Journl of Humn Hypertension (1998) 12, 363 371 1998 Stockton Press. All rights reserved 0950-9240/98 $12.00 http://www.stockton-press.co.uk/jhh ORIGINAL ARTICLE Blood pressure nd diurnl vrition in sodium, potssium, nd wter excretion AR Dyer 1, GJ Mrtin 2, WN Burton 3, M Levin 2 nd J Stmler 1 1 Deprtment of Preventive Medicine, Northwestern University Medicl School, Chicco, IL; 2 Deprtment of Medicine, Northwestern University Medicl School, Chicgo, IL; 3 First Ntionl Bnk of Chicgo, Chicgo, IL, USA The objective of this study ws to exmine ssocitions of blood pressure (BP) with rtios of overnight to 24-h urinry excretion of sodium, potssium, nd wter. Ech of 125 men 27 64 yers of ge, not tking diuretics, hd BP mesured during the dy on Mondy. Beginning Mondy evening, ech prticipnt provided three crefully timed 24-h urine collections, divided into dytime nd overnight (bedtime to wkening) specimens. Proportion of totl 24-h excretion of sodium, potssium, nd wter in the overnight specimen, stndrdised for cretinine excretion, ws determined for ech 24-h period. Associtions of systolic nd distolic BP (SBP/DBP) with these proportions were exmined with control for ge, body mss index, lcohol intke, nd hert rte. Men BP ws 116/71 mm Hg; 15 men were on non-diuretic nti-hypertensive therpy. Men 24-h urinry excretion ws 168 mmol for sodium, 68 mmol for potssium, nd 16 mmol for cretinine. Men overnight to 24-h proportions verged over the 3 dys were 30.7% for sodium, 22.0% for potssium, 32.1% for urinry volume, nd 33.2% for cretinine. Prtil correltions of SBP nd DBP with the 3-dy verges were 0.257 (P 0.01) nd 0.210 (P 0.05) for sodium; 0.223 (P 0.05) nd 0.222 (P 0.05) for potssium; 0.127 nd 0.091 for urinry volume; nd 0.033 nd 0.014 for cretinine. Correltions for sodium proportions were lrger for the first 24-h period, compred to the second or third 24-h period. These results indicte tht higher BP ws ssocited with reltively greter proportion of sodium nd potssium excretion t night. Further work is needed to clrify temporl sequence, ie, whether reltively greter sodium nd potssium excretion t night is risk fctor for higher BP (eg, vi renl mechnisms), or whether higher BP results in reltively greter sodium nd potssium excretion t night, or both. Keywords: blood pressure; sodium; potssium; diurnl ptterns Introduction Diurnl vritions in urinry excretion of sodium, chloride, potssium nd wter hve long been recognised, with excretion of wter nd electrolytes generlly reching mximum sometime during middy nd minimum sometime during sleep. 1 16 A reversl of the usul diurnl cycle of sodium, chloride, nd wter excretion (ie, higher excretion t night) hs been reported for persons with number of diseses. 10,17 22 Investigtors hve lso reported reversl or flttening of the usul cycle of sodium nd chloride excretion in hypertensives. 17,23 27 In previous report, Dyer et l 26 found on verge no diurnl vrition in excretion of sodium nd wter in group of hypertensive men nd women, with more thn hlf showing higher rte of sodium nd wter excretion t night thn during the dy. A stronger ssocition between blood pressure (BP) nd overnight excretion of sodium, compred to dytime or 24-h excretion, hs lso been reported. 28 The present study ws undertken to further Correspondence: Dr Aln R Dyer, Deprtment of Preventive Medicine, Northwestern University Medicl School, 680 N. Lke Shore Dr, Suite #1102, Chicgo, IL 60611, USA Received 5 August 1997; revised 19 Jnury 1998; ccepted 23 Jnury 1998 exmine reltions between BP level nd diurnl vrition in the excretion of sodium, potssium, nd wter. Subjects nd methods Subjects Subjects were recruited in 1988 1990 from ptients of the Generl Internl Medicine Clinic of the Northwestern Medicl Fculty Foundtion, employees of the First Ntionl Bnk of Chicgo, nd through dvertisements in community newsppers nd on the rdio. A totl of 149 men ged 26 64 yers completed questionnire nd hd BP, height nd weight mesured. Of these 149, 137 ged 27 64 yers provided urine collections for ssessment of sodium, potssium, nd cretinine. Becuse of known effects of diuretics on sodium nd wter excretion, 12 men tking diuretics t the time of exmintion were excluded from these nlyses. Prticipnts provided informed written consent following pprovl of ll study procedures by the Northwestern University Institutionl Review Bord.
