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(Hypertension. 1997;29:802-807.)
© 1997 American Heart Association, Inc.
Articles |
Baroreflex Impairment by Low Sodium Diet in Mild or Moderate Essential Hypertension
Cattedra di Medicina Interna (G.G., G.M.), Ospedale S. Gerardo, Monza, Universita di Milano; Centro di Fisiologia Clinica e Ipertensione, Ospedale Maggiore (G.G., B.M.C., A.L., G.B., G.M.); and Centro Auxologico Italiano (G.S., G.M.), Milan, Italy.
Correspondence to Prof Giuseppe Mancia, Centro Fisiologia Clinica e Ipertensione, Via F. Sforza 35–Policlinico, 20122 Milan, Italy.
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Abstract |
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Low sodium intake is the most widely used nonpharmacological approach to the treatment of hypertension. Although nonpharmacological treatment is by definition regarded as safe, the suggestion has been made that low sodium intake is not totally devoid of inconveniences, and animal data have shown it to be accompanied by an impairment of reflex blood pressure control and homeostasis. However, no data exist on this issue in humans. In mild essential hypertensive patients (age, 34.1±3.3 years [mean±SEM]), we measured beat-to-beat arterial blood pressure (finger photoplethysmographic device), heart rate (electrocardiogram), and efferent postganglionic muscle sympathetic nerve activity (microneurography) at rest and during baroreceptor stimulation and deactivation, induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Measurements were performed at the end of three dietary periods, ie, after 8 days of regular sodium intake (210 mmol NaCl/d), low sodium intake (20 mmol NaCl/d) with unchanged potassium intake, and again regular sodium intake. Compared with the initial regular sodium diet, low sodium intake reduced urinary sodium excretion, whereas urinary potassium excretion was unchanged. Systolic blood pressure was significantly (P<.05), although slightly, reduced, whereas diastolic blood pressure was unaffected. Muscle sympathetic nerve activity was increased by 23.1±5.2% (P<.05). The increase was accompanied by a clear-cut impairment of the baroreceptor ability to modulate muscle sympathetic nerve activity, ie, by a 43.9±5.7% (P<.01) reduction in the sensitivity of the baroreceptor–muscle sympathetic nerve activity reflex compared with the control condition. Baroreceptor modulation of heart rate was also impaired, although to a smaller and less consistent extent. When regular sodium intake was restored, all the above-mentioned parameters and baroreflex responses returned to the values observed at the initial regular sodium diet. These data raise evidence that in humans sodium restriction may impair the arterial baroreflex. This may be responsible for the sympathetic activation occurring in this condition and for the impairment of blood pressure homeostasis.
Key Words: diet, low sodium • baroreceptors • reflex • sympathetic nervous system • autonomic nervous system
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Introduction |
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Dietary sodium restriction is a widely used method to treat hypertension in the absence of or in association with antihypertensive drugs.1 2 3 4 5 In recent years, however, several studies have suggested that although effective in at least a fraction of the hypertensive population,5 6 7 8 sodium restriction has potential inconveniences.5 9 10 One of these inconveniences has emerged from experiments performed in dogs, rats, and monkeys showing that sodium depletion reduces the responsiveness of carotid baroreceptors and cardiopulmonary stretch receptors to physiological stimuli, thereby impairing reflex cardiovascular homeostasis.11 12 13 14 An impairment of cardiovascular homeostasis by sodium restriction has also been shown in rats in which survival to progressive hemorrhage was shortened by a modest reduction of sodium intake.15
Only few studies have addressed the effect of sodium restriction on reflex cardiovascular control in humans,16 17 and no information exists as to whether this restriction affects the major reflex function involved in blood pressure control, ie, arterial baroreceptor modulation of sympathetic nerve activity. We have addressed this issue in subjects with mild or moderate hypertension in whom sympathetic nerve traffic was quantified by microneurography during arterial baroreceptor stimulation and deactivation at regular and reduced sodium intakes.
