(Hypertension. 1996;28:139-142.)
© 1996 American Heart Association, Inc.
Articles |
High Sodium Sensitivity Implicates Nocturnal Hypertension in Essential Hypertension
the Division of Nephrology, National Cardiovascular Center, Osaka, Japan.
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Abstract |
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We investigated the relationship between sodium sensitivity and diurnal variation of blood pressure in patients with essential hypertension. Twenty-eight inpatients with essential hypertension were maintained on high sodium (12 to 15 g NaCl per day) and low sodium (1 to 3 g NaCl per day) diets for 1 week each. Twenty-four-hour blood pressure and urinary sodium excretion were measured at the end of each diet period, and the sodium sensitivity index was calculated as the ratio of the change in mean arterial pressure to the change in urinary sodium excretion rate by sodium restriction. Patients whose average mean arterial pressure was lowered more than 10% by sodium restriction were assigned to the sodium-sensitive group (n=16); the remaining patients, whose mean arterial pressure was lowered by less than 10%, were assigned to the non-sodium-sensitive group (n=12). In the non-sodium-sensitive group, mean arterial pressure and heart rate fell during the nighttime, and average values of systolic, diastolic, and mean arterial pressures during the night were significantly lower than those during the day during both low and high sodium diets. On the other hand, in the sodium-sensitive group, there was no nocturnal fall in mean arterial pressure, and none of the systolic, diastolic, and mean arterial pressure values during the nighttime was different from the respective pressure values during the daytime during either sodium diet. The sodium sensitivity index was positively correlated with the fall in mean arterial pressure during the nighttime during a high sodium diet (r=.55, P<.01). These results indicate that in patients with sodium-sensitive essential hypertension, blood pressure fails to fall during the night. High sodium sensitivity may be a marker of greater risk of renal and cardiovascular complications, as has been found in nondippers, patients whose blood pressure fails to fall during the night.
Key Words: sodium • blood pressure • natriuresis • circadian rhythm
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Introduction |
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Whole-day BP recordings in healthy subjects are characterized by a nocturnal fall in BP values. In patients with essential hypertension, it has been proposed that the lack of this nocturnal fall is associated with more serious end-organ damage, such as left ventricular hypertrophy, microalbuminuria, or cerebrovascular disease.1 2 3 4 SS essential hypertensive patients are also more likely to manifest left ventricular hypertrophy and microalbuminuria than NSS hypertensive patients.5 On the other hand, we have proposed that glomerular capillary pressure is elevated in SS hypertension.6 7 8 Recently, it was reported that urinary excretion of albumin, which may be a marker of glomerular capillary hypertension,9 10 is greater in patients whose BP does not fall during the night, called nondippers, than in those with a normal circadian rhythm, called dippers,1 as well as in SS hypertensive patients than in NSS hypertensive patients.10 Thus, a relationship seems to exist between the absence of nocturnal BP fall and the sodium sensitivity of BP. To determine the circadian rhythm of BP in SS patients with essential hypertension, we measured 24-hour BP in two groups of patients with essential hypertension classified on the basis of their salt sensitivity.
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Methods |
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Patients
Twenty-eight Japanese inpatients with essential hypertension (17 men and 11 women; aged 38 to 66 years; mean±SE, 51±2 years; body weight, 66.7±2.6 kg; height, 162±2 cm), all of whom had given their informed consent, were studied in the Nephrology Unit of the National Cardiovascular Center Hospital. Patients with a history of myocardial infarction, congestive heart failure, stroke, diabetes mellitus, or liver disease were excluded from the study. Antihypertensive drugs were discontinued at least 2 weeks before hospitalization. During the initial hospitalization, a routine examination was performed to exclude secondary hypertension as well as to evaluate the severity of the hypertensive state. Digital subtraction renal angiography or a radioisotope renogram was performed, especially in NSS patients, to exclude renovascular hypertension. In SS patients, aldosterone was measured in both plasma and urine, and computerized tomography of the adrenal gland was performed to exclude primary aldosteronism. No patient showed evidence of a detectable secondary cause for hypertension or malignant hypertension.
Study Protocol
After the initial 1- to 2-week hospitalization, during which BP was stabilized, patients were subjected to the respective study protocols, which lasted another 2 weeks with patients hospitalized. Before the study was started, baseline BP and serum creatinine concentration were determined with patients on a regular sodium diet. Baseline BP was measured by nurses with a mercury sphygmomanometer around 10 AM after patients had rested for at least 30 minutes. All diets were isocaloric and contained the same amount of lipid and protein throughout the studies. No antihypertensive drugs were administered during the study periods.
