Salt-induced exacerbation of morning surge in blood pressure in patients with essential hypertension

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1 (2000) 14, Macmillan Publishers Ltd. All rights reserved /00 $ ORIGINAL ARTICLE Salt-induced exacerbation of morning surge in blood pressure in patients with essential hypertension T Osanai, T Okuguchi, T Kamada, N Fujiwara, T Kosugi, G Saitoh, T Katoh, T Nakano, K Takahashi, W Guan and K Okumura The Second Department of Internal Medicine, Hirosaki University School of Medicine, Hirosaki, Japan The morning surge in blood pressure (BP) is related to the morning occurrence of lethal cardiovascular events. We tested the hypothesis that salt intake may be associated with the morning surge in BP in essential hypertension. Seventy-six patients were admitted and placed on a low salt diet (2 g/day) for 7 days followed by a high salt diet (20 23 g/day) for another 7 days. At the end of each salt diet, 24-h ambulatory BP and heart rate monitorings and head-up tilt (HUT) test were performed. Patients whose average mean BP (MBP) was increased by more than 10% by salt loading were assigned to the salt-sensitive (SS) group (n 37); the remaining patients, whose MBP was increased by less than 10%, were assigned to the non-salt-sensitive (NSS) group (n 39). The increase in ambulatory MBP during am above the baseline ( am) was significantly enhanced by salt loading in the NSS group (P 0.05), but not in the SS group. The coefficient of variation of 24-h MBP and heart rate was increased by salt loading only in the NSS group. The significant elevation of plasma noradrenaline concentration after awakening, which was noted during the low salt diet period, was unchanged during the high salt diet period in the NSS group, but abolished in the SS group. Salt loading enhanced HUT-induced decrease in systolic BP without affecting the heart rate response only in the NSS group. We conclude that the morning surge in BP is enhanced by salt loading in the NSS type of essential hypertension, presumably by the excessive activation of the sympathetic nervous system. (2000) 14, Keywords: morning surge; salt; catecholamine; head-up tilt; baroreflex Introduction The distribution of the onset of lethal cardiovascular events such as myocardial infarction (MI) has been reported to show a circadian periodicity. Muller et al 1 demonstrated that a marked circadian peak in the frequency of the onset of MI was present from 6.00 am to 12 noon. An additional peak in the late evening or in the very early morning was reported in other studies. 2 5 Among them, the morning onset (6.00 am am) of MI has been studied extensively, 4,5 and a causative relationship has been suggested to the morning surge in blood pressure (BP) 6 as well as the morning rises in platelet aggregability, 7 thrombotic activity, 8 and serum concentrations of cortisol and catecholamines. 9,10 Based on the suppressant effect of sympatholytic drugs, 11 the morning surge in BP is thought to be associated with the excessive activation of the sympathetic nervous system. 12 Extensive evidence has shown that salt intake has an influence on sympathetic nervous system including baroreflex function. A Correspondence: Dr Tomohiro Osanai, The Second Department of Internal Medicine, Hirosaki University School of Medicine, Zaifu-cho 5, Hirosaki, Japan Received 25 February 1999; revised 5 August 1999; accepted 9 September 1999 high salt diet elicits an increase in urinary noradrenaline (NA) excretion in patients with essential hypertension (EH), 13 whereas it suppresses the function of arterial baroreflex Taken together, this evidence suggests a possibility that salt intake plays an important role in the morning surge in BP by modulating the sympathetic nervous activity. This study was therefore designed to investigate the effect of salt intake on the morning surge in BP in human hypertension. We demonstrate that the morning surge in BP is enhanced by salt loading in patients with EH, presumably by the excessive activation of the sympathetic nervous system including the impaired baroreflex function. Subjects and methods Subjects Seventy-six patients with EH (38 men, 38 women), all of whom had given their informed consent before the study, were investigated during admission to our hospital. They had mild-to-moderate hypertension with casual clinic systolic BP between 150 and 180 mm Hg and diastolic BP between 90 and 115 mm Hg. Secondary hypertension was excluded by physical examination, urinalysis, rapid sequential intravenous pyelography, adrenal computed tomo-

