Baroreceptor Activity in Normotensive and Hypertensive Uremic Patients

Transcription

1 Broreceptor Activity in Normotensive nd Hypertensive Uremic Ptients By J. M. LAZARUS, M.D., C. L. HAMPERS, M.D., E. G. LOWRIE, M.D., AND J. P. MERIILL, M.D. SUMMARY Broreceptor ctivity nd posturl blood volum3 chnges were evluted in four normotensive nd nine hypertensive uremic ptients before nd fter bilterl nephrectomy. Broreceptor ctivity, reflected by the slope of liner regression of R-R intervl with drug-induced systolic blood pressure elevtion, ws significntly lower in hypertensive thn in normotensive ptients. Six of nine ptients hd norml blood pressure following bilterl nephrectomy; however, the men slopes of ll nine ptients, irrespective of postnephrectomy blood pressure, pproched tht of normotensive uremic ptients. The slopes of both normotensive nd hypertensive ptients, before nd fter bilterl nephrectomy, were significntly less thn norml controls. Similr results were found in lowering blood pressure with myl nitrite. Depressed broreceptor ctivity is suggested to be secondry to neuropthy of the utonomic nervous system, chronic hypertension, hert disese, nd nemi. It is speculted tht this reduced broreceptor sensitivity my ccentute the posturl symptoms primrly induced by volume reduction on hemodilysis. There is no evidence in this study tht depressed broreceptor ctivity, s opposed to reset broreceptor, is cuse of hypertension in ptients with chronic renl filure. Downloded from by on November 1, 218 Additionl Indexing Words: Renoprivl hypertension Uremi Broreceptor Bilterl nephrectomy Posturl Ihypotension HYPERTENSION cn be controlled in the mjority of ptients with terminl renl filure by reduction of extrcellulr volume with hemodilysis.'-6 In the smll percentge of ptients not responsive to ultrfiltrtion, bilterl nephrectomy hs proven successful.k2 Recent evidence indictes tht those hypertensive hemodilysis ptients with elevted renin levels respond more predictbly to bilterl nephrectomy,5' 6, 13 thereby incriminting the renin-ngiotensin system s cuse of elevted blood pressure. The etiology of hypertension in the normovolemic nephric ptient nd normovolemic prenephrectomy ptient with norml renin levels is unknown. Resetting of the From the Deprtment of Medicine, Peter Bent Brighm Hospitl nd Hrvrd Medicl School, Boston, Msschusetts. Presented in prt t the 53rd Scientific Session of the Americn College of Physicins, Atlntic City, New Jersey, April 17-23, Address for reprints: J. Michel Lzrus, M.D., Peter Bent Brighm Hospitl, 721 Huntington Ave., Boston, Msschusetts Received August 7, 1972; revision ccepted for publiction Jnury 3, Circultion, Volume XLVII, My Hypertension A.N.S. neuropthy broreceptor mechnism hs been suggested s cuse for elevted rteril pressure in ptients with chronic renl hypertension14 15 nd renoprivl hypertension,16' 17 nd perhps is the etiology of this nonrenin, nonvolume dependent hypertension. Recent informtion by Pickering, Gribbin, nd Oliver'8 suggests tht broreflex sensitivity chnges very little t different rteril pressures in group of chronic uremic ptients, indicting resetting of the reflex. We hve observed in some hypertensive dilysis ptients bnorml vsculr responses-widely fluctuting blood pressures during hemodilysis nd posturl hypotension with supine hypertension while on no ntihypertensive mediction. In pilot study of 14 hemodilysis ptients, blood pressures 48 hours fter dilysis, tken in the recumbent position, nd immeditely fter stnding, reveled n increse in posturl chnges of men nd distolic pressures of hypertensive ptients (tble 1). This pilot study suggested hypertensive ptients on hemodilysis, both before nd fter bilterl nephrectomy, hve bnorml posturl blood pressure chnges while normotensive uremic ptients