364 Methods Dt collection included three 24-h urine collections, divided into dytime nd overnight specimens, for ssessment of dytime nd overnight excretion of sodium, potssium, cretinine, nd wter; mesurement of BP, height nd weight; nd completion of questionnire deling with lcohol intke, current tretment sttus nd medictions for high BP, use of other medictions ffecting BP, history of M.D. dignosed high BP, stroke, nd myocrdil infrction, fmily history of high BP, cigrette use, chnges in dietry hbits, nd demogrphic vribles. To mke dt collection uniform for ll prticipnts, ll exmintions were on Mondys, with collection of overnight urine smples on Mondy, Tuesdy, nd Wednesdy, nd collection of dytime urine on Tuesdy, Wednesdy, nd Thursdy. Prticipnts returned the Mondy nd Tuesdy overnight collections nd the Tuesdy dytime collection on Wednesdy morning, nd the remining three collections on Fridy morning. Blood pressure (sitting) ws mesured three times on the dy of the first overnight urine collection with use of rndom-zero sphygmomnometer (Hwksley) fter the prticipnt hd emptied his bldder nd st quietly for 5 min. Systolic BP (SBP) ws recorded s ppernce of sound (phse I) nd distolic s disppernce (phse V). Pulse in 30 s ws lso mesured t the time of ech BP. Averges of the three pulse nd BP mesurements were used in nlyses. Height nd weight were ech mesured twice with height rule ttched to wll nd bem blnce scle. Height ws mesured to the nerest hlf inch nd weight to the nerest pound. The verge of the two mesurements ws used in nlyses. Body mss index (BMI) ws clculted s weight in kilogrms divided by height in meters squred. The questionnire ssessed dily intke of lcoholic drinks over the preceding 7 dys. Ech dy s intke ws converted into milliliters of bsolute lcohol bsed on estimtes tht beer ws 4.7% lcohol, tble wine 11.5%, nd hrd liquor 43%. 29,30 Totl intke over the period ws divided by 7 to obtin n verge dily intke. Becuse the distribution of lcohol intke ws skewed to the right, 1.0 ws dded to ech person s verge dily intke nd the result log trnsformed to reduce skewness. Prticipnts provided three crefully timed 24-h urine collections divided into dytime nd overnight periods. Specil ttention ws pid to completeness of ll specimens. Detiled instructions on methods for collection for ech time period were included in ech urine collection kit. Ech prticipnt ws lso verblly instructed until it ws evident tht ll collection procedures were clerly understood. For the Mondy night collection, the prticipnt ws told to empty his bldder completely t bedtime nd to discrd tht specimen. For the other two overnight collections, urine voided t bedtime ws included in the dytime collection. Time of bedtime voiding ws entered on the urine jr lbel to mrk the beginning of ech overnight collection. All urine voided during the night nd the first specimen pssed on rising in the morning constituted ech overnight collection. Time of first morning void ws entered on the overnight collection lbel s well s on the next dytime collection lbel, since the end of the overnight collection lso mrked the beginning of the next dytime collection. Ech dytime collection included ll urine pssed during the dy s well s the lst specimen pssed before bedtime. Time of this specimen ws dded to the lbel of ech dytime collection to mrk its end, nd to the collection lbel for the next overnight collection. Jrs for ech collection period were pre-mrked with different coloured stripe to help the prticipnt remember which urine collection jrs to use for ech collection. Extr, unmrked jrs were lso provided in cse the number given for specific collection period ws insufficient. On return of collections to the clinic on Wednesdy nd Fridy, prticipnts were crefully questioned on completeness of collection. Ech jr lbel lso sked the prticipnt to indicte whether or not ll urine pssed during tht time period ws voided into the jr. Urine liquots for ech of the six collection periods were prepred. In ddition, one collection period ws selected for submission of n dditionl liquot, to serve s blind duplicte for ssessment of lbortory qulity control. Thus, for ech prticipnt, seven liquots were submitted to the lbortory. Aliquots were nlysed t the Clinicl Reserch Center of Northwestern University nd Northwestern Memoril Hospitl. Sodium nd potssium were nlysed by ion-selective electrode with Nov I instrument (Newton, MA, USA). Cretinine ws nlysed by the Jffe lkline picrte method with Gilford 203S clinicl chemistry nlyser (Oberlin, OH, USA). Technicl error of