2 58 Salt and morning surge in blood pressure graphy scan, renal arteriography, and hormonal examinations such as plasma renin activity (PRA), plasma aldosterone concentration (PAC), plasma catecholamine concentration, and 24-h urinary excretions of 17-hydrocorticosteroids and 17-ketosteroids. Study 1 All antihypertensive medications were discontinued at least 2 weeks before admission. Of the 76 study patients, 49 were involved in the following study. They maintained a constant daily activity pattern and adhered to specific diets arranged by the amount of salt. A 12 g salt diet (normal salt diet) was administered for the initial 10 days, 2 g salt diet (low salt diet) for the next 7 days, and then g salt diet (high salt diet) for the last 7 days. Compliance to the prescribed diet was assessed by the measurement of 24-h urinary sodium excretion on the last day of each salt diet period. On the last day of the normal salt diet, BP was measured at 6.00 am in a recumbent position and blood was drawn from all subjects for the determination of serum creatinine, sodium, potassium, PRA, PAC, plasma NA concentration (PNA), and plasma adrenaline concentration (PA). Twenty-four hour urine was collected for the measurements of urinary NA, adrenaline (A), dopamine, and creatinine clearance. At the end of each salt diet period, every 30-min non-invasive ambulatory BP and heart rate monitorings were performed for 24 h using the ABPM-630 (Nippon Kohrin Co, Komaki, Japan). The ambulatory data were calculated by the oscillometric method. When the average of mean BP (MBP) ([systolic BP diastolic BP]/3 + diastolic BP) measured for 24 h at the end of high salt diet period was greater than that at the end of low salt diet period by more than 10% of the latter value, the patients were classified as the salt-sensitive (SS) group. In contrast, when the increase in the average of mean BP during the high salt diet period was less than 10%, the patients were classified as the non-salt-sensitive (NSS) group. The coefficient of variation of MBP or heart rate was calculated by the formula of (standard deviation/ average of the 24-h ambulatory MBP or heart rate) 100 (%). Morning surge in BP was assessed by the morning increase in MBP which was calculated by subtracting the average of MBP during am (baseline MBP) from each MBP value during am. The baseline MBP was selected by the previous study that MBP during am represented the lowest value. Subjects were asked to record daily activities. In the present study, all subjects reported no disturbance of sleep by the noise of the monitor. At the end of each salt diet period, blood specimens were obtained from the cubital vein at 5.00 am and am for the measurement of PNA, PA, PRA and PAC. Study 2 The remaining 27 patients maintained the same constant daily activity pattern as in study 1. The same series of salt diets as in study 1 were administered to each patient, and the patients were classified into the NSS or SS group. On the 5th day of each salt diet period, a head-up tilt test was undertaken on each subject: after keeping a recumbent position for 30 min, the transit from 0 to 70 was passively completed for 30 sec and its position was maintained for 9. min. During the head-up tilt test (10 min), BP and heart rate were monitored every minute and blood specimens were obtained from the cubital vein before and just after the test to determine the plasma concentration of catecholamines. The ratio of an increase in heart rate to a decrease in systolic BP at 1 min after the initiation of the transit was calculated to simply evaluate the function of arterial and cardiopulmonary baroreflex. Laboratory procedures Plasma was separated by centrifugation at 4 C for 10 min, and stored at 80 C until the measurement of various items. Serum sodium and potassium ion concentrations were measured with a flame photometer. Serum and urinary creatinine was measured by an autoanalyzer method. NA, A, and dopamine concentrations were measured by