2 116 LAZARUS ET AL. Downloded from by on November 1, 218 C;3 4l2.2 c) ).1. -e X S. W m = -H. be C 'S : U X SGC 2. p >2 cc _; Xl C.C ±± csx c m c+ m X t- O CM t'- 1-H ~ + Cl u l-in t O o s - c) e mxd >2 co zi - - Gc v v cl cm 1- r- --_ _ L-Xcc C: M! C1-1. ic fl. 1 - c S 2 2. tic >+ -. c. - o Q -. Q Q2Q ,.. 2., 2 S tic 2+.. LO c3 O l *_ - ;. C)I 11C * o+e o o. +. -e >, X i Oz differ only slightly from controls. This ws felt to be due primrily to contrction of extrcellulr volume with rigorous ultrfiltrtion in hypertensive ptients; however, the role of n bnorml broreceptor, lredy suggested to be of etiologic importnce in the hypertension, ws questioned s fctor in the posturl chnges. This pper reports the effect of uremi nd hypertension on the broreceptor mechnism in hemodilyzed ptients. Methods Thirteen hemodilysis ptients, consecutively selected only on the bsis tht they were prepring to undergo bilterl nephrectomy, were studied to evlute more criticlly the response of broreceptor mechnism to elevtion nd reduction in rteril pressure induced by chnge in posture nd with phrmcologic gents. Ptients were divided into the pproprite blood pressure group bsed on history nd demonstrtion of hypertension before initition of nd during dequte hemodilysis. Hypertension, defined s systolic pressure greter thn 15 mm Hg nd distolic pressure greter thn 9 mm Hg, hd been present t lest 1 yer. Studies on ech ptient were performned t time when extrcellulr volume ws estimted to be norml nd t lest 48 hours following the lst hemodilysis. Methyldop, the only ntihypertensive mediction used in three ptients, ws discontinued t lest 1 week prior to study. The indiction for nephrectomy in the normotensive ptients ws preprtion for trnsplnttion. Infonned consent ws obtined from ll ptients. Ptients were plced in the recumbent position for 3 min nd rteril pressure ws mesured from the rteril side of Scribner A-V shunt vi Stthm P-23 pressure trnsducer. Respirtions were mesured with pneumogrph nd the R-R intervl ws mesured from led I of n electrocrdiogrm. These prmeters were recjrded simultneously using Gilson polygrph. The venous side of the A-V shunt ws kept ptent with slow dextrose nd wter drip (less thn 2 cc during the study). To evlute the effect of posture on plsm volume, smples for hemtocrit, serum sodium, serum osmollity, totl serum protein, nd lbumin-tgged 1131 plsm volume were tken with ptients in the supine position. Blood pressure, respirtion, nd pulse rte ws simultneously recorded, nd the ptient plced in the stnding position. After 15 min in the upright position, the bove studies were repeted. Ptients were returned to the recumbent position nd when blood pressure, pulse rte, nd respirtions hd stbilized, received n ngiotesin bolus through the venous limb of the A-V shunt. In most instnces, n increse in systolic blood pressure of 3-5 mm Hg ws dequte to crete chnge in the pulse rte; however, in two cses up to 1 mm Hg were necessry. The dose required rnged from.25 to 1. jug of ngiotensin. Simultneous electrocrdiogrm, respirtlons, nd systolic pressure were mesured with ech drug dministrtion. This procedure ws repeted twice fter return of ll prmeters to bsel ne vlues. Three Circultion, Volume XLVII, My 1973

3 Downloded from by on November 1, 218 BARORECEPTOR ACTIVITY IN UREMICS similr recordings were mde following single inhltion of n myl nitrite mpule which cused drop in systolic pressure of 3-5 mm Hg. Ptients were crefully monitored during the trnsient mnipultions of blood pressure nd the procedure terminted if ny symptoms developed. Broreceptor ctivity ws interpreted from the pulse response (R-R intervl) to chnges in systolic pressure s described by Smyth, Sleight, nd Pickering'9 nd Bristow, Honour, Pickering, Sleight, nd Smyth.2 R-R intervls were mesured during expirtion to eliminte the effect of sinus rrhythmi nd systolic pressures were mesured two bets prior to ech R-R intervl. Liner regression of the R-R intervl systolic pressure ws performed by method of lest-squres utilizing ll points in the three determintions. Smyth et l.19 nd Bristow et l.2t suggested tht the slope of line relting R-R intervls to systolic pressure elevted with pressor gents reflects the sensitivity of broreceptor mechnism nd the position of the regression long the blood pressure xis represents "resetting." Ech ptient underwent the bove study before nd 3-6 months following bilterl nephrectomy. Five norml volunteers underwent percutneous brchil rtery ctheteriztion for mesurement of rteril pressure while simultneous respirtory nd R-R intervl mesurements were obtined. The verge ge ws 25, while tht of the ptients ws 34 yers. These subjects were normotensive nd hd no history or