lbortory mesurements, bsed on split smples, ws clculted from the formul d 2 /2N, where d is the difference between pir of mesurements nd N the number of split pirs. Percentge technicl error (defined s 100 times technicl error divided by the men vlue of the split smples) ws 1.3% for sodium, 2.0% for potssium, nd 1.8% for cretinine. Dytime excretion vlues were converted to 16- h bse by multiplying by 16 nd by dividing by ctul time in hours of collection. Overnight vlues were converted to n 8-h bse in similr fshion. The 24-h vlues were then obtined by summing 8-h overnight nd 16-h dytime vlues. For ech 24- h period, the rtio of the 8-h overnight to 24-h excretion ws computed for ech vrible. Overnight to 24-h rtios were computed rther thn 24- h to overnight rtios becuse rtios with overnight excretion in the numertor were generlly less skewed thn rtios with overnight excretion in the denomintor. Rtios for 24-h period were initilly treted s missing if the prticipnt indicted tht either the overnight or dytime specimen ws incomplete. Further review of the dt suggested tht there were other collections, both overnight nd dytime, in which there were potentil problems with electrolyte vlues bsed on comprison of the 16-h or
8-h cretinine excretion for tht collection period with the 16-h or 8-h cretinine excretion for the other two dytime or overnight collections. In this review, n overnight collection ws flgged for further exmintion if the 8-h cretinine for tht collection ws less thn 50%, or more thn 200%, of either of the other two 8-h cretinines. Similrly, dytime collection ws flgged for review if the 16- h cretinine for tht collection ws less thn 50%, or more thn 200%, of either of the other two 16-h cretinines. Where it ppered possible to determine which of the collections flgged ppered to be in error, eg, due to potentilly incorrect recording of its strt or end, tht collection ws considered problem collection nd ws initilly excluded from these nlyses. This pproch led to exclusion for five of the 125 men of ll three 24-h collections, becuse either the overnight or dytime collection (or both) ws n incomplete or problemtic collection. In ddition, mong the remining 120 men, there were two men for whom two of the three 24-h collections needed to be excluded, nd 22 for whom one of the collections needed to be excluded. Becuse this pproch to exclusion of urine collections ws rbitrry nd could impct study power, nd 3-dy verges of overnight to 24-h rtios would be bsed on fewer thn three 24-h collections for some men, unless nlyses were restricted to those 96 men with no collections excluded, we sought wy to correct ll dytime nd overnight collections for cretinine excretion. Correction for cretinine excretion would llow use of ll collections, even those known to be incomplete, in nlyses of ssocitions of BP with overnight to 24-h rtios for sodium, potssium, nd volume. We therefore defined the cretinine corrected 8-h overnight to 24-h rtio for sodium s: N o /Cr o Corrected N rtio = N o /Cr o + 2 N d /Cr d N o = N o + N d (2 Cr o )/Cr d ) where N o nd Cr o re the 8-h overnight vlues for sodium nd cretinine, respectively, nd N d nd Cr d the corresponding 16-h dytime vlues. Cretinine corrected 8-h overnight to 24-h rtios for potssium nd urinry volume were defined similrly. The rtionle behind this correction is tht this nd other studies indicte tht cretinine excretion is on verge constnt throughout the dy, 2,7,11,26,28 ie, the totl mount of cretinine excreted in 16-h dytime collection should on verge be pproximtely twice the mount excreted in n 8-h overnight collection. Under this ssumption, the cretinine term in the denomintor of the second eqution, ie, (2 Cr o )/Cr d, should be close to one. Where this rtio differs from 1.0 for the dytime nd overnight portions of given 24-h collection, the difference could be due to problems in recording strt or end of the overnight or dytime collection, or to incomplete collection not reported s such by the prticipnt. Hence, correction for cretinine hs the potentil to djust sodium, potssium, nd volume rtios for ny problems in the recording of strting or ending times. This pproch lso llows inclusion in nlyses of collections reported by prticipnts to be incomplete. In fct, in the present study, cretinine excretion in most self-reported incomplete collections differed less from cretinine excretion in the prticipnt s other overnight or dytime collections thn the differences used to define problem collections. To verify tht correcting for cretinine excretion ws