Stress-induced renal alterations in normotensives offspring of hypertensives and in hypertensives

AJH

2002; 15:346 –350

Stress-Induced Renal Alterations in Normotensives Offspring of Hypertensives and in Hypertensives Michel Ducher, Delphine Bertram, Nicole Pozet, Maurice Laville, and Jean Pierre Fauvel Background: Scarce information is available on stress-induced renal behavior in humans, especially in normotensives offspring of hypertensives (HP) and in hypertensives (HT). Methods: Ten HP and 10 HT were compared to 10 normotensives with normotensive parents (NP). Systolic blood pressure (SBP) and renal functional parameters were determined during rest and stress periods. Results: The stress SBP reactivity was significantly (P ⬍ .05) higher in HP than in NP and HT. At rest, HP were characterized by a significantly (P ⬍ .05) higher glomerular filtration rate. Stress significantly reduced glomerular filtration rate (⫺14 ⫾ 4 mL/min/1.73 m2, P ⬍ .05) only in HT. Renal plasma flow significantly (P ⬍ .05) decreased during stress in NP (⫺35 ⫾ 16 mL/min/1.73 m2) and in HT (⫺49 ⫾ 25 mL/min/1.73 m2), whereas it did not change in HP. The resulting filtration fraction increased significantly during stress only in NP (1.5% ⫾ 0.6%, P ⬍ .05). Despite the increase in BP, stress induced a similar

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tress is hypothesized to be one of the major environmental factors in the pathogenesis of essential hypertension. Acute stress, elicited by laboratory stressors, triggers transient increases in blood pressure (BP), heart rate, and cardiac output. Hypertensives1 and normotensives with hypertensive parents2,3 have been reported to exhibit a higher cardiovascular reactivity than normotensives with normotensive parents. Consistently, in longitudinal studies, the magnitude of cardiovascular responses to laboratory stressors has been reported to predict risk of future hypertension.4,5 Alterations in renal hemodynamics could occur at an early stage in the development of essential hypertension. Both the pre- and postglomerular resistances have been reported to be higher in subjects with parental hypertension than in subjects without a history of familial hypertension.6 Because stress and renal

Received November 6, 2001. First Decision November 9, 2001. Accepted November 28, 2001. From the De´partement de Ne´phrologie et d’Hypertension Arte´rielle, 0895-7061/02/$22.00 PII S0895-7061(01)02333-0

decrease in sodium excretion rate in NP (⫺52 ⫾ 26 ␮mol/min) and in HT (⫺56 ⫾ 24 ␮mol/min). The stressinduced sodium reabsorption occurred only in the proximal part of the tubules (lithium clearance). In HP, stress did not alter either sodium excretion rate or plasma renin activity. Conclusions: The stress-induced renal modifications are characterized by an efferent vasoconstriction and a paradoxical increase in sodium reabsorption that occurred in the proximal part of the tubules in NP. In HP, genetically at risk of hypertension, basal renal alterations may explain a different stress-induced renal behavior. In HT, stress-induced increase in sodium reabsorption may be involved in the sustained BP level. Am J Hypertens 2002;15:346 –350 © 2002 American Journal of Hypertension, Ltd. Key Words: Hypertension, mental stress, renal function, sodium excretion. functional alterations7,8 have been associated with the development of hypertension later in life,9 we studied renal function in subjects with various risks of hypertension taking an efficient and reproducible mental stress test.

Methods Subjects Ten hypertensive patients (HT) were matched for age (HT: 39 ⫾ 1 years v normotensive parents (NP): 42 ⫾ 2 years) and gender (4 women and 6 men) with 10 normotensive volunteers with NP. Furthermore, 10 normotensives with one (n ⫽ 5) or two (n ⫽ 5) hypertensive parents (HP, 5 women and 5 men; 30 ⫾ 3 years) were included in the study. In HT, onset of hypertension was recent (4.3 ⫾ 1.0 years). The NP (mean BP, 122 ⫾ 3/76 ⫾ 2 mm Hg), HP Hoˆpital Edouard Herriot, Universite´ C. Bernard Lyon, Lyon, France. Address correspondence and reprint requests to Dr. J.P. Fauvel, De´partement de ne´phrologie, Hoˆpital Edouard Herriot, 69437 Lyon Cedex 03, France; e-mail: [email protected] © 2002 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.