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Methods |
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The present study included 15 untreated male patients with mild or moderate essential hypertension, ie, with (1) diastolic blood pressure between 95 and 105 mm Hg on repeated sphygmomanometric measurements; (2) no history and physical or laboratory evidence of cardiovascular disease or major target organ damage, such as congestive heart failure, coronary heart disease, stroke, peripheral artery disease, renal insufficiency, or "echocardiographic" left ventricular hypertrophy; and (3) no major concomitant noncardiovascular diseases. However, because in 6 subjects compliance to sodium restriction was poor and/or sympathetic nerve recording (see below) was unsatisfactory, the study was successfully completed in 9 subjects. These subjects had a body mass index <25 kg/m2 and an age ranging from 20 to 45 years (mean±SEM, 34.1±3.3 years). All subjects had sedentary habits, and none were cigarette smokers.
The protocol of the study was approved by the Ethics Committee of our institution. The patients agreed to participate in the study after explanation of its nature and purpose.
Dietary regimen
For each subject, three experimental sessions were performed sequentially. The first session was performed after 8 days of regular sodium diet; the second session, after 8 days of low sodium diet; and the third session, after 8 days of regular sodium diet again. The regular sodium diet contained 210 mmol sodium chloride; the low sodium diet contained 20 mmol sodium chloride. Both the regular and low sodium diets were designed to contain 100 mmol potassium. They were also designed to contain 50% carbohydrates, 18% proteins, and 32% fats, ie, to be isocaloric.
During the whole period of the study, the subjects were hospitalized, and 24-hour urine samples were collected before and, on a daily basis, during each 8-day period to measure urinary sodium and potassium content and thus to ensure that the selected dietary regimens were followed. Sodium balance was achieved by day 6 of each dietary regimen. Lifestyle and physical activity were not standardized, and the subjects were left free to walk in the hospital area, watch TV, and visit with relatives. They were asked, however, to be in the ward for meals and bedtimes.
Measurements
Blood Pressure, Heart Rate, Respiration Rate, and Central Venous Pressure
Blood pressure was measured by a mercury sphygmomanometer, taking the first and fifth Korotkoff sounds to identify systolic and diastolic values, respectively. In addition, blood pressure was monitored by a finger photoplethysmographic device (Finapres 2300, Ohmeda) capable of providing accurate and reproducible beat-to-beat systolic and diastolic values.18 Heart rate was also monitored beat to beat by a cardiotachometer triggered by the R wave of an electrocardiographic lead. Respiration rate was monitored by a strain-gauge pneumograph, positioned at the midchest level. Central venous pressure was measured in 5 subjects by a catheter placed in the right atrium from an antecubital vein and connected with a transducer (model P23XL, Gould Instruments) also positioned at the midchest level.
Sympathetic Nerve Traffic
Multiunit recording of efferent postganglionic sympathetic nerve activity to skeletal muscle district (muscle sympathetic nerve activity [MSNA]) was obtained from a microelectrode directly inserted in the right or left peroneal nerve posterior to the fibular head, as previously described.19 The microelectrode was made by tungsten and had a diameter of 200 µm in the shaft, tapering to 1 to 5 µm at the level of the uninsulated tip. A reference electrode positioned subcutaneously 1 to 3 cm from the recording electrode served as ground. The nerve signal was amplified x70 000, fed through a band-pass filter (700 to 2000 Hz), and integrated with a custom nerve traffic analysis system (Bioengineering Department, University of Iowa, Iowa City). Integrated nerve activity was monitored by a loudspeaker, displayed on a storage oscilloscope (model 511 A, Tektronix), and recorded together with blood pressure, heart rate, respiratory rate, and central venous pressure on an ink polygraph. The muscle nature of MSNA was assessed according to the criteria outlined in previous studies,20 21 and the recording was considered acceptable if the signal-to-noise ratio exceeded a value of 3.
Under baseline conditions, MSNA was quantified as bursts per minute and bursts per 100 heartbeats and as integrated MSNA (bursts per minute times mean burst amplitude expressed in arbitrary units).