pproprite, ie, tht correltions between uncorrected nd corrected rtios were high nd tht there were no systemtic differences between uncorrected nd corrected rtios, we computed correltions nd men differences for the uncorrected overnight to 24-h rtios nd the cretinine corrected rtios, with ll problem nd incomplete urine collections excluded. For sodium, the correltion ws 0.942 for the verge of three rtios, with rnge of 0.919 to 0.945 for the three 24-h periods. For potssium, the correltion for the verge ws 0.904, with rnge of 0.864 to 0.932, nd for urinry volume, the correltion for the verge ws 0.949, with rnge of 0.926 to 0.959. None of the men differences for corrected nd uncorrected rtios ws significntly different from zero (smllest P-vlue 0.611), nd ll men differences were 0.0022 or less. Bsed on these high correltions nd comprble men vlues, nlyses involving rtios for these three vribles were bsed on cretinine corrected rtios for ll 125 men, while nlyses involving cretinine rtios nd descriptive sttistics on 24-h, dytime, nd overnight electrolyte excretion were bsed on 120 men, with exclusion of their dt for problem nd incomplete urine collections. Anlyses were lso repeted with exclusion of 15 men tking non-diuretic nti-hypertensive mediction. Becuse results of these ltter nlyses were similr to those including these men, only results tht included them re reported here. Sttisticl nlyses Person product moment correltion ws used to exmine univrite ssocitions of rtios of overnight to 24-h excretion with BP, ge, BMI, hert rte, nd log lcohol intke, nd prtil correltion ws used to djust ssocitions of rtios with BP for the foregoing potentil confounding vribles. To provide insight into the results of the correltion nlyses, nlysis of covrince ws lso used to compute men differences in BP between the top nd bottom qurtile of ech overnight to 24-h rtio, with nd without djustment for the potentil confounding vribles. All tests on correltions were two-sided, with results considered sttisticlly significnt for P 0.05. Power ws 0.80 to detect true correltions of 0.248 between rtios of overnight to 24-h excretion nd BP for nlyses involving 125 men. Results Descriptive sttistics Tble 1 gives mens nd stndrd devitions for the 125 men for SBP nd DBP, ge, BMI, hert rte, log 365
366 Tble 1 Mens nd stndrd devitions of study vribles Vrible Men s.d. All men (n = 125) Systolic BP (mm Hg) 116.3 13.1 Distolic BP (mm Hg) 70.8 9.9 Non-optiml BP (%) 45.6 Age (yers) 43.8 9.7 BMI (kg/m 2 ) 27.3 4.1 Hert rte (bets/min) 74.0 9.5 Log lcohol intke 3.33 2.27 Three-dy verge overnight to 24-h rtio (%) b Sodium 30.7 9.1 Potssium 22.0 6.3 Urinry volume 32.1 9.3 Exclusive of problem or incomplete urine collections (n = 120 c ) Urinry sodium excretion (mmol) Averge 24-h 168.0 55.3 Averge overnight 52.0 26.7 Averge dytime 115.8 40.4 Averge overnight to 24-h rtio (%) 30.7 10.1 Urinry potssium excretion (mmol) Averge 24-h 67.7 19.0 Averge overnight 14.4 5.7 Averge dytime 53.1 16.9 Averge overnight to 24-h rtio (%) 21.7 7.0 Urinry volume (1) Averge 24-h 1.83 0.75 Averge overnight 0.58 0.33 Averge dytime 1.25 0.58 Averge overnight to 24-h rtio (%) 32.1 10.8 Urinry cretinine (mmol) Averge 24-h 16.0 3.0 Averge overnight 5.3 1.2 Averge dytime 10.6 2.0 Averge overnight to 24-h rtio (%) 33.2 3.9 Systolic pressure 120 mm Hg nd/or distolic pressure 80 mm Hg, or use of non-diuretic nti-hypertensive therpy. b Corrected for cretinine excretion. c Five men for whom ll three 24-h urine collections were either incomplete or problemtic were excluded. lcohol intke, nd the 3-dy verges of cretinine corrected rtios of 8-h overnight to 24-h excretion for sodium, potssium, nd urinry volume, expressed s percentge of totl 24-h excretion. The tble lso gives mens nd stndrd devitions for verge 24-h, 8-h overnight, nd 16-h dytime excretion of sodium, potssium, urinry volume, nd cretinine, nd 3-dy verges of uncorrected rtios for these vribles, fter exclusion of the five men for whom ll three 24-h urine collections were either incomplete or problemtic. Seventy of the 125 men hd BP levels in the optiml rnge, s defined by JNC V criteri, 31 nd 20 were hypertensive, ie, were either tking nti-hypertensive mediction or hd SBP 140 mm Hg or DBP 90 mm Hg. For comprison of these results with other studies tht clculted rtios of 24-h to 8-h overnight excretion, rther thn rtios of 8-h overnight to 24- h excretion, the cretinine corrected rtios give hrmonic mens for 24-h to 8-h overnight excretion of 3.26 (1.0/0.307) for sodium, 4.55 for potssium, 3.12 for volume, nd 3.01 for cretinine. 