high performance liquid chromatography. PRA and PAC were measured by radioimmunoassay. Statistics Values were shown as the mean ± one standard error. Differences in clinical data, physiological variables, MBP, heart rate, PNA, PA, PRA, and PAC were statistically analysed by unpaired Student s t- test between the NSS and SS groups, and by paired Student s t-test between low and high salt diet periods in each group. Differences in the morning increases in MBP between low and high salt diet periods and those between NSS and SS groups were analysed by multivariate analysis of variance (ANOVA). Differences in the baseline and morning MBP between low and high salt diet periods were assessed by two-way ANOVA. Comparison of the changes in systolic BP and heart rate during the head-up tilt test at each time point was performed by Contrast. A P value less than 0.05 was evaluated as statistically significant value. Results Study 1 Of the 49 patients, 24 were classified as NSS group and the remaining 25 as SS group. Table 1 shows clinical data and physiological variables for each group on the last day of normal salt diet period. The distributions of age, sex, height, weight, and heart rate did not differ between the two groups. There was no significant difference in systolic BP, diastolic BP, serum creatinine, creatinine clearance, PAC, PNA, PA, urinary NA, urinary A, urinary dopamine, and plasma electrolytes between the two groups, except that PRA tended to be less in the SS group than in the NSS group. No patients had diabetes

3 Table 1 Clinical data and physiological variables 59 Variables Study 1 Study 2 Non-salt-sensitive Salt-sensitive Non-salt-sensitive Salt-sensitive Number Age (years) 48 ± 2 52 ± 2 49± 3 54 ± 2 Sex (men, women) 13, 11 10, 15 10, 5 5, 7 Height (cm) ± ± ± ± 2.9 Weight (kg) 60.2 ± ± ± ± 3.4 Systolic BP (mm Hg) 129 ± ± ± ± 5 Diastolic BP (mm Hg) 80 ± 3 83 ± 3 82± 4 83 ± 5 Pulse rate (beats/min) 63 ± 1 64 ± 1 64± 3 62 ± 2 Serum creatinine (mg/dl) 1.0 ± ± ± ± 0.2 Serum sodium concentration (meq/l) 142 ± ± ± ± 0.4 Serum potassium concentration (meq/l) 4.1 ± ± ± ± 0.1 Creatinine clearance (ml/min) ± ± ± ± 9.7 Plasma renin activity (ng/ml/hr) 0.6 ± ± ± ± 0.1 Plasma aldosterone concentration 9.6 ± ± ± ± 1.2 (ng/dl) Plasma noradrenaline (ng/ml) 0.18 ± ± ± ± 0.06 Plasma adrenaline (ng/ml) 0.01 ± ± ± ± Urinary noradrenaline ( g/day) 78.8 ± ± ± ± 23.1 Urinary adrenaline ( g/day) 9.4 ± ± ± ± 1.4 Urinary dopamine ( g/day) ± ± ± ± Values are mean ± s.e. Data refer to values obtained when the balance had been achieved with 12 g (normal) salt diet. Blood pressures were measured, and blood samples were obtained at 6.00 am from all subjects in recumbent position. mellitus and target organ damage such as stroke, MI, and renal failure. Urinary sodium excretion was increased by salt loading from 28 ± 3 to 336 ± 24 meq/day in the NSS group and from 33 ± 5 to 342 ± 20 meq/day in the SS group. Ambulatory MBP and morning surge in BP: As shown in Table 2, ambulatory MBP did not differ between the NSS and SS groups during both waking and sleeping periods under the low salt diet. Under the high salt diet, however, that during the sleeping period was higher in the SS group than in the NSS group. The coefficient of variation of MBP was increased by salt loading in the NSS group, but decreased in the SS group. Figure 1 (left panel) illustrates the change in ambulatory MBP from midnight to noon. In NSS group, MBP during am tended to be greater during the high salt diet period compared to that during the low salt diet period (two-way ANOVA) despite no change in the baseline MBP ( am). In the SS group, MBP during am under the high salt diet was greater than that under the low salt diet (P 0.01, two-way ANOVA). However, the baseline MBP also elevated to a similar degree after salt loading. Compared between NSS and SS groups, MBP during am did not differ during both salt diet periods. As shown in Figure 1 (right panel), the morning increase in MBP, which was calculated by subtracting the average of baseline MBP ( am) from each MBP value during am, was significantly higher in the NSS group during the high salt diet period compared to that during the low salt diet period (P 0.01, multivariate ANOVA). It was also higher in the NSS group during the high