Patients were maintained on a high sodium diet containing 12 to 15 g NaCl per day (stage I) and a low sodium diet containing 1 to 3 g NaCl per day (stage II) for 1 week each. The order of stage I and II was randomized. The food was the same except for the amount of NaCl added to the food in the two stages. Essentially no NaCl was added to the low sodium diet in stage II, whereas 11 to 12 g NaCl per day was added as seasoning during cooking of the high sodium diet in stage I.
Twenty-four-hour BP measurements were noninvasively performed every hour with an automatic oscillometric device (model BP8800NC, Nippon Colin) with patients in the supine position after they had rested for at least 15 minutes to prevent the marked changes in BP induced by activity and position. Patients were allowed their usual daily life activities between the measurements, except that they were asked to get up at 6 AM and to go to sleep at 10 PM. MAP was calculated as diastolic BP plus one third of the difference between systolic and diastolic BPs. Daytime BP was calculated as the average of the readings between 6 AM and 10 PM and nighttime BP as the average of the remaining readings. UNaV was measured on the last 3 days of each stage.
Patients whose average 24-hour MAP was lowered more than 10% by sodium restriction from stage I to stage II were assigned to the SS group; the remaining patients were assigned to the NSS group.7 A pressure-natriuresis curve11 12 13 14 15 16 was constructed by plotting UNaV on the ordinate as a function of MAP on the abscissa, both variables having been measured after a steady-state sodium balance had been achieved during normal and low sodium diets. The sodium sensitivity index was calculated as the ratio of the change in MAP to the change in UNaV from stage I to stage II by sodium restriction,17 which is the reciprocal of the slope of the pressure-natriuresis curve. The nocturnal fall in MAP was calculated as the difference in the average between daytime MAP and nighttime MAP.
Statistical Analysis
Results are expressed as mean±SE. The significance of differences in parameters between daytime and nighttime was determined by Student's t test for paired samples, and that between SS and NSS groups was examined by Student's t test for nonpaired samples. The correlation coefficient was obtained by the method of least squares.
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Results |
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The clinical characteristics of all study patients are shown in Table 1
. Sixteen patients were classified as SS and 12 as NSS. No significant differences were detected in age (49±3 versus 52±2 years), sex distribution (male/female: 7/5 versus 10/6), and body mass index (24.5±1.3 versus 26.2±1.2 kg/m2) between the NSS and SS groups. Neither baseline BP nor serum creatinine concentration differed between the groups.
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UNaV was measured during low (stage I) and high (stage II) sodium diets. When sodium intake was restricted from the high to low sodium diet, UNaV in the SS and NSS groups decreased from 194±10 to 15±4 and 194±8 to 14±4 mmol/d, respectively. UNaV was similar in NSS and SS patients. The pressure-natriuresis curve (arterial pressure-urinary sodium output relationship) was obtained by plotting UNaV (millimoles per day) in stage I and II on the ordinate as a function of MAP (millimeters of mercury) on the abscissa. The extrapolated x intercept of the pressure-natriuresis curve was 99±4 and 98±2 mm Hg, and the sodium sensitivity index, which is the reciprocal of the slope, was 0.008±0.020 and 0.11±0.01 mm Hg/(mmol/d) in the NSS and SS groups, respectively.
Fig 1 shows the circadian rhythm of MAP and heart rate in the study patients. In the NSS group, MAP and heart rate gradually fell during the evening, reached a nadir between 1 and 3 AM, and then began to rise again gradually. On the other hand, in the SS group, there was a similar nocturnal fall in heart rate but not in BP. Although MAP was significantly lowered by sodium restriction only in the SS group, the pattern of circadian rhythm of MAP was not altered by sodium restriction in either group.
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) and high (
) sodium diets in NSS (left) and SS (right) patients with essential hypertension. Values are mean±SE.
The average values of systolic BP, diastolic BP, and MAP during the daytime and nighttime are shown in Table 2. In the NSS group, nighttime systolic BP, diastolic BP, and MAP were significantly lower than the respective daytime values during both low and high sodium diets. On the other hand, in the SS group, nighttime BPs did not differ from daytime BPs during either sodium diet. Systolic BP, diastolic BP, and MAP during both the day and night were all significantly higher in the SS than NSS group during the high sodium diet, but there was no difference during the low sodium diet.
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The nocturnal falls in MAP in the NSS and SS groups during low and high sodium diets are shown in Fig 2. MAP fell less during the night in the SS group compared with the NSS group during the high sodium diet but not during the low sodium diet. The fall in nocturnal MAP did not differ significantly during low and high sodium diets in either the NSS or SS group.
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The relationships between sodium sensitivity index and the nocturnal fall in MAP during high and low sodium diets were evaluated, as shown in Fig 3. Although there was no significant relation between sodium sensitivity index and nocturnal fall in MAP during the low sodium diet, sodium sensitivity index was positively correlated with MAP fall during the nighttime during the high sodium diet (r=.55, P<.01).