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(mean BP, 125 ⫾ 3/76 ⫾ 3 mm Hg), and HT (mean BP, 159 ⫾ 3/102 ⫾ 2 mm Hg) volunteered to participate in a BP survey, among salaried personnel working in our hospital (4000 salaried personnel). Parental BP was considered positive only when the name of the current antihypertensive medication taken by the first degree parental could be given. In previously treated hypertensives, treatment was discontinued 2 weeks before a 2-week placebo period. Hypertensives were included if the mean of three supine office diastolic BP remained higher than 95 mm Hg at the end of the placebo period. Subjects with diabetes mellitus, cardiovascular complications, impaired renal function, or other systemic diseases were excluded from the study. The protocol was approved by the hospital’s ethic committee and all the subjects signed an informed consent. Mental Stress Test Mental stress was induced by a computerized version of Stroop’s color word conflict test (CWT). It consisted of three types of questions about colors that appeared in a randomized order on the screen: 1) color words, 2) colored spots, 3) color words written in incongruent colors. The subjects had to type 1) the name of the color, 2) the color, and 3) the color of the word on a selected key from the keyboard. An audio signal was provoked if a wrong response was made. Protocol The subjects did not change their usual diet. The evening before the study, at 10 PM, the subjects were given 750 mg of lithium carbonate orally to obtain, throughout the clearance procedure, a relatively stable lithium concentration. Each renal study began at 8:30 AM and took place in a quiet room kept at a constant temperature. After overnight fasting, before the clearance measurements, the subjects were hydrated with 200 mL of tap water. Subjects remained in a reclining position throughout the study except for active voiding. During the first 30 min, an intravenous cannula was inserted to collect fasting blood samples. Thirty minutes later, inulin (Inutest, Laevosan, Linz, Austria) and para-aminohippurate (PAH: Nephrotest, BA Gmbh, Lich, Germany) were administered as a priming infusion, followed by a sustained infusion to ensure stable plasma concentrations throughout the study, as previously described.8 After a 30-min equilibration period, two 30-min clearance periods were considered as baseline. Then, two 20-min stress test sessions were applied, each followed by a 10-min period for the collection of blood and urinary samples. Measurements Office BP was measured with a mercury sphygmomanometer. For the protocol, systolic (SBP) and diastolic (DBP) BP were measured by an oscillometric method (Dinamap; Critikon, Tampa, FL) every 5 min during the rest period

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and every 2 min during the stress period. Glomerular filtration rate (GFR) was evaluated by inulin clearance and renal plasma flow (RPF) by PAH clearance. At each period (rest and stress), measurements were performed during two 30-min periods. Plasma aldosterone and plasma renin activity were determined by radioimmunoassay at the end of each period. Calculations and Statistics Cardiovascular parameters were, for each subject, the mean of 10 measurements during rest and of 20 measurements during stress. The GFR, RPF, filtration fraction (FF), sodium excretion rate, fractional sodium reabsorption, and fractional lithium reabsorption were calculated according to standard formulas. Results expressed for each period (rest and stress) were the mean of two consecutive determinations. The GFR and RPF were corrected for body surface area. All values are presented as means ⫾ standard errors. A three-way (stress effect, group, and repetition) ANOVA was used to analyze each parameter. Subsequent Wilcoxon rank paired test was used to compare values during rest and stress within each group and a MannWhitney test was used to compare values between groups. A P value ⬍ .05 was considered as significant.

Results The ANOVA did not reveal any repetition effect for each of the analyzed parameter. Cardiovascular Parameters At rest, SBP and DBP were similar in NP (111 ⫾ 3/67 ⫾ 2 mm Hg) and HP (120 ⫾ 2/67 ⫾ 3 mm Hg). Hypertensives exhibited significantly higher SBP and DBP (148 ⫾ 4/87 ⫾ 2 mm Hg) than in both NP and HP. Stress-induced increase in SBP was significantly (P ⬍ .05) higher in HP (25.1 ⫾ 2.4 mm Hg) than in HT (15.4 ⫾ 2.3 mm Hg) and in NP (14.6 ⫾ 2.1 mm Hg). The stress-induced increase in DBP was significantly (P ⬍ .05) higher in HP (14.0 ⫾ 1.3 mm Hg) than in HT (8.4 ⫾ 1.0 mm Hg) and in NP (8.6 ⫾ 1.0 mm Hg). Among all the included subjects gender and stress session did not interfere with the magnitude of the BP response to stress. Renal Hemodynamic Parameters At rest, GFR in NP (110 ⫾ 4 mL/min/1.73 m2) was similar to GFR in HT (117 ⫾ 8 mL/min/1.73 m2), but significantly lower than in HP (128 ⫾ 7 mL/min/1.73 m2) (Fig. 1). Renal plasma flow in NP (561 ⫾ 26 mL/min/1.73 m2) was similar to RPF in HT (531 ⫾ 37 mL/min/1.73 m2), but significantly lower than in HP (618 ⫾ 30 mL/min/1.73 m2). The resulting FF in NP (19.7% ⫾ 0.8%) was lower than in HP (20.9 ⫾ 0.9%) and significantly lower (P ⬍ .05) than in HT (21.9% ⫾ 0.7%).