salt diet period than in the SS group during both salt diet periods (P 0.01, respectively). In the SS group, the morning increase in MBP during the high salt diet period did not differ from that during the low salt diet period. Heart rate: Table 3 summarises the effect of salt loading on ambulatory heart rate. In the NSS group, salt loading decreased the average heart rate during the sleeping period without affecting that during the waking period. In the SS group, however, it decreased the average heart rate during both periods. The coefficient of variation was increased in Table 2 Comparison of ambulatory mean BP between low and high salt diets Group Parameters Low salt diet High salt diet NSS Average of waking period (mm Hg) 97.5 ± ± 3.0 Average of sleeping period (mm Hg) 88.1 ± ± 3.0 Coefficient of variation (%) 11.1 ± ± 0.8* SS Average of waking period (mm Hg) 92.8 ± ± 2.0*** Average of sleeping period (mm Hg) 82.5 ± ± 2.5*** Coefficient of variation (%) 12.4 ± ± 0.6** Values are mean ± s.e. *P 0.05; **P 0.01; ***P 0.001, vs low salt diet; P 0.05, vs NSS. Waking period: 8.00 am 8.00 pm; sleeping period: pm 6.00 am.

4 60 Figure 1 Effects of salt loading on ambulatory mean blood pressure (MBP) from midnight to noon (left panel) and increases in the morning ambulatory MBP after awakening (right panel). The increase in the morning ambulatory MBP after awakening ( MBP) was calculated by subtracting the average of MBP at night ( am) from each MBP value during am. Note that salt loading enhanced the increase in morning ambulatory MBP only in the non-salt-sensitive (NSS) group. *P 0.01, multivariate ANOVA. Table 3 Comparison of heart rate between low and high salt diets Group Parameters Low salt diet High salt diet NSS Average of waking period (beats/min) 74.8 ± ± 1.6 Average of sleeping period (beats/min) 58.7 ± ± 1.3** Coefficient of variation (%) 17.8 ± ± 0.7** SS Average of waking period (beats/min) 74.4 ± ± 1.3* Average of sleeping period (beats/min) 60.4 ± ± 0.8** Coefficient of variation (%) 16.4 ± ± 0.6* Values are mean ± s.e. *P 0.05; **P 0.01, vs low salt diet. Waking period: 8.00 am 8.00 pm; sleeping period: pm 6.00 am. both groups, but the increment was greater in the NSS group than in the SS group. PNA, PA, PRA, and PAC: As illustrated in Figure 2, the elevation of PNA after awakening was unaffected by salt loading in the NSS group, but was abolished in the SS group. PNA at 5.00 am was suppressed by salt loading in both groups (P 0.01, respectively), but the suppression rate was less in the SS group than in the NSS group (P 0.05). Thus, during the high salt diet period, PNA at 5.00 am tended to be greater in the SS group than in the NSS group. PA was increased after awakening to a similar extent under each salt diet in both groups. PRA showed no changes after awakening and no differences between the NSS and SS groups. PAC was decreased after awakening during the low salt diet period in the SS group. Study 2 Of the 27 patients, 15 were classified as NSS group and 12 as SS group. As shown in Table 1, none of the patient profiles differed between both groups, except that PRA tended to be lower in the SS than in the NSS group. No patients had diabetes mellitus and target organ damage. Urinary sodium excretion was increased by salt loading from 30 ± 4 to 336 ± 24 meq/day in the NSS group and from 29 ± 5 to 342 ± 20 meq/day in the SS group. Head-up tilt: Figure 3 demonstrates changes in systolic BP and heart rate from the baseline during the head-up tilt test. In the NSS group (left panel), head-up tilt caused a transient decrease in BP during the low salt diet period, but there was a sustained decrease during the high salt diet period. At an early phase (2 min) and a late phase (7 min), the decrease

