resting supine for 1 hour. While still in the supine position nd fter instruction on the use of the hnd-grip dynmometer, the subjects gripped the instrument mximlly with their hnd for few seconds. The highest vlue of three grip contrctions ws tken s the mximum voluntry contrction (MVC). Hnd-grip ws then mintined stedily t 3% MVC to the end-point of tiring. Hert rte nd blood pressure were mesured, nd blood smples were obtined t the end-point of the sustined hnd grip. Fifteen minutes lter nd while the subjects were still supine, they performed the Visiv mneuver t n expirtory pressure of 4 mm Hg for 12 sec while blowing through mouthpiece connected to mercury mnometer. The Vlslv mneuver ws repeted three times. Hert rte ws continuously recorded throughout the mneuver nd for 6 sec fter its completion. The hert rte response to the Vlslv mneuver ws expressed s the Vislv rtio [9]. This is defined s the rtio between the longest R-R intervl (msec) during the relese phse nd the shortest R-R intervl during the strin phse of the mneuver. The vlue selected ws the best of the three ttempts. The subjects were sked not to tke deep inspirtion before the Vlslv mneuver becuse we found tht the Vlslv rtio ws significntly (P <.1) lower when the mneuver is performed following deep inspirtion (1.77.5) thn during norml respirtion (1.99.6). The effects of orthostsis were exmined 15 mm fter the Vlslv mneuver. Blood pressure, hert rte, NE, PE, nd PR were mesured fter 1 mm of pssive stnding nd fter n dditionl 5 mm of mbultion. To determine the vsculr responsiveness to NE, we infused the gonist into 5 of the predilysis nd 6 of the dilysis ptients, 1 norml subjects, nd 1 ptients with essentil hypertension. The subjects were kept resting in the supine position for 1 hour, nd n indwelling i.v. ctheter ws inserted into forerm vein t lest 3 mm before strting the NE infusion. L-Norepinephrine (Levophed bitrtrte; Winthrop Lbortory, New York) ws infused t rte delivering incresing mounts of 2, 5, nd 1 nglkg/min with ech rte given for 1 mm. Blood pressure nd hert rte were mesured before nd t the end of ech rte of the infusion. The effects of stndrd 4-hour hemodilysis on blood pressure, hert rte, plsm ctecholmine, nd PR were exmined in n dditionl 16 ptients. This group included 1 mles nd 6 femles whose ges rnged between 23 nd 54(36 3) yers. In ll studies, blood pressure ws mesured with n utomtic recorder (Physiometric SRII, Sphygmetrics, Woodlnd Hills, Cliforni), nd ech dt point is the verge of three consecutive mesurements. Men blood pressure ws clculted s the sum of distolic blood pressure nd one-third of pulse pressure.

3 248 Cmpese et l C, 22. > T- ntrols 9 Predilysis Dilysis Chronic illness Fig. 1. Vlslv rtio, tht is, the rtio between the longest RR intervl during the relese phse nd the shortest RR intervl during the strin phse of the Vlslv mneuver, in 6 norml subjects, 21 predilysis ptients, 16 ptients on mintennce hemodilysis, nd 15 ptients with chronic illnesses but with norml renl function. The brckets denote the mens SEM. Hert rte ws determined from electrocrdiogrphic trcings. Plsm renin ctivity (PR) ws mesured by the rdioimmunossy method of Seley, Gerten-Bnes, nd Lrgh [1], with the ntiserum provided by Endocrine Sciences (Trzn, Cliforni), the '251-ngiotensin I (5I-I) from New Englnd Nucler (Boston, Msschusetts), nd the! stndrd provided by Cl Biomed (Sn Diego, Cliforni). The interssy coefficient of vribility for PR ws 7.3% (for 4 consecutive determintions). Plsm ctecholmines were mesured in duplicte by the rdioenzymtic method of DPrd nd Zurcher [11]; the enzyme ctechol-o-methyl trnsferse ws prepred ccording to the method of xeirod nd Tomchick [12], nd 3H-methyl-sdenosine-methionine (New Englnd Nucler, Boston, Msschusetts) ws used s methyl donor. The sensitivity of this method is 1 pg for NE nd E. This method is highly specific. mong physiologic substnces, only epinin nd 3-4 dihydroxyphenyl-glycol showed miniml interference. Men coefficient of intrssy nd control plsm vritions in 78 unselected consecutive determintions with this method were 5.1% nd 12.1% for PNE, 5.7 nd 1.1% for PE. Sodium nd potssium were determined by flme photometry (Instrumenttion Lbortories) nd