Quantification of MSNA by this integration was shown to be highly reproducible, ie, to differ by only 3.8% when assessed on the same tracing in two separate occasions by a single investigator.22 Changes in integrated MSNA from baseline were used to quantify the effects of baroreceptor stimulation, baroreceptor deactivation, and cold pressor test (see below).
Plasma Renin Activity and Aldosterone
Plasma renin activity and plasma aldosterone were measured by radioimmunoassay23 24 on blood withdrawn from an antecubital vein of the arm contralateral to that used for blood pressure measurements. The same blood sample was used to measure plasma electrolyte concentration. As previously mentioned, 24-hour urine sodium and potassium content was also evaluated.
Evaluation of Baroreflex and Cold Pressor Test
Baroreceptor modulation of MSNA and heart rate was assessed by infusion of vasoactive drugs.25 Briefly, phenylephrine was incrementally infused in an antecubital vein at the doses of 0.3, 0.6, and 0.9 µg/kg per minute, each step being maintained for 5 minutes. Nitroprusside was also incrementally infused in an antecubital vein at the doses of 0.4, 0.8, and 1.2 µg/kg per minute, each step being also maintained for 5 minutes. In any given subject, the vasoactive drug to be infused first was selected randomly.
Mean arterial pressure (diastolic pressure plus one third of pulse pressure), MSNA, and heart rate were averaged for the 5 minutes before infusion and for the 5 minutes of each step infusion. Baroreceptor modulation of MSNA and heart rate was estimated by calculating the percent change in MSNA and the absolute change in heart rate in relation to the change in mean arterial pressure induced by each dose of phenylephrine and nitroprusside. The reflex heart rate and MSNA changes in response to mean arterial pressure changes were also averaged separately for the three doses of phenylephrine and nitroprusside to obtain average baroreflex sensitivities during baroreceptor stimulation and deactivation.
A cold pressor test was performed by immersion of the hand contralateral to that used for blood pressure measurements in iced water (3°C) for 2 minutes. Hemodynamic variables and MSNA were averaged for the 5 minutes before the cold pressor test and for the 2 minutes during the cold pressor test.
Protocol and Data Analysis
The first experimental session was performed in the morning. After a light breakfast, the subject was put in the supine position and fitted with the intravenous cannulas, the microelectrodes for MSNA recording, and the other measuring devices. The blood sample for assessment of plasma renin activity and plasma aldosterone was withdrawn, and blood pressure was measured three times by the mercury sphygmomanometer. After a 30-minute time period, blood pressure, heart rate, respiratory rate, central venous pressure, and MSNA were continuously monitored during (1) a 10-minute baseline state, (2) infusion of one vasoactive drug, (3) a second 10-minute baseline state, (4) infusion of the second vasoactive drug, (5) a 5-minute baseline state, and (6) a 2-minute cold pressor test. A 45-minute recovery period was allowed between (1) the end of the first drug infusion and the beginning of the second drug infusion and (2) the second drug infusion and the performance of the cold pressor test. The second and third experimental sessions followed the same protocol, including the order of the infusion of the vasoactive drugs.
Data were calculated by a single investigator unaware of the experimental design. Baseline blood pressure, heart rate, ventilation rate, central venous pressure, and MSNA obtained in individual subjects were averaged separately for each experimental session and expressed as mean±SEM. Calculations were also performed for (1) the changes in the above variables induced by each dose of phenylephrine, each dose of nitroprusside, and the cold-pressor test and (2) plasma renin activity, plasma aldosterone, and plasma and urinary electrolytes.
Comparisons between data obtained in each experimental session were made by two-way analysis of variance. The Spearman analysis was used to correlate changes in different variables. A value of P<.05 was taken as the level of statistical significance.