5 61 Figure 2 Effects of salt loading on changes in plasma noradrenaline concentration (PNA) and plasma adrenaline concentration (PA), plasma renin activity (PRA), and plasma aldosterone concentration (PAC) after awakening. Note that the increase in PNA by awakening was not affected by salt loading in the non-salt-sensitive (NSS) group, but was abolished in the salt-sensitive (SS) group. in BP during the high salt diet period was significantly greater than that during the low salt diet period (P 0.05, by Contrast, respectively). The heart rate response was unaffected by salt loading. In the SS group (right panel), neither the decrease in BP nor the increase in heart rate due to the head-up tilt test was affected by salt loading. As shown in Figure 4, the ratio of the increase in heart rate to the decrease in systolic BP was reduced by salt loading only in the NSS group. Figures 5 and 6 demonstrate the response of PNA and PA to the head-up tilt test. There were no differences in PNA and PA at baseline between the two groups during both salt diet periods. PNA and PA were significantly increased after head-up tilt during both salt diet periods in the two groups. The percent change in PNA and PA due to head-up tilt was greater during the high salt diet period than that during the low salt diet period in the NSS group (PNA: 111 ± 28 vs 175 ± 32%, P 0.05; PA: 20 ± 11 vs 122 ± 37%, P 0.05), while it was unchanged in the SS group. Discussion The present study showed that the morning surge in BP was exacerbated by salt loading in the NSS group and not in the SS group, that the ratio of the increase in heart rate/the decrease in BP during head-up tilt was reduced by salt loading in the NSS group and not in the SS group, that the coefficient of variation of BP and heart rate was increased by salt loading in the NSS group, and that the nocturnal fall of PNA was unaffected by salt loading in the NSS group but blunted in the SS group. Effect of salt loading on morning surge in BP Much evidence have indicated that the severity of left ventricular hypertrophy and hostility are associated with the morning surge in BP. 11,18 Although clinical studies on the effect of salt intake on the circadian rhythm of BP were investigated, little attention has been paid to the morning surge in BP during the high salt intake. The observation that the nocturnal fall in BP was diminished in the SS group during the high salt diet period is consistent with the previous report. 19 However, the present result further showed that a high salt intake induced the exacerbation of the morning surge in BP without affecting the baseline BP at night in the NSS group. This suggests that in the NSS group, the morning rise in BP is a surge type. In the SS group, the BP level in the morning was similar to that in the NSS group during the high salt diet period, while the morning rise in BP was less than that in the NSS

6 62 Figure 3 Effects of salt loading on changes in systolic BP and heart rate in response to the head-up tilt test. As shown in the left panel, salt loading enhanced the decrease in systolic BP at 2 and 7 min after the initiation of the transit without affecting the heart rate response in the non-salt-sensitive (NSS) group. *P 0.05, vs systolic BP under the low salt diet (Contrast). group. This indicates that in the SS group, the morning rise in BP is a sustained type rather than a surge type which was seen in the NSS group. It has been reported that the lack of a nocturnal fall in BP is associated with more serious end-organ damage, such as left ventricular hypertrophy, microalbuminuria, and cerebrovascular disease, than is found in dippers, whose BP falls during the night Thus, the diminished nocturnal fall in BP in the SS group may correlate with a greater risk of renal and cardiovascular complications. On the other hand, the surge type of the morning rise in BP is another important factor relating to the morning onset of lethal cardiovascular attacks. 1 6 Thus, the result indicates that salt intake plays a crucial role in the morning onset of their attacks even in the NSS group, which showed the surgetypeofthemorningriseinbp. Mechanism for salt-induced exacerbation of morning surge in BP The different responsiveness of PNA to awakening was demonstrated between the NSS and SS groups. This appeared to be associated with the difference in the responses of nocturnal PNA to the high salt diet. During the high salt diet period, the nocturnal suppression of PNA was sufficient in the NSS group, but not in the SS group, resulting in a high level of nocturnal PNA in the SS group. Thus, the higher Figure 4 Effects of salt loading on the ratio of an increase in heart rate (HR)/a decrease in systolic BP during the head-up tilt test in salt-sensitive (SS) and non-salt-sensitive (NSS) groups.