cretinine by Technicon utonlyzer. The sttisticl evlutions of the dt were mde by one-wy nlysis of vrince (nov) for comprison between mens, by the Tukey-HSD multiple comprisons, by unpired nd pired Student's t test nd by liner regression nlysis. Vlues re expressed s the mens SEM. Results The vlues of the Vlslv rtio in ll subjects re given in Fig. 1. The Vlslv rtio ws significntly lower (P <.1) in both the predilysis (1.51 SEM.8) nd dilysis ptients (1.62.9) thn control subjects (2.1.5) nd those with chronic illness (2..13). The rtio ws not different mong the predilysis nd the dilysis ptients. Even though there ws considerble overlp between groups, lmost hlf of the predi- S S S.. I ) I loot o Norml Dilysis o Predilysis I I I I Time, sec Fig. 2. Hert rte before nd during the Vlslv mneuver in norml subjects nd predilysis nd dilysis ptients. During the relese phse, hert rte ws significntly lower (P <.1) in norml subjects thn it ws in the two groups of uremic ptients, nd it ws lower in dilysis (P <.5) thn in predilysis ptients. Dt re presented s mens SEM. lysis (52%) nd of the dilysis (44%) ptients hd vlues of Vlslv rtio lower thn the lowest vlue seen in norml subjects or in those with chronic illness. The difference in the Vlslv rtio ws minly due to significntly different flls in pulse rte (s determined by RR intervls) during the relese phse of the Vlslv mneuver (Fig. 2). The highest hert rte chieved during the strin phse ws not different between the three groups; lthough the chnge in hert rte from bseline vlues ws smller in the uremic ptients. During the relese phse, the lowest hert rte ws 57 1 bets/mm in the norml subjects, 8 4 bets/mm in the predilysis (P <.1) nd 68 4 bets/mm in the dilysis ptients (P <.1). The vlues were significntly lower (P <.5) in dilysis thn they were in predilysis ptients. To determine whether there is reltionship between the bnormlity in the Vlslv rtio nd the nemi of uremi, we compred the hemtocrit of the ptients with overtly low Vlslv rtio with those who hd rtio within the norml rnge. Predilysis ptients with Vlslv rtio of hd hemtocrits of 15.8 to 37.3% ( %), nd those with Vlslv rtio of hd hemtocrits of 18.8 to 29.1% ( %). mong the dilysis ptients, the hemtocrit ws

4 utonomic nervous system in uremi to 32.9% ( %) with Vlslv rtio of nd 19.4 to 38.8% ( %) with Vlslv rtio of Furthermore, there ws no significnt correltion between the individul vlues of the Vlslv rtio nd the hemtocrit for the entire uremic popultion. There ws no correltion between the men blood pressure (BP) nd the Vlslv rtio. mong the predilysis ptients, 8 hd norml men BP (84 4 mm Hg) with Vlslv rtio of nd 13 were hypertensive (113 5 mm Hg) with Vlslv rtio of Similrly, the Vlslv rtio in the 1 normotensive (88 4 mm Hg) dilysis ptients ws nd in the 6 hypertensive (18 2 mm Hg) ones. Finlly, hlf of the uremic ptients who hd overtly low Vlslv rtio were hypertensive. During hnd-grip exercise, men BP nd hert rte incresed significntly (P <.1, pired nlysis) in ll four groups of ptients studied, but the mgnitude of the chnges between the different groups ws different (Tble 1). The increment in blood pressure in norml subjects (28 1 mm Hg) ws significntly (P <.1) higher thn the predilysis (15 3 mm Hg) nd the dilysis (21 2 mm Hg) ptients but not different from those with chronic illness (25 3 mm Hg). In 7 of 2(35%) predilysis ptients nd in 2 of 16 (13%) dilysis ptients, the chnge in blood pressure ws lower thn the lowest vlue observed in norml subjects (Fig. 3). The increment in hert rte in norml subjects (21 1 bets/mm) ws significntly higher (P <.1) thn predilysis (11 2 bets/mm) nd dilysis (1 2 bets! mm) ptients nd those with chronic illness (13 2 bets/mm). In 16 of 36 (44%) uremic ptients, the increment in hert rte ws lower thn the lowest vlue observed in norml subjects (Fig. 4). Only in 4 of 15 ptients (27%) with chronic illness ws the chnge in hert rte below the norml rnge. It is of interest tht 8 of 11 predilysis (73%) nd 5 of 7 dilysis (71%) ptients who hd low Vlslv rtio lso hd n bnorml hert rte response to the hnd-grip exercise. The vlues for men BP, hert rte, PNE, E, nd PR during the supine position nd the effect of orthosttic stress on these prmeters in ll subjects