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Discussion |
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Our results in 28 patients with essential hypertension revealed remarkable differences in the circadian rhythm of BP between the NSS and SS groups. In recent years, the circadian rhythm in normotensive subjects and essential hypertensive patients has been documented with the use of automated indirect ambulatory BP measurement. In most normotensive and some hypertensive individuals, BP tends to be highest during the early morning, decreases gradually during the day, and reaches the lowest level at night.18 19 In some patients with essential hypertension or renal dysfunction, however, BP fails to fall during the night; these patients have been called nondippers, whereas those with a normal circadian rhythm have been called dippers.3 Our finding that the night-day BP difference was not observed and the nocturnal fall in BP was reduced in an SS group indicates that SS patients with essential hypertension are likely to manifest as nondippers. This is consistent with a report that black Americans, who are very sodium sensitive, have a minimal nocturnal decline in BP.20 It is well known that approximately 50% of patients with essential hypertension are salt sensitive.19 21 22 Verdecchia et al2 defined daytime as 6 AM to 8 PM and nighttime as 8 PM to 6 AM, similar to our definition, and found a 40% prevalence of nondippers in essential hypertension. The similar prevalence between SS patients and nondippers supports our results on the link between these two pathophysiological states. Probably, most of the NSS patients with essential hypertension manifest as dippers, whereas in SS patients, the prevalence of nondippers becomes relatively higher. On the other hand, we have postulated on a theoretical basis that in SS hypertension, glomerular capillary hydraulic pressure is elevated; in all animal models examined whose BP is sensitive to changes in sodium intake, glomerular capillary pressure was indeed elevated.6 7 8 In fact, Campese and colleagues23 found that glomerular capillary pressure was elevated in blacks with SS hypertension and that urinary albumin excretion rate, which may be a marker of glomerular capillary hypertension (Yoshioka et al9 and Bigazzi et al10 ) is greater in SS essential hypertension than in NSS hypertension.10 In addition, they also showed that urinary excretion of albumin is greater in nondippers than in dippers (Bianchi et al1 ). Several studies have shown that nondippers manifest greater evidence of end-organ damage, such as left ventricular hypertrophy, microalbuminuria, or cerebrovascular disease, than dippers.1 2 3 4 It is well known that in patients with renal dysfunction, the nocturnal fall of BP is lost, and they manifest as nondippers.24 As renal function deteriorates and the number of functioning nephrons is reduced, glomerular capillary pressure is elevated in the remaining nephrons.25 26 In turn, this glomerular hypertension accelerates the speed of the long-term loss of function, resulting in glomerulosclerosis and eventual end-stage renal failure.27 28 29 30 It is also interesting to note that nondippers with renal dysfunction progress more rapidly to renal failure than dippers.31 Thus, a diminished nocturnal fall in BP, that is, nocturnal hypertension, in SS patients may correlate with increased glomerular capillary hydraulic pressure, that is, glomerular hypertension. High sodium sensitivity may be a marker of greater risk of renal and cardiovascular complications, as has been found in nondippers.
A nocturnal fall in BP during the high sodium diet was positively correlated with sodium sensitivity index, but that during the low sodium diet was not. When sodium intake was restricted, the nocturnal fall in MAP in the NSS and SS groups changed from -6.7±1.7 to -5.2±1.1 and from -0.8±2.3 to -2.9±2.0 mm Hg, respectively. In either NSS or SS group, the magnitude of the nocturnal fall was not affected by sodium restriction. However, sodium restriction tended to increase the difference between daytime and nighttime BP values in SS patients. Recently, it was reported that high salt exposure increased nighttime MAP but did not alter daytime MAP in Wistar-Kyoto rats.32 It also has been reported that UNaV was positively correlated with BP during the night but not during the day in humans.18 Coca33 found a significant increase in standard deviations of 24-hour BP by increasing sodium intake in SS hypertensive individuals. Thus, changes in dietary sodium intake might modify the circadian rhythm of BP.
In conclusion, in this study we demonstrated that in SS essential hypertensive patients, BP fails to fall during the night. Further studies are required to clarify (1) whether high sodium sensitivity leads to worse renal and cardiovascular complications and (2) the mechanism of the link between high sodium sensitivity and nocturnal hypertension.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by Research Grants for Cardiovascular Diseases (C-1994-6 and C-1995-3) and for "Progressive Renal Disease" from "Specially selected diseases by the Ministry of Health and Welfare Research Project" from the Ministry of Health and Welfare of Japan.
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Footnotes |
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Reprint requests to Takashi Uzu, MD, Division of Nephrology, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565, Japan.
Received October 23, 1995;
first decision March 18, 1996;
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