7 63 Figure 5 Effects of salt loading on plasma noradrenaline concentration (PNA) and plasma adrenaline concentration (PA) in response to the head-up tilt test. PNA and PA were increased after head-up tilt test during low and high salt diet periods in the nonsalt-sensitive (NSS) group but not in the salt-sensitive (SS) group. level of PNA during the sleeping period may attenuate the further additional discharge of NA in response to awakening in SS group. In contrast, the lower level of PNA during the sleeping period may augment the further excessive discharge of NA after awakening in the NSS group. Because salt loading enhances the pressor response to infused NA, 24 it would exacerbate the morning surge in BP despite the similar increase in PNA after awakening in NSS group. The non-dippers, whose BP does not fall during the night, were shown to manifest dysfunction of autonomic nervous system using power spectral analysis of the 24-h RR interval. 25,26 This evidence may explain the mechanism for the insufficient suppression of PNA at night in the SS group, which demonstrated nocturnal hypertension. When the function of either arterial baroreceptors or cardiopulmonary receptors was impaired by salt loading, BP manifests lability since both of them buffer changes in BP and avoid excessive fluctuations of BP. 27 Thus, we undertook the head-up tilt test which reflects the functions not only of arterial baroreceptors but also of cardiopulmonary receptors. The attenuated response of heart rate in the NSS group indicates the impairment of arterial baroreceptor reflex and/or cardiopulmonary receptor reflex. Indeed, the coefficient of variation of BP and heart rate as the hallmark of their volatility was increased by salt loading in the NSS group. The enhanced elevation rate of PNA and PA to head-up Figure 6 Effects of salt loading on percent changes in plasma noradrenaline concentration (PNA) and plasma adrenaline concentration (PA) in response to the head-up tilt test. The percent increases in PNA and PA above the baseline were enhanced by salt loading in the non-salt-sensitive (NSS) group but not in the salt-sensitive (SS) group. tilt under the high salt diet in the NSS group also explains the tendency of excessive fluctuations of BP. Furthermore, the previous evidence that the baroreflex function of both arterial and cardiopulmonary receptors is desensitized after salt loading 14 16,28 31 appears to support the present result that high salt intake unmasks the impairment of baroreflex in the NSS type of EH. Study limitations Studies of salt responsiveness are difficult because of the moderate to low reproducibility and the confounding by age and BP level that generate risk of higher BP response to salt loading. Because the categories of salt sensitivity depend on arbitrary cutoffs and a clear bimodality in the arterial pressure response to changes in salt intake has not been established, the reproducibility of salt sensitivity has been argued. In normotensive subjects, almost perfect agreement was found between the first and second salt challenges. 32,33 In EH patients, however, reports are inconsistent with each other. Weinberger et al 34 reported that BP responses were significantly reproducible, whereas Zoccali et al 35 concluded that it was not despite similar BP changes being found within the groups when the study was repeated.

8 64 Salt and morning surge in blood pressure Because there are limitations as to the number of subjects and the range of sodium intake in their reports, this issue may still remain to be elucidated. The present study included only the patients with mild-to-moderate hypertension whose BP on the last day of the 10-day normal salt diet was in normal range. Thus, it is not clear whether our findings of salt-induced exacerbation of the morning surge in BP in NSS patients would also be found in patients with severe or sustained hypertension. Further studies will be required. References 1 Muller JE et al, MILIS study group. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 1985; 313: Hjalmarson A et al. Differing circadian patterns of symptom onset in subgroups of patients with acute myocardial infarction. Circulation 1989; 80: Tsuda M et al. 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