re given in Tble 1. The men BP in predilysis (1 4 mm Hg) nd dilysis ptients (95 4 mm Hg) ws significntly greter (P <.1) thn it ws in controls (81 1 mm Hg). The hert rte in predilysis (8 3 bets/mm) nd dilysis ptients (79 3 bets/mm) ws lso significntly higher (P <.1) thn it ws in controls (64 1 bets/mm) or in those with chronic illness (67 2 bets/mm). The concentrtions of PNE in predilysis ptients (35 4 ng/dl) were significntly higher (P <.1) thn they were in dilysis ptients (24 3 ng/dl), controls (21 1 ng/dl) nd in those with chronic illness (21 3 ng/dl). Similrly, PE levels in predilysis ptients (3.3.6 ng/dl) were significntly greter (P <.5) thn they were in dilysis ptients (2.1.4 ng/di), controls (2.5.2 ng!dl) nd in those with chronic illness (2.1.4 ng/dl). PR in predilysis (3.4.6 nglml'hr) nd in dilysis ptients (3.2.6 ng/ml/hr) ws significntly higher (P <.1) thn in controls (1.3.1 nglml/hr) nd in ptients with chronic illness (1.6.2 ng!ml/hr). Urine sodium excretion during the 24 hr preceding the study ws (rnge, 59 to 277 meq/24 hr) in controls nd (rnge, 85 to 25 meq/24 hr) in ptients with chronic illness. No systemtic ttempt ws mde to determine sodium excretion in uremjc ptients becuse of their renl filure. There ws modest fll in the men BP fter stnding nd mbultion in norml subjects nd those with chronic illness, but the chnge ws significnt only in the norml controls. Dilysis ptients did not hve decrese in BP during these mneuvers. But, mrked nd significnt (P <.1) decrese in the men BP occurred in the predilysis ptients; it fell by 15 4 nd 15 3 mm Hg fter 1 nd 6 mm of mbultion, respectively. The concentrtion of PNE incresed significntly in ll four groups. But, the mgnitude of rise in PNE fter 6 mm of mbultion in the predilysis ptients (6 7 ng/dl) ws significntly (P <.1) higher thn tht in norml subjects (28 2 ng/dl) dilysis ptients (3 5 ng/dl) nd those with chronic illness (37 5 ngldl). The increments in hert rte fter orthostsis were not different mong the four groups of subjects. Both PE nd PR incresed significntly with orthostsis in ll subjects nd the mgnitude of the increments were not different mong the four groups studied. The effect of hemodilysis on men BP, hert rte, PNE, PE nd PR in 16 dditionl dilysis ptients, studied in the supine position, re shown in Tble 2. There were no significnt chnges in these prmeters except for significnt decrese in body weight nd in the plsm concentrtion of sodium nd potssium. The chnges in men BP nd hert rte during the NE infusion in norml subjects, predilysis, nd dilysis ptients, nd in those with essentil hypertension nd norml renl function re shown in Fig. 5. There ws dose-response reltionship between the chnges in both men BP nd hert rte nd the mount of NE infused. In the predilysis ptients, the chnges in men BP with 2, 5, 1 ng/kg/min of NE were , , nd mm Hg, vlues significntly (P <.5) lower thn those observed in norml subjects ( , nd mm Hg) nd in those with essentil hypertension nd norml renl function ( , , mm Hg). The chnges in the ltter groups were significntly (P <.1) greter thn they were in norml controls. The chnges in men BP in the dilysis ptients were ( , , mm Hg), not different thn they were in norml subjects. Similrly, the decrements in hert rte were significntly smller (P <.5) in the predilysis ptients ( 2..7, , nd bets/mm) thn they were in dilysis ptients ( , , bets/mm), norml subjects ( , , bets/mm), nd in those with essentil hypertension ( , , bets/min). There ws no significnt difference in the chnges in hert rte between the dilysis ptients nd norml subjects. Discussion lthough dysfunctions in the utonomic nervous system (NS) hve been previously reported in ptients treted with mintennce dilysis [3 8], similr bnormlities hve not been documented in ptients prior to tretment with dilysis. Furthermore, the mechnisms responsible for the dysfunction in the NS in uremi hve not, s yet, been elucidted. We hve evluted NS function in predilysis nd dilysis ptients, determined the blood levels of ctecholmines, nd exmined the rectivity of the trget orgns to norepinephrine (NE) in n effort to understnd the genesis nd the pthwys involved in the derngement of the utonomic nervous function in uremi.