symptoms of posturl hypotension. Compred to uremic ptients, they required much smller doses of ngiotensin nd myl nitrite to develop blood pressure nd R-R intervl chnges. Significnt differences were screened for ech test by vrince nlysis.2' If the resultnt F indicted differences between groups (norml controls; prenephrectomy normotensive uremic ptients; postnephrect-'mv normotensive uremic ptients; prenephrectomy hvpertensive uremic ptients, nd postnephrectomy hvpertensive uremic ptients) (P <.5), the differences were identified by Duncn's Multiple Rnge Test.22 Student's pired t test ws employed where pproprite. Results Four of the 13 ptients studied in detil hd never been hypertensive nor treted for hypertensxon. Their pressures on multiple determintions with sphygmomnometers verged 143/58, while the verge blood pressure in the five norml controls ws 124/74. The verge intrrteril systolic pressures of the four normotensive uremic ptients, however, ws pproximtely 6 mm greter thn the five norml controls. This ws felt to be due prtilly to rel differences in pressure, but to gret extent due to differences in the mesurement of blood pressure through the percutneous needle s compred to the indwelling rteril shunt. The remining nine uremic ptients hd significnt histories of hypertension prior to nd Circultion, Volume XLVII, My fter the initition of hemodilysis. With bilterl nephrectomy, six of the nine becme normotensive nd remined so throughout the reminder of their hemodilysis tretment. Tble 2 outlines the effect of upright posture on hemtocrit, serum osmollity, serum sodium, serum protein, nd lbumin-tgged 1311 plsm volume in both hypertensive nd normotensive uremic ptients before nd fter nephrectomy. Twenty min fter ssuming the upright position ll ptients hd consistent nd significnt (P <.2) increses in hemtocrit nd totl serum protein by pired nlysis. Although lbumin-tgged 1311 plsm volume determintions vried with n SEM of.5 liters, decrese ws seen with stnding in normotensive ptients nd postnephrectomy hypertensive ptients (P <.1). Serum sodium nd osmollities did not chnge. Men chnges of the five test prmeters from lying to stnding did not differ significntly between test groups by nlysis of vrince. Chnges in hemtocrit, totl protein, nd 131I plsm volume together indicte tht there is slight reduction in plsm volume with ssumption of upright position, but the mgnitude of this chnge is not significntly different in hypertensive nd normotensive uremic ptients. The differences in response to posture between normotensive nd hypertensive uremic ptients is therefore on the bsis of differences in intrvsculr volume induced by hemodilysis nd not due to differences in volume cused by the level of blood pressure. Chnges in plsm volume with upright posture were not ffected by removl of disesed kidneys. In these 13 ptients, before nd fter bilterl nephrectomy, ssumption of the upright position resulted in drop in blood pressure nd tchycrdi. In this smll group verge orthosttic hypotension in normotensive uremic ptients (systolic = ; distolic = ) ws not significntly different from hypertensive uremic ptients (systolic = ; distolic = -9.9 ± 4.8); however, both were significntly greter thn normls (systolic = , distolic = +3.8 ± 1.82). Liner regressions of the R-R intervl vs chnge in blood pressure with stnding were without significnt correltion. On the other hnd, phrmcologiclly induced chnges in blood pressure usully resulted in pulse chnges which relted to the pressure chnge with high degree of significnce. Ptients tolerted elevtions of pproximtely 3-1 mm Hg in systolic pressure nd 3-5 mm of pressure drop without difficulty. Individul nd