26 With respect to reproducibility of rtios over the three 24-h periods, the intr-clss correltion of the three rtios ws 0.518 for sodium, 0.441 for potssium, 0.340 for volume, nd 0.338 for cretinine. These correltions indicte tht for the rtio of 8-h overnight to 24-h excretion of sodium clculted from single 24-h urine collection, pproximtely hlf the observed vrition in the rtio is due to true between person vrition nd hlf to within-person vrition. For the other vribles, the correltions indicte tht s much s two-thirds of the observed vrition in the rtio is due to within-person vrition nd only one-third to true between person vrition. The results for cretinine re not unexpected given the reltively smller stndrd devitions of the overnight to 24-hour cretinine rtios compred to those for sodium, potssium, nd volume, nd the finding in this nd other studies tht cretinine excretion is on verge constnt throughout the dy. 2,7,11,26,28 Correltions with possible confounding vribles Systolic BP ws significntly correlted with ge, BMI, nd hert rte nd DBP with BMI nd hert rte (Tble 2). While SBP nd DBP were positively correlted with log lcohol intke, these correltions did not differ significntly from zero. Three-dy verges of overnight to 24-h rtios for sodium, potssium, nd urinry volume were positively nd significntly correlted with ge nd negtively nd significntly correlted with log lcohol intke. Averge rtios for sodium nd potssium were lso significntly correlted with hert rte. The verge cretinine rtio ws not significntly correlted with ny of these vribles, nd no rtio ws significntly correlted with BMI, lthough ll correltions were positive. Men overnight to 24-h rtios were lso compred for men less thn 40 yers of ge nd men ged 40+. Proportions of totl 24-h excretion of sodium, potssium nd volume in 8-h overnight collections were significntly greter (P 0.01 for sodium nd potssium; P 0.05 for volume) for men 40+ compred to men 40, with proportions of 32.6% nd 27.5%, respectively, for sodium, 23.2% nd 20.1% for potssium, nd 33.7% nd 29.6% for urinry volume. Men proportions for cretinine did not differ significntly by ge, being 33.0% for men ged 40+ nd 33.5% for men 40. Reltion of urinry rtios to blood pressure Tble 3 gives correltions nd prtil correltions of BP with 8-h overnight to 24-h rtios for sodium nd potssium, together with the undjusted nd djusted men differences in BP between the top nd bottom qurtiles of ech rtio. For sodium, correltions with BP were lrgest for rtios from the first 24-h period, nd correltions decresed progressively from the first to third collection period. The verge rtio nd the rtio for the first 24-h period were significntly correlted with SBP nd DBP with nd without djustment for other vribles. While the rtio for the second 24-h period ws significntly correlted with BP without djustment for other vribles, the rtio for the third period ws not significntly correlted with BP in ny nlysis.
Tble 2 Correltions of systolic nd distolic BP nd verge overnight to 24-h rtios with ge, BMI, hert rte, nd log lcohol intke 367 Vrible Age Body mss index Hert rte Log lcohol Systolic pressure 0.221* 0.390*** 0.250** 0.138 Distolic pressure 0.162 0.331*** 0.260** 0.156 Averge sodium rtio 0.299*** 0.129 0.197* 0.217* Averge potssium rtio 0.214* 0.065 0.222* 0.335*** Averge volume rtio 0.285** 0.041 0.160 0.224* Averge cretinine rtio 0.105 0.121 0.102 0.030 Correltions for systolic nd distolic BP re for 125 men. Rtios for sodium, potssium, nd urinry volume re cretinine corrected rtios; correltions re for 125 men. The rtio for cretinine excludes problem nd incomplete urine collections; correltions re for 120 men. *P 0.05, **P 0.01, ***P 0.001. Tble 3 Correltions of systolic nd distolic BP with overnight to 24-h rtios for sodium nd potssium nd men differences in BP between top nd bottom qurtiles of rtios Rtio Correltion Top nd bottom qurtile men difference Undjusted Adjusted Undjusted Adjusted Sodium rtios nd systolic BP Averge 0.305*** 0.257** 11.1 8.7 First 0.365*** 0.351*** 11.0 9.9 Second 0.250** 0.156 10.2 5.1 Third 0.142 0.120 7.7 4.8 Sodium rtios nd distolic BP Averge 0.251** 0.210* 5.8 4.3 First 0.270** 0.245** 6.5 6.0 Second 0.236** 0.165 6.0 3.1 Third 0.115 0.100 3.6 1.7 Potssium rtios nd systolic BP Averge 0.220* 0.223* 9.3 9.2 First 0.220* 0.213* 7.9 7.6 Second 0.237** 0.223* 8.2 7.7 Third 0.066 0.076 3.3 3.2 Potssium rtios nd distolic BP Averge 0.211* 0.222* 5.8 6.1 First 0.216* 0.219* 5.8 6.2 Second 0.148 0.122 3.2 2.8 Third 0.143 0.175 3.0 