5 25 Cmpese et! Tble 1. Men blood pressure, hert rte, plsm levels of norepinephrine, epinephrine, nd plsm renin ctivity during supine position, hndgrip exercise, nd orthostsis N ge yr Supine Men blood pressure mm Hg Stnding Hnd-grip exercise 1 mm 5 mm Supine Hert rte bets/mm Stnding Hnd-grip exercise 1 mm 5 mm Norml subjects b 76 lb 76 lb b 85 2b 85 2b Ptients with chronic illness nd norml renl function b " 87 4b 89 4" Predilysis ptients " 115 6" 84 5b.c 85 4b. 8 3' 9 3" 98 4"" 1 4bc Dilysis ptients ' 117 5" 94 5' 93 5" 79 3' 88 3" 98 4b.c 96 5b.c One-wy nov NS <.1 NS <.1 <.1 <.1 NS <.1 <.1 Dt re presented s the mens SEM. b P <.1, compred with vlues in the supine position (Student's pired t test). P <.1, compred with vlues in the norml subjects (by Tukey-HSD multiple comprisons) Norml Predilysis Dilysis Fig. 3. Chnges in men blood pressure in norml subjects, in predilysis nd dilysis ptients, nd in ptients with chronic illnesses but with norml renl function in response to sustined hnd-grip exercise t one third of mximum voluntry contrction. The increment in men blood pressure ws significntly lower (P <.1) in the two groups of uremic ptients. The brckets denote the men SEM. The results of our studies demonstrte tht lrge number of predilysis nd dilysis ptients hd dysfunction of NS. These included bnorml Vlslv rtio, bnorml response to hndgrip tests, nd bnorml fll in blood pressure (BP) during orthostsis. The disturbnces pper to be relted to uremi itself or to some of its consequences rther thn to the stte of chronic illness, becuse ptients with other chronic disese, but norml renl function, did not hve such bnormlities. Two findings in our dt indicte tht some of these bnormlities re more extensive in the predilysis ptients. First, the bnorml response of blood pressure during the hnd-grip exercise ws more frequent mong the predilysis ptients. Second, the mjority of the predilysis ptients (67%) displyed orthosttic hypotension wheres the response to upright posture in the dilysis ptients ws not different from norml subjects.. S.. :i:. $ J- T I Chronic illness 'O C I ±- l Norml Predilysis Dilysis Chronic illness FIg. 4. Chnges in hert rte in norml subjects, in predilysis nd dilysis ptients, nd in ptients with chronic illnesses but with norml renl function in response to sustined hnd-grip exercise t one third of mximum voluntry contrction. The increment in hert rte ws significntly lower (P <.1) in the two groups of uremic ptients. The brckets denote men SEM. It is plusible tht the nemi of uremi nd the presence or bsence of hypertension my ffect the function of the NS. Our dt do not support either of these notions. First, the bnorml Vlslv rtio nd the bnorml response to hndgrip exercise were not relted to the mgnitude of the nemi. Second, mny of the uremic ptients hd bnorml hert rte response but norml BP response to hnd-grip exercise. Third, the response to orthostsis ws bnorml in the predilysis ptients nd norml in the dilysis ptients despite no significnt difference in hemtocrit. Finlly, the bnormlities in the function of NS did not correlte with the presence or bsence of n elevted men BP. The bnormlity in hert rte response during the Vlslv mneuver ws more pronounced during the relese phse of the test in both the predilysis nd dilysis ptients. During this phse, n increse in systemic rteril pressure occurs, which is