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Results |
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Baseline Values
Table 1
shows that compared with the initial regular sodium diet, sodium restriction caused a marked reduction in 24-hour urinary sodium excretion (last measurement), no change in 24-hour urinary potassium excretion, and a marked increase in plasma renin activity and plasma aldosterone. Serum sodium concentration, serum potassium concentration, and body weight did not show any significant change. Both the sphygmomanometric and finger systolic blood pressures were significantly, although slightly, reduced by sodium restriction. Diastolic blood pressure was also slightly reduced, although the reduction did not achieve statistical significance. This was also the case for heart rate and ventilation rate. When a regular sodium diet was restored, all variables returned to the control pre–low sodium diet values.
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As shown in the original example of Fig 1 and in the average data of Table 1
, when expressed as bursts per minute and as bursts per 100 heartbeats, MSNA was significantly increased by sodium restriction and returned to the pre–low sodium diet values when regular sodium intake was restored. There was no significant relationship between the increase in MSNA induced by sodium restriction and the concomitant changes in 24-hour urinary sodium excretion and plasma renin activity (r=.15 and .18, respectively; P=NS).
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Baroreceptor Reflex
As shown in Fig 2, during the initial regular sodium diet, the stepwise infusion of phenylephrine caused a progressive increase in mean arterial pressure, a progressive decrease in heart rate, and a progressive reduction in MSNA, whereas the stepwise infusion of nitroprusside had opposite effects. This was also the case during sodium restriction, although at each step of the infused vasoactive drug the MSNA reflex changes were significantly less than those observed during the preceding regular sodium diet. The reflex heart rate changes were also less, but the differences were statistically significant only for the last step of either drug infusion. Both the MSNA and heart rate changes returned to the values seen in the pre–low sodium diet period when regular sodium diet was restored. The sensitivity of the baroreceptor–sympathetic nerve activity reflex was markedly reduced at the low sodium diet compared with the preceding and with the subsequent regular sodium diet. This was also the case for the sensitivity of the baroreceptor–heart rate reflex, although the differences were significant only for the baroreceptor stimulation induced by phenylephrine (Fig 3). The reduction in the sensitivity of the baroreceptor sympathetic reflex induced by sodium intake was significantly (although not closely) correlated with the increase in baseline MSNA (r=.63, P<.05).
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HR) and in muscle sympathetic nerve activity (
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Table 2 shows that in 5 subjects low sodium diet caused a slight reduction in central venous pressure. Central venous pressure showed a slight progressive increase during phenylephrine infusion and a slight progressive reduction during nitroprusside infusion. All changes were superimposable for the regular and low sodium diets.
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Cold Pressor Test
For the initial regular sodium diet, the cold pressor test increased mean arterial pressure (+13.1±2.8 mm Hg), heart rate (+10.2±1.9 bpm), and MSNA (+68.2±9.4% integrated activity). For each variable, the increase was similar at low sodium intake (+12.8±3.1 mm Hg, +11.4±2.2 bpm, and +64.2±8.9% integrated activity) and when regular sodium intake was restored (+13.5±3.0 mm Hg, +11.1±2.3 bpm, and +64.0±7.1% integrated activity).
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Discussion |
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In the essential hypertensive subjects of our study, the progressive reduction in sympathetic nerve traffic induced by a progressively more pronounced stimulation of arterial baroreceptors was clearly blunted after a dietary manipulation that reduced sodium intake without affecting potassium intake and with only a slight reduction in blood pressure. Furthermore, the progressive increase in sympathetic nerve traffic induced by a progressively more pronounced unloading of the arterial baroreceptors was clearly less at low than at regular sodium intake. Thus, in essential hypertension a sodium intake reduction impairs the baroreceptor's ability to modulate sympathetic nerve activity. This impairment worsens the baroreflex function throughout the whole stimulus-response curve.