3.4 Adjusted for ge, BMI, hert rte, nd log lcohol intke. *P 0.05, **P 0.01, ***P 0.001. Undjusted men BP differences between the top nd bottom qurtiles of the verge rtio were 11.1 mm Hg for SBP nd 5.7 mm Hg for DBP; djusted men differences were 8.7 nd 4.3 mm Hg, respectively. Men BP differences between top nd bottom qurtiles of sodium rtios lso decresed from the first to third collection period. The verge rtio for potssium ws lso significntly correlted with SBP nd DBP with nd without djustment for other vribles. While the rtio for the first 24-h period ws significntly correlted with SBP nd DBP, the second rtio ws not significntly correlted with DBP, nd the third rtio ws not significntly relted to SBP or DBP. Undjusted men BP differences between top nd bottom qurtiles of the verge rtio were 9.2 mm Hg for SBP nd 5.8 mm Hg for DBP; djusted men differences were 9.2 nd 6.1 mm Hg. Adjusted men differences in BP between top nd bottom qurtiles of potssium rtios lso tended to decline from the first to third 24-h collection period. Tble 4 presents results for ssocitions of BP with overnight to 24-h rtios for urinry volume nd cretinine. For urinry volume, the verge rtio ws not significntly correlted with BP. However, the first rtio ws significntly correlted with SBP with nd without djustment for other vribles, but not DBP. Correltions with BP for the second nd third rtios were smller thn those for the first rtio. Men BP differences between top nd bottom qurtiles of rtios for urinry volume were substntilly smller thn those for sodium nd potssium. No overnight to 24-h rtio for cretinine ws significntly correlted with BP; correltions generlly did not exceed 0.10 in bsolute vlue. Differences in men BP between top nd bottom qurtiles of cretinine rtios were lso generlly smll. Anlyses were lso done to ssess whether overnight to 24-h rtios for 15 men on nti-hypertensive mediction reflected their hypertensive sttus or their current BP level (Tble 5). The dt include undjusted nd djusted mens of verge overnight
368 Tble 4 Correltions of systolic nd distolic BP with overnight to 24-h rtios for volume nd cretinine nd men differences in BP between top nd bottom qurtiles of rtios Rtio Correltion Top nd bottom qurtile men difference Undjusted Adjusted b Undjusted Adjusted b Volume rtios nd systolic BP Averge 0.162 0.127 5.2 4.9 First 0.212* 0.190* 6.4 4.8 Second 0.072 0.014 2.9 0.1 Third 0.087 0.112 3.1 3.1 Volume rtios nd distolic BP Averge 0.119 0.091 2.0 2.0 First 0.163 0.144 3.2 2.2 Second 0.055 0.017 1.8 0.2 Third 0.055 0.079 1.3 1.5 Cretinine rtios nd systolic BP Averge 0.011 0.033 3.2 3.6 First 0.102 0.081 0.5 0.1 Second 0.052 0.012 0.5 0.9 Third 0.029 0.020 1.3 3.2 Cretinine rtios nd distolic BP Averge 0.052 0.014 1.9 2.3 First 0.072 0.050 0.5 0.0 Second 0.084 0.044 1.5 0.7 Third 0.065 0.024 0.8 1.9 Associtions for volume rtios re for 125 men. Associtions for cretinine rtios re for 120, 114, 111, nd 109 men for the verge, first, second, nd third rtios, respectively. b Adjusted for ge, BMI, hert rte, nd log lcohol intke. *P 0.05, **P 0.01, ***P 0.001. Tble 5 Men of verge overnight to 24-h rtios by use of nti-hypertensive mediction Rtio Mediction No. Blood pressure use Undjusted Adjusted Fully (%) (%) djusted (%) Sodium Yes 15 32.2 30.8 30.0 No 110 30.5 30.7 30.8 Potssium Yes 15 23.0 22.2 21.9 No 110 21.9 22.0 22.0 Volume Yes 15 33.3 32.7 32.0 No 110 32.0 32.1 32.2 Cretinine Yes 14 32.2 32.0 32.1 No 106 33.3 33.3 33.4 Adjusted for ge, BMI, hert rte, nd log lcohol intke, in ddition to systolic nd distolic BP. to 24-h rtios for ech vrible for these men nd the 110 other men. Mens re djusted first for SBP nd DBP, nd then lso for ge, BMI, hert rte, nd log lcohol intke, in ddition to BP. With no djustment, men on nti-hypertensive mediction hd slightly higher rtios for sodium, potssium, nd urinry volume. Men BPs for men on nti-hypertensive therpy were 122 mm Hg for SBP nd 77 mm Hg for DBP compred to 115 nd 70 mm Hg, respectively, for men not on mediction. With djustment for these BP differences, men rtios for sodium nd potssium were virtully identicl for the two groups, nd the difference in the volume rtio ws reduced. With dditionl djustment for the other vribles, mens for sodium, potssium, nd volume rtios becme slightly smller for men on tretment thn for men not on tretment. None of these men differences in rtios between the two groups ws sttisticlly significnt. Discussion For decdes excess sodium intke hs been implicted in the etiopthogenesis of high BP. 32 46 Dt from epidemiologicl, clinicl, nd niml experimentl studies ll indicte direct cusl ssocition between excess slt intke nd hypertension. Severl investigtors suggest tht hypertension is the result of n inbility of the kidney to excrete slt nd wter normlly. 35,40,47 52 These investigtors