4 118 LAZARUS ET AL. Plsm-Volume Chnges with Stnding Tble 2 Hemtocrit Serum osmollity Serum sodium Sertum protein Plsm volume Group (%) (mosm) (meq/liter) (g %) (liters) Prenephrectomy normotensive (N = 4) Lying 21.45* s Stnding =(.5() Postnephrectomy niormotensive (N 4) Lying Stnding Prenephrectomy hypertensive (N = 9) Lying O Stndinig Postnephrectomy hypertensive (N 9) Lying Stnding *Men i SEM. Downloded from by on November 1, 218 men slopes in ech of the groups re listed in tble 3. Angiotensin test slopes illustrted in figure 1 indicte tht prior to nephrectomy the men ngiotensin slope of the hypertensive ptients (b = ) is significntly less (P <.1) thn the normotensive group (b = +2.16). After bilterl nephrectomy the verge reduction in systolic blood pressure in the nine hypertensive ptients ws 36 mm Hg. This reflects "resetting" of the slope down the systolic scle. The men slopes fter nephrectomy in hypertensive (b =-.31) nd normotensive (b ±+2.16) ptients re not significntly different from their respective prenephrectomy vlues by pired nlysis. The six hypertensive ptients who becme normotensive with surgery hve men postnephrectomy slope of b = -.312, nd the three postnephrectomy persistently hypertensive ptients men slope of b = The ltter figure is not significntly different from the men slope of the prenephrectomy or either postnephrectomy normotensive group. The men slopes of hypertensive nd normotensive uremic ptients before nd fter nephrectomy re ll significntly less (P <.1) thn tht observed in norml subjects. Figure 2 illustrtes similr slopes developed by lowering blood pressure with inhltion of myl nitrite. This mneuver revels no significnt difference between the men slopes of the four uremic groups; however, they re ll significntly lower (P <.1) thn the men slope of norml individuls given myl nitrite. --- Kb. ro) 16o 12 _ Pre Nephrectomy - Post Nephrectomy p NcQlM ANGIOTENSIN STUDY Nor m;/ NORM(lOTENSIVE (N.S.) -i NS -LHYPTENSIVE SYSTOLIC BLOOD PRESSURE (m,mhg) Figure 1 Comprison of the men slopes of liner regressions developed by blood pressure elevtion with ngiotensin in norml subjects, normotensive uremic ptients before nd fter bilterl nephrectomy, nd hypertensive uremic ptients before nd fter bilterl nephrectomy. Circultion, Volume XLVII, My 1973

5 BARORECEPTOR ACTIVITY IN UREMICS 119 Tble 3 Liner Regression Slopes before nd fter Bilterl Nephrectomy Angiotensin slope Amyl nitrite slope Subject Prenephrectomy Postnephrectomy Prenephrectomy Postnephrectomy Normotensive uremics Men- SEM Hypertensive uremics Men - SEM i Norml subjects Men- SEM Downloded from by on November 1, 218 Discussion The 13 ptients studied did not experience symptomtic posturl hypotension; however, ll hd mesurble decreses in blood pressure with stnding which ws significntly greter thn in normls. In five norml subjects given ngiotensin the slope of the line relting R-R intervls to 6. i:k 16 _ 12 _ 8 8N / ----Pre Nephrectomy AMYL NITRITE STUDY -Post Nephrectomy Normls / - 5 N NORMOTENSIVE HYPERTENSIVE (NS.) S SYSTOLIC BLOOD PRESSURE (mm Hg) Figure 2 Comprison of the men slopes of liner regression developed by blood pressure lowering with myl nitrite in norml subjects, normotensive uremic ptients before nd fter bilterl nephrectomy, nd hypertensive uremic ptients before nd fter bilterl nephrectomy. Circultion, Volume XLVII, My 1973 systolic pressure ws found to be b = +9.83, which pproches tht of norml subjects reported by Bristow et l.2 nd Eckberg, Brbinsky, nd Brunwld.23 The effect on the broreceptor function of lowering blood pressures hs not been previously exmined. In norml controls we found the slope of the liner regression with pressure lowered by myl nitrite to be b = , which is essentilly the sme s the slope with blood pressure elevtion. The men slope of the 13 uremic ptients is significntly lower thn tht derived in norml individuls given myl nitrite. Within the uremic group there re no significnt differences between the men slopes of the four subgroups. The men slope with ngiotensin ws significntly less in hypertensive ptients thn tht in normotensive ptients prior to bilterl nephrectomy. In fct, negtive slopes were found in some hypertensive uremic ptients. We hve no explntion for this finding but consider it possibly due to the combined effects of hypertension nd uremi. Following bilterl nephrectomy nd lowering of blood pressure in six of nine ptients, the men slope of the hypertensive group becme insignificntly different from the normotensive group,