The reduction of sodium intake used in our study was also accompanied by a reduction of the reflex heart rate responses to baroreceptor stimulation and deactivation. However, this reduction was statistically significant only at maximal changes of baroreceptor drive, and the average sensitivity of the baroreceptor–heart rate reflex was not significantly less at low compared with regular sodium intake. Thus, the adverse influence of a sodium intake restriction is less consistent and manifest for the heart rate component than for the sympathetic nerve activity component of the baroreflex. Because the baroreceptor–heart rate reflex depends to a large extent on the vagus,25 this might imply that reflex vagal modulation of the sinus node is more resistant to the blunting effect of sodium restriction than reflex sympathetic modulation of the cardiovascular system. Another possibility, however, is that the baroreceptor–heart rate reflex is less markedly impaired by sodium restriction, because this baroreflex component is already compromised to a greater extent by mild hypertension than by the baroreceptor modulation of sympathetic tone, vascular resistance, and blood pressure.25 26 Indeed, compared with previous data by our group21 26 and others27 on normotensive subjects, in the present 9 hypertensive patients the sensitivity of the baroreceptor–heart rate reflex was more compromised than the sensitivity of the baroreceptor-MSNA reflex.
Anderson et al28 have shown that in subjects with borderline hypertension, sympathetic nerve traffic is greater at a sodium intake of 10 mmol daily than at a sodium intake of 400 mmol daily. Our findings extend these results because they provide evidence that sodium restriction is accompanied by a greater MSNA (about 23%) not only compared with a high sodium intake but also compared with a regular sodium intake regimen. More important, they provide evidence that during sodium restriction the magnitude of sympathetic activation is related to the impairment of the baroreceptor ability to modulate sympathetic nerve traffic. This activation may thus have a reflex origin; ie, it may be induced by an impaired restraint of sympathetic tone by arterial baroreceptors. Because during sodium restriction there was a significant, although small, reduction in central venous pressure, it is possible that a reduced reflex restraint from afferents originating in the cardiopulmonary region29 is also involved.
Our study does not clarify the mechanisms responsible for the impairment of the baroreceptor modulation of sympathetic nerve traffic brought about by sodium restriction. However, in 5 subjects the small changes in central venous pressure observed during the infusion of the vasoactive drugs required to stimulate and deactivate arterial baroreceptors were superimposable for regular and low sodium diets, making it unlikely that a differential participation of reflexes originating from the cardiopulmonary region and interacting with the baroreflex29 30 31 was involved. Furthermore, in our subjects the hemodynamic and sympathetic effects of the cold pressor test were similar at regular and low sodium intakes, indicating that no generalized dysfunction of autonomic cardiovascular control occurred during sodium restriction and that the impairment rather specifically involved the arterial baroreflex. We can speculate that this is due to an impairment of central integration of the baroreceptor input caused by the increased circulating (and possibly central) levels of angiotensin II that accompanied sodium restriction.32 It is also possible, however, that sodium restriction affects the afferent portion of the baroreflex arch because (1) the increased levels of angiotensin II enhance smooth muscle contraction in the vessel walls where baroreceptors are located, reducing arterial distensibility and making stretch sensors such as baroreceptors less responsive to changes in intravascular pressure,25 33 34 and/or (2) the alteration of the sodium gradient across the cell membrane may impair the action potential and the excitability of baroreceptors themselves.35
Our results have at least two clinical implications. First, the impairment of the baroreflex induced by sodium restriction may oppose, via a sympathetically mediated vasoconstriction, the blood pressure–lowering effect of a low sodium diet and thus be one of the factors accounting for its limited blood pressure effect in our patients as well as in the overall hypertensive population.5 6 7 8 Second, the impairment may affect a major mechanism for blood pressure control and thus negatively influence blood pressure homeostasis.5 25 Thus, this intervention should not be regarded as by definition devoid of inconveniences, and its possible consequences for blood pressure homeostasis should be more carefully investigated in the clinical setting. This should particularly be the case in aged and diabetic hypertensive patients in whom several factors responsible for blood pressure control may already be compromised.25 29 It should be emphasized, however, that our data concern the effect of a relatively marked sodium restriction for a relatively short time and that the effect of milder reductions in sodium intake for longer periods of time, such as those more frequently used in the clinical practice, still needs to be determined.
Received May 29, 1996;
first decision June 21, 1996;
first decision October 1, 1996;
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