hypothesise tht development of chronic BP elevtion results from need of the kidneys to increse urine volume nd sodium excretion in the presence of hbitul sodium intke severl-fold bove physiologic requirement in order to mintin homeostsis of the extrcellulr fluid volume. 40,43,47 49,52 Diurnl vritions in excretion of sodium, chloride, potssium, nd wter hve been observed in mny studies. 1 16 Cretinine excretion hs generlly been reported to be firly constnt over 24 h, 2,7,11,26,28 nd on verge this ws the cse for the men in this study. Wter nd electrolyte excretion in helthy individuls generlly reches mximum sometime round middy nd minimum towrd the end of sleep. 5,6,13,14,16 Previous studies hve suggested tht the dytime excretion rte exceeds the night-time rte by 50 to 100%. 15 Reversl of this diurnl cycle in excretion of sodium, chloride, nd wter hs been reported for severl diseses including hypertension. 10,17 27 In study of 12 hypertensive ptients, Vgnucci nd Wesson 17 found tht mximl chloride excretion occurred during dytime in seven persons nd during sleep in five. There ws no reversl in the diurnl pttern of potssium excretion. In study of eight young borderline hypertensives, Bultsov et l 27 found tht the curve of urinry sodium excretion ws flt over 24 h, wheres six gemtched normotensives exhibited the usul pttern of higher dytime excretion. Urinry potssium excretion exhibited the usul diurnl pttern in both groups. In study of 107 hypertensive men nd women from clinicl tril on control of hypertension by non-phrmcologic mens (the Hypertension Control Progrm (HCP)), Dyer et l 26 reported hrmonic mens for rtios of 24-h to 8-h overnight excretion of 2.81, 3.83, 3.00, nd 2.80 for sodium, potssium, cretinine, nd wter, respectively. 26 For this group of hypertensives, there ws thus on verge no diurnl vrition in excretion of sodium nd wter, with more thn hlf showing higher rte of sodium nd wter excretion t night thn during the dy. When 24-h to overnight rtios for HCP hypertensives were compred to those for 30 men nd women with DBP of 80 89 mm Hg, HCP hypertensives hd significntly smller hrmonic mens for sodium, potssium, nd urinry volume, ie, 2.81 vs 3.33 for sodium, 3.83 vs 4.47 for potssium, nd 2.80 vs 3.29 for urinry volume. The rtio of men 24-h to men overnight excretion of sodium observed in HCP hypertensives ws lso lower thn similr rtios derived from published dt for young dults, normotensives, nd borderline hypertensives. 53 58 Given the ges of HCP prticipnts (41 80 yers), it ws not cler whether the observed reversl of diurnl ptterns of sodium nd wter excretion ws ssocited with hypertension per se, or reflected decline of renl functionl cpcity with ge, since ge ppers to modify fctors which determine renl sodium hndling, including glomerulr filtrtion rte nd renl hemodynmics. 59 Furthermore, in one study, persons over ge 40 hd lower rtio of men 24-h to men overnight excretion of sodium thn persons under 40. 56 For 30 men nd women under 40, rtios on two diets were 4.35 nd 4.54, respectively, fter correction for cretinine excretion, while for 13 persons over 40, rtios were 3.23 nd 3.40. These ltter vlues were similr to those reported for persons with DBP of 80 89 mm Hg 26 nd to those derived from dt on borderline hypertensives in Tuomilehto et l. 26,34 The present study ws undertken s follow-up to the study in HCP hypertensives, to exmine further ssocitions of BP with diurnl vrition in excretion of sodium, potssium, nd wter, with control for potentil confounding vribles including ge. In these nlyses, SBP nd DBP were positively nd significntly correlted with 3-dy verges of 8-h overnight to 24-h urinry excretion of sodium nd potssium, but not with urinry volume or cretinine, with control for ge, BMI, lcohol intke, nd hert rte. Men BP differences between highest nd lowest qurtiles of verge rtios, with djustment for these sme vribles, were 8.7 nd 4.3 mm Hg for SBP nd DBP for sodium, nd 9.2 nd 6.1 mm Hg for potssium. Averge rtios for sodium, potssium, nd urinry volume were lso significntly correlted with ge. For those under ge 40, men proportions of 24-h excretion in the 8-h overnight collection corresponded to hrmonic mens for rtios of 24-h to 8-h overnight excretion of 3.63 for sodium, 4.96 for potssium, nd 3.38 for urinry