6 Downloded from by on November 1, suggesting the reduced blood pressure hd llowed some improvement in broreceptor function. However, the men slope of the three ptients who remined hypertensive fter bilterl nephrectomy lso improved nd ws not significntly different from the men slope of the six hypertensive ptients who becme normotensive or the four who were initilly normotensive. One might expect these three ptients to continue to exhibit slopes lower thn the other groups if ltered broreceptor were importnt in the etiology. It is possible, lthough unlikely, tht nephrectomy, independent of its effect on hypertension, cused the pprent improvement in slope of these three ptients. The discrepncy in these three ptients might be explined by the smll smple size nd lrge stndrd error of the men. Liner regressions, developed with both elevtion nd lowering of blood pressure in hypertensive nd normotensive uremic ptients (before nd fter nephrectomy) hd men slopes ll significntly lower thn the men slope of norml individuls. The norml controls hd intrrteril blood pressures lower thn the normotensive uremic ptients which ws possibly due to difference in the technic of pressure mesurement. Differences in the men slopes of norml controls nd normotensive uremics ws felt, therefore, not to be on the bsis of pprent differences in blood pressure. Bsed on the work by Gribbin et l.24 exmining the effect of ge on broreflex sensitivity, it ws felt the 9 yer verge ge difference in controls nd study ptients ws not significnt contributing fctor. Eckberg et l.23 studying ptients with hert disese found liner regression relting R-R intervl to systolic pressure with men slope of 4.4 nd concluded tht the broreceptor bnormlity reflected profound bnormlity in the prsympthetic crdiovsculr regultion in hert disese. Hert disese-induced chnges in broreceptor function could be importnt in the broreceptor bnormlity in these uremic ptients. Three to 6 months fter nephrectomy, two of the nine hypertensive ptients continued to hve obvious clinicl evidence of hert disese nd both hd persistent hypertension. The four normotensive ptients hd no history or evidence by exmintion, chest X-ry, or electrocrdiogrm of hypertensive crdiovsculr disese, rteriosclerotic hert disese, or uremic myocrdiopthy during this study. Hemtocrits were low in these 13 ptients nd were further decresed with bilterl nephrectomy. The chronic nemi ws compensted for by increse in LAZARUS ET AL. extrcellulr volume nd there ws no resting tchycrdi. The effect of chronic stble nemi on broreceptor function is unknown but certinly might ply role. Another possible explntion for the bnormlity of broreceptor response in these ptients is tht of uremic neuropthy of the utonomic nervous system. Hennessy nd Siemsen25 found impired eccrine swet glnd function in uremic ptients who lso hd somtic neuropthy. Abnorml utonomic nervous system function hs been demonstrted in uremic ptients responding to the Vlslv mneuver nd pilocrpine26 nd tropine.27 We suggest tht the blunted broreceptor function demonstrted here my lso be evidence of neuropthy of the utonomic nervous system. In conclusion, uremic ptients hve blunted broreceptor response to phrmcologiclly induced blood pressure chnges. Hypertensive pients hve blunted nd reset broreceptor mechnisms which, following bilterl nephrectomy, tend to correct pproching tht seen in normotensive ptients. One cnnot incriminte n ltered broreceptor s the cuse of hypertension since the broreceptor ctivity in the persistently hypertensive ptients ws not different from tht in normotensive ptients. It is pprent tht "reset" liner regression s mesured here simply reflects the blood pressure level t which the study ws initited. We concur with Pickering, Gribbin, nd Oliver'8 tht there is persistently ltered sensitivity t different blood pressure mesurements; however, we feel this does not necessrily represent cuse nd effect. The evidence, lthough not supportive, does not exclude the possibility tht "reset" s opposed to blunted broreceptor sensitivity plys some role in the hypertension of these ptients. In neither the hypertensive nor the normotensive uremic ptient does removl of the kidneys nd correction of hypertension correct the slope of liner regression to tht seen in norml individuls. It is theorized tht these uremic ptients hve blunted broreceptor responses due to combintion of fctors-neuropthy of the utonomic nervous system, hert disese, chronic hypertension, nd chronic nemi. Posturl hypotension seen in hypertensive uremic ptients on hemodilysis is undoubtedly due primrily to contrcted extrcellulr volume induced by ultrfiltrtion but is possibly ccentuted by blunted broreceptor sensitivity. Circultion, Volume XLVII, My 1973