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Renal Handling of Sodium Sodium diet, evaluated by means of 24-h urinary sodium excretion, was not significantly different in the three groups (NP, 146 ⫾ 5 mmol/24 h; HP, 184 ⫾ 8 mmol/24 h; HT, 173 ⫾ 4 mmol/24 h). At rest, sodium excretion rate, fractional sodium reabsorption, and fractional lithium reabsorption were comparable in the three groups (Table 1). During stress, sodium excretion rate significantly decreased in NP (⫺52 ⫾ 26 ␮mol/min) and in HT (⫺56 ⫾ 24 ␮mol/min), but did not change in HP (⫺17 ⫾ 25 ␮mol/min). Expressed as fractional reabsorption of sodium, results are similar (Table 1). Fractional reabsorption of lithium increased in NP (1.68% ⫾ 1.26%) and in HP (1.67% ⫾ 1.32%), and significantly (P ⬍ .05) in HT (1.84% ⫾ 0.61%). Plasma Renin Activity and Aldosterone At rest, plasma renin activity and aldosterone were similar in the three groups. The stress-induced increase in plasma renin activity was of similar magnitude in the three groups but significant only in NP and in HT. Plasma aldosterone was not altered by stress in the 3 groups (Table 1).

Discussion

FIG. 1. Rest and stress renal hemodynamic parameters in NP (n ⫽ 10), HP (n ⫽ 10), and HT (n ⫽ 10). GFR ⫽ glomerular filtration rate; RPF ⫽ renal plasma flow; FF ⫽ filtration fraction. HP ⫽ hypertensive parents; HT ⫽ hypertensive patients; NP ⫽ normotensive parents. Values are mean ⫾ SEM. *P ⬍ .05 v rest; †P ⬍ .05 v NP; ‡P ⬍ .05 v HP.

The GFR was not altered by stress in NP (1 ⫾ 4 mL/min/1.73 m2) and HP (⫺2 ⫾ 5 mL/min/1.73 m2), whereas it significantly decreased in HT (⫺14 ⫾ 4 mL/ min/1.73 m2). The stress decrease in RPF was significant in NP (⫺35 ⫾ 16 mL/min/1.73 m2) and HT (⫺49 ⫾ 25 mL/min/1.73 m2), but not in HP (⫺14 ⫾ 31 mL/min/1.73 m2). Filtration fraction dramatically increased in NP (1.5% ⫾ 0.6%, P ⬍ .05) during stress, whereas FF was insensitive to the stressful stimulation in HP (0.3% ⫾ 1.1%) and in HT (⫺0.2% ⫾ 0.7%).

Most studies dealing with stress reactivity have focused on BP and HR reactivity. Restriction to cardiovascular reactivity limits information about BP regulatory mechanisms involved and, therefore, scarce information is available on the effects of stressors on renal function in humans. Our major finding is that stress-induced renal modifications are characterized by an efferent vasoconstriction and a paradoxical increase in sodium reabsorption that occurred in the proximal part of the tubules in NP. In HP, genetically at risk of hypertension, basal renal alterations may explain a different stress-induced renal behavior. In HT, stressinduced increase in sodium reabsorption may be involved in the sustained BP level. The ability of our computerized CWT to stimulate the sympathetic nervous system has previously been demonstrated using plasma or urinary catecholamine measurements. The stress-induced increase in BP in normotensives was in the upper range of those usually reported. The careful standardization and the computerization of the test ensured for a good temporal stability, which proved to be satisfactory at a 1-month interval in a group of 10 NP and 10 placebo-treated HT. Our version of the CWT is to our knowledge the only one reported to provide such an efficient and sustained increase in BP allowing us to use it in analyzing renal alterations induced by a mental stress test. At rest, HP exhibited a higher GFR and FF than NP. The increased basal FF in HP is consistent among published studies, but the increased basal GFR appears to be

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Table 1. Stress-induced changes in renal handling of sodium, in plasma renin activity and in plasma aldosterone