volume, while for men ged 40 nd over, men proportions corresponded to lower hrmonic mens of 3.06, 4.32, nd 2.97, respectively. In study of 301 mle British civil servnts ges 37 to 58, Stessen et l 28 reported tht csul SBP nd DBP, mesured on verge 7 dys erlier, were positively nd significntly relted to overnight sodium excretion with djustment for ge nd BMI, but not to dytime or 24-h excretion. Systolic nd distolic BP were lso positively relted to overnight potssium excretion, but inversely to dytime nd 24-h excretion. None of these ssocitions ws sttisticlly significnt. These findings re consistent with those of the present study, since positive ssocitions of BP with rtios of overnight to 24-h excretion re indictive of stronger ssocition of BP with overnight excretion thn with dytime or 24-h excretion. Positive ssocitions of BP with overnight to 24- h rtios of sodium nd potssium in these men indicte tht with higher BP, reltively greter proportion of 24-h urinry sodium nd potssium excretion occurred t night. These results lso indicte however, tht with higher BP, reltively smller proportion of 24-h urinry sodium nd potssium excretion occurred during the dytime, since the proportion excreted during the dy is simply 100 minus the proportion excreted t night. Temporl sequence of the cross-sectionl findings reported here remins to be elucidted. In prticulr it is uncler whether reltively greter sodium nd potssium excretion t night is risk fctor for higher BP (eg, vi renl mechnisms), or whether higher BP results in reltively greter sodium nd potssium excretion t night, or both. Dt presented here provide some support for the expl- 369
370 ntion tht higher BP results in greter sodium nd potssium excretion t night. In prticulr, BP tended to be more highly correlted with the rtio of overnight to 24-h excretion for the first 24-h period thn for the second or third 24-h period for both sodium nd potssium. Such result might be expected if higher BP results in greter excretion, becuse BP ws mesured closer to the time of the first 24-h period thn the second or third 24-h periods. However, weker ssocitions with rtios for the second nd third 24-h periods could lso be due to prticipnts being less conscientious in regrd to timing nd completeness of the second nd third 24-h collections compred to the first. While rtios were corrected for cretinine excretion, this pproch my not hve fully ddressed this potentil problem. Stessen et l 28 found significnt positive ssocition between csul BP nd overnight sodium excretion even when BP ws mesured on verge 7 dys prior to urine collection. Reltively greter sodium nd potssium excretion t night with higher BP could lso reflect impired bility to excrete slt nd wter in response to n ingested sodium lod. In prticulr, if pressure rises in response to sodium lod, but dytime renl excretion of slt nd wter remins impired, compenstion my be chieved with nocturnl ntriuresis. Studies of sodium loding hve shown delyed ntriuretic response to sline infusion in normotensive persons t greter risk of hypertension. 60 In these studies, investigtors found tht blck subjects nd older persons hd delyed ntriuretic response fter sline lod compred with white persons nd younger persons. With sodium loding, the proportion of 24-h excretion during sleep ws greter for blcks thn whites nd for persons ges 40 nd over compred to those under ge 40. Bultsov et l 27 showed in young borderline hypertensives tht the circdin rhythm of sodium excretion ws lredy disturbed. They hypothesised tht the likely cuse ws n exggerted rise in renl drenergic ctivity during the dy, induced by orthostsis nd the concomitnt physicl nd/or mentl ctivity, indequtely compensted for by ctivtion of ntriuretic mechnisms. The finding in the present study tht differences in rtios of overnight to 24-h excretion of sodium nd potssium between hypertensives on nondiuretic therpy nd the other men were essentilly explinble by the higher BPs of the hypertensives suggests tht the reltively greter sodium nd potssium excretion observed with higher BP in this study is not relted to hypertension per se, ie, the incresed excretion t night is reversible with effective nti-hypertensive therpy. This result is consistent with the suggestion of Cowley nd Romn, 58 in review of current knowledge on the role of the kidney in hypertension, tht ll effective nti-hypertensive drugs promote excretion of sodium nd wter nd shift the reltion between BP nd sodium excretion towrd lower pressures. 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