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Enalapril and Losartan Reduce Sympathetic