6 utonomic nervous system in uremi 251 Plsm norepinephrine ng/dl Tble 1. (ntinued) Plsm epinephrine ngldl Plsm renin ctivity g/mi/hr Stnding Stnding Stnding Hnd-gnp Hnd-grip Hnd-grip Supine exercise 1 mm 5 mm Supine exericse 1 mm 5 mm Supine exercise 1 mm 5 mm 21±1 29±2b 47±3b 48±2b 2.5±.2 3.8±5b 4.4±.4b4.9±.4b 1.3±.1 1.7±.2" 2.±.3" 2.4±.2" 21±3 24±3b 52±6b 57±7b 2.1±.4 3.2±.7" 4.2±.7"5.3±1.1" 1.6±.2 2.1±.3" 2.6±.4" 3.7±.6b b. 24±3 29±3b <.1 < C 97 9b, 3.3.6c 4.2.7b 6.5 l.2b b, b b,c 4.8.9b. 53 7b 55 5b b 4. 1." " b.c 4.6.8b,c 5 1.Ob.c <.1 <.1 <.5 NS NS <.5 <.1 <.1 <.1 <.1 Tble 2. Effect of single hemodilysis on men blood pressure, hert rte, plsm norepinephrine, epinephrine, plsm renin ctivity, body weight, nd plsm concentrtion of sodium nd potssium in 16 ptients Men BP mm Hg Hert rte bets/mm PNE ng/di PE ng/dl PR g/mi/hr Body wt kg 5N meqiliter 5K meq/liter Before dilysis fter dilysis P NS NS NS NS NS <.1 <.1 <.1 Dt re the mens SEM. These ptients re not mong the ptients included in Tble 1. bbrevitions re defined s follows: BP, blood pressure; F, plsm concentrtion; NE, norepinephrine; E, epinephrine; PR, plsm renin ctivity; 5, serum concentrtion; N, sodium; K, potssium. sensed by the broreceptors in the ortic rch nd crotid rteries, subsequently leding to reflex brdycrdi [13, 14]. The increse in BP is due to n increse in crdic output secondry to enhnced venous return nd to incresed peripherl vsculr resistnce produced by ugmented sympthetic tone [13 16]. The bnorml response in hert rte during the relese phse could be due to filure of the BP to rise secondry to n inpproprite chnge in peripherl vsculr resistnce, derngement in the vgl pthwy, nd/or disturbnce in crdic function. We did not use invsive techniques to monitor rteril pressure during the Vlslv mneuver, but others hve shown tht dilysis ptients disply blunted rteril-pressure overshoot during the relese phse of the test [7]. The more pronounced bnormlity in hert rte response during the relese phse of the Vlslv in the predilysis ptients could be, t lest prtilly, due to greter impirment in rteril pressure response during this phse. This impirment could be secondry to resistnce to the ction of NE on blood vessels. The demonstrtion in the dilysis ptients tht n elevtion in BP with the infusion of NE produced norml fll in hert rte suggests tht the bnorml response in hert rte during the relese phse of the Vlslv mneuver my be due to filure of rteril pressure to rise in this phse of the test. It should be emphsized, however, tht bnormlities in the vgus pthwys could lso be responsible for the bnorml response in hert rte both in the predilysis nd dilysis ptients. Support for this ide is found in the results of hnd-grip test s discussed below. The hnd-grip exercise is ssocited with n increse in hert rte, crdic output, nd rteril pressure [18 2]. The pressor response is believed to be medited by crdic ccelertion [18], but even when hert rte fils to increse during the test, the pressor response occurs most probbly due to incresed peripherl vsculr resistnce [21. lthough the mechnisms for these hemodynmic responses re not fully elucidted, prticiption of the sympthetic nd prsympthetic nervous systems hs been proposed [18, 2]. Certin dt suggest tht the chnge in hert rte is due to prsympthetic inhibition (vgus relese) [2], nd tht the incresed peripherl resistnce is secondry to enhnced sympthetic ctivity [2]. The observtion in our study tht the mjority of the ptients who displyed n bnorml response of hert rte during the hndgrip exercise hve lso n bnorml Vlslv rtio is consistent with the notion tht disturbnce in the vgus pthwys is present in uremic ptients. Furthermore, the demonstrtion tht 35% of the predilysis ptients, but only 13% of the dilysis ptients, hd bnorml pressor response (despite similr incidence of dernged hert rte response) suggests tht disturbnce in sympthetic ctivity is more predominnt in the predilysis ptients. This proposl is consistent with the finding of peripherl resistnce to NE infusion in the predilysis ptients. The mintennce of rteril pressure during orthostsis is dependent on the bility to ugment peripherl vsculr resistnce [21, 22]. Our dt clerly demonstrte tht the mjority of the predilysis ptients displyed mrked posturl hypotension ( men BP> 12 mm Hg), wheres the chnges in BP were not different from tht in norml subjects in the dilysis ptients. The reson for this difference is most probbly due to trgetorgn resistnce to NE present only in the predilysis ptients. Our dt do not necessrily imply tht orthosttic hypoten-

7 252 Cmpese et! w U -1 3 I- 2 ft 1 Essentil hypertension z Norml Dilysis Predilysis Norepiriephrine dose, ng/kg/min Fig. 5. Chnges in men blood pressure nd hert rte during norepinephrine infusion t progressive doses of 2, 5, 1 ng/kg/min in JO norml subjects, 5 of the predilysis, nd 6 of the dilysis ptients included in Tble I nd in 1 ptients with essentil hypertension nd norml renl function. Ech infusion rte ws given for 1 mm. The chnges in men blood pressure nd hert rte were significntly (P <.1) lower in dilysis but not in predilysis ptients, then in norml subjects. sion due to utonomic nerve dysfunction is not encountered in dilysis ptients but would suggest tht such problem is not frequent. It is our opinion tht if orthosttic hypotension is noticed in dilysis ptient, vigorous serch for cuses other thn uremic NS dysfunction should be undertken. Our dt do not provide informtion on the mechnism of the resistnce to the ction of NE in the predilysis ptients. Becuse the resistnce improves or disppers with dilysis therpy it is tempting to speculte tht dilyzble mteril is responsible for the phenomenon. It is lso possible tht occuption nd/or down regultion of the -receptors of the vsculr smooth muscle due to elevted level of PNE plys role in decrese response to the gonist. It is of interest tht the blood levels of NE re elevted in the predilysis ptients nd re norml in the dilysis subjects. tuck et! [231 lso found elevted blood levels of NE in predilysis ptients. The mechnisms for elevtion in blood levels of NE in uremi re not cler. Severl fctors could be contributory, including decresed renl clernce, diminished degrdtion secondry to reduced ctechol-o-methyl trnsferse ctivity [23], reduced reuptke of the gonist from the sympthetic neurons end-terminls [24], or incresed relese of the hormone. The presence of resistnce to the ction of NE results in hemodynmic consequences tht would dictte n incresed need for the gonist nd would result in the stimultion of its relese. The normliztion of the blood levels of NE in our dilysis ptients is most probbly secondry to n improvement or disppernce of the resistnce to the ction of the hormone rther thn to its loss during dilysis. Indeed, our observtion tht blood levels of NE do not decrese during the dilysis procedure is consistent with this postulte. Others hve lso found tht the dilysis procedure does not lower blood levels of NE [25] wheres Lke et l [26] reported n increse in these levels during dilysis. The norml bsl concentrtions of PNE found in our dilysis ptients re in greement with the results of Lke et! [26] nd t vrince with those of others [27 29]. The resons for this discrepncy re not obvious. It my be due to different methodology or to vrible degrees in the improvement of the resistnce to the ction of NE. 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