7 Downloded from by on November 1, 218 BARORECEPTOR ACTIVITY IN UREMICS ReferenCes 1. HEGSTROM RM, MURRAY JS, PENDRAS JP, BURNELL JM, SCRIBNER BA: Two yer's experience with periodic hemodilysis in tretment of chronic uremi. Trns Amer Soc Artif Intern Orgns 8: 266, BLUNIBERG A, HEGSTROM RM, NELP WB: Extrcellulr volume nd exchngeble sodium in chronic hypertensive renl disese. Proc Europ Dily Trnsplnt Ass 1: 199, COMTY C, ROTTKA H, SHALDON S: Blood pressure control in ptients with end-stge renl filure treted by intermittent hemodilysis. Proc Europ Dily Trnsplnt Ass 1: 29, HAMPERS CL, SCHUPAK E: Long Term Hemodilysis: The Mngement of the Ptient with Chronic Renl Filure. New York, Crune nd Strtton, 1967, p VERTES V, CANGIANO JL, BERMAN LB, GOULD A: Hypertension in end-stge renl disese. New Eng J Med 28: 978, WILKINSON R, SCOTT DF, ULDALL PR, KERR DNS, SWINNEY J, ROBSON V: Plsm renin nd exchngeble sodium in the hypertension of chronic renl filure. Qurt J Med 39: 377, SETO D, FRITZ W, NAKAMOTO S, KOLFF WJ: The effect of bilterl nephrectomy nd of sodium nd wter content on hypertension. Trns Amer Soc Artif Intern Orgns 9: 35, ONESn C, SWARTZ C, RAMIREZ O, BREST AN: Bilterl nephrectomy for control of hypertension in uremi. Trns Amer Soc Artif Intern Orgns 14: 361, DUCROT H, FUNCK-BRENTANO I1L, VANTELON J. KLEINKNECHT D, JUNGERS P: Evolution tensionelle et ctivite renine plsmtique chez sept sujets nephriques. Communic Societe de Nephrologie (Pris) 2: 95, KOLFF WJ, NAKAMOTO S, POUTASSE EF, STRATTON RA, FIGUEROA JE: Effect of bilterl nephrectomy nd kidney trnsplnttion on hypertension in mn. Circultion (suppl II) 29: II-23, TOUSSAINT C, VERNIORY A, CREMIER M, VERGER- STRAETEN P, KINNAERT P, VAN GEERTRUYDEN J: Blood renin level in terminl Bright's disese treted by hemodilysis nd by renl llotrnsplnttion. In Interntionl Congress Series no. 179: Europen Dilysis nd Trnsplnttion Assocition Proceedings 5th Congress, Edited by Kerr DNS, Amsterdm. Excerpt Medic, 1969, p HAMPERS CL, ZOLLINGER RM, SKILLMAN JJ, GUMPERT RW, BAILEY GL, MERRILL JP: Hemodynmic nd 121 body composition chnges following bilterl nephrectomy in chronic renl filure. Circultion 4: 367, WEIDMAN P, MAXWELL MH, LuPu AM, LEWIN AJ, MASSRY SC: Plsm renin ctivity nd blood pressure in terminl renl filure. New Eng J Med 285: 757, MCCUBBIN JW, GREEN JH, PAGE IH: Broreceptor function in chronic renl hypertension. Circ Res 4: 25, KEZDI P, WENNEMARK JR: Broreceptor nd sympthetic ctivity in experimentl renl hypertension in the dog. Circultion 17: 785, MERRILL JP, SCHUPAK E: Mechnisms of hypertension in renoprivl mn. Cnd Med Ass J 9: 328, HAMPERS CL, SKILLMAN JJ, LYONS JH, OLSEN JE, MERRILL JP: A hemodynmic evlution of bilterl nephrectomy nd hemodilysis in hypertensive mn. Circultion 35: 272, PICKERING TC, CRIBBIN B, OLIVER DO: Broreflex sensitivity in ptients on long-term hemodilysis. Clin Sci 42: 1, SMYTiH HS, SLEIGHT P, PICKERING GW: Reflex regultion of rteril pressure during sleep in mn: A quntittive method ssessing broreflex sensitivity. Circ Res 24: 19, BRISTOW JD, HONOUR AJ, PICKERING GW, SLEIGHT P, SMYTH HS: Diminished broreflex sensitivity in high blood pressure. Circultion "'9: 48, STEEL RC, TORRIE IN: Principles nd Procedures of Sttistics. New York, McGrw-Hill Co, 196, p STEEL RG, TORRIE JN: Principles nd Procedures of Sttistics. New York, McGrw-Hill Co, 196, p ECKBERG DL, BRABINSKY M, BRAUNWALD E: Defective crdic prsympthetic control in ptients with hert disese. New Eng J Med 285: 877, GRIBBIN B, PICKERING TG, SLEIGHT P, PETO R: Effect of ge nd high blood pressure on broreflex sensitivity in mn. Circ Res 24: 424, HENNESSY WJ, SIEMSEN AW: Autonomic neuropthy in chronic renl filure. Clin Res 16: 385, GOLDENBERGER S, THOMPSON A, GUHA A: Autonomic nervous dysfunction in chronic renl filure. Clin Res 19: 531, LOWENTHAL DT, REIDENBERG MM: The hert rte response to tropine in uremic ptients, obese subjects before nd during fsting, nd ptients with other chronic illnesses. Proc Soc Exp Biol Med 139: 39, 1972 Circultion, Volume XLVII, My 1973