Sodium excretion rate (␮mol/min) Rest Stress Fractional sodium reabsorption (%) Rest Stress Fractional lithium reabsorption (%) Rest Stress Plasma renin activity (ng/L/min) Rest Stress Plasma aldosterone (pmol/L) Rest Stress

NP (n ⴝ 10)

HP (n ⴝ 10)

HT (n ⴝ 10)

298 ⫾ 34 256 ⫾ 26*

312 ⫾ 24 300 ⫾ 32

398 ⫾ 36 333 ⫾ 36*

98.1 ⫾ 0.2 98.4 ⫾ 0.2*

98.3 ⫾ 0.1 98.4 ⫾ 0.1

97.7 ⫾ 0.3 97.9 ⫾ 0.3*

69.3 ⫾ 1.2 71.0 ⫾ 1.1

70.7 ⫾ 1.9 72.3 ⫾ 0.9

69.0 ⫾ 0.7 70.8 ⫾ 1.0*

71 ⫾ 26 118 ⫾ 39*

89 ⫾ 25 135 ⫾ 47

51 ⫾ 12 128 ⫾ 46*

158 ⫾ 25 169 ⫾ 23

159 ⫾ 30 186 ⫾ 43

231 ⫾ 65 202 ⫾ 40

NP ⫽ normotensive parents; HP ⫽ hypertensive parents; HT ⫽ hypertensive patients. Values are mean ⫾ SEM. * P ⬍ .05 stress v rest.

more controversial.10,11 In our recent and uncomplicated HT, basal GFR is maintained at a normal level by an increase in filtration fraction. Despite a normal BP, the increase in filtration fraction observed in HP suggests that an enhanced FF could be an inherited trait of hypertension rather than a consequence of a sustained increase in BP. Stress induced a slight increase in GFR and a significant decrease in RPF in NP. The resulting FF that significantly increased during stress could be related to a postglomerular vasoconstriction. The stress-induced increase in FF, which is associated with a significant increase in plasma renin activity could be a consequence of an increase in renal sympathetic drive as demonstrated in rats.12,13 In HT, the stress-induced decrease in GFR paralleled the decrease in RPF, therefore FF was unaffected. HP, exhibiting a higher basal GFR and FF than NP, did not react to the stressful stimulation. Thus, the basal HP glomerular hyperfiltration could be responsible for the lack of renal response to the stressful stimulus in spite of the dramatic response in systemic BP. In each group, stress induced a decrease in sodium excretion that reached statistical significance only in HT. Segmental tubular sodium handling was estimated by means of lithium clearance, because lithium, competitively with sodium, is mainly reabsorbed in the proximal parts of the tubules. In NP, stress induced a nearly significant (P ⫽ .08) increase in fractional reabsorption of lithium. It should be noted that the stressful stimulation produced an antinatriuretic response, despite an increase in BP, which would generally be expected to produce an increase in natriuresis, according to the pressure–natriuresis mechanism. Our results that confirm those obtained in rats13 are contrary to the one recently reported by Schneider et al.14 This might be explained by the lower stress

stimulus intensity (⌬ SBP/DBP ⫽ 8/3 mm Hg) used by these investigators. In NP, the increase in filtration fraction, which increases capillary oncotic pressure, may account for the enhanced proximal uptake of sodium. This stress-induced antinatriuresis was mainly due to an increase in proximal tubular sodium reabsorption, which has been shown to be abolished by a pretreatment with an angiotensin converting enzyme inhibitor or an angiotensin-1 receptor blocker.13,15 The HP, who have a higher basal filtration fraction and proximal lithium reabsorption, did not react to the stressful stimulus despite the exaggerated response in arterial BP. The basal glomerular hyperfiltration in HP could blunt the action of angiotensin II on efferent arterioles and proximal tubular sodium reabsorption. In HT, despite no modification in FF, stress induced an increase in plasma renin and in proximal lithium reabsorption. Endogenous renal stress-induced release of angiotensin II could be implicated because an angiotensin converting enzyme inhibitor blunted, but did not abolish, the stress-induced antinatriuresis in HT.15 In conclusion, undergoing a stressing stimulation, the physiologic renal response was characterized by an efferent vasoconstriction and by a paradoxical decrease in sodium excretion, mainly due to an increase in tubular sodium proximal reabsorption. These renal modifications could be related to a renal sympathetic stimulation, which overcame the expected pressure–natriuresis effect. The basal renal hyperfiltration observed in HP might explain the lack of stress-induced renal modifications, despite an exacerbated stress-induced increase in arterial BP. In HT, a stress-induced increase in BP associated with an increase in sodium reabsorption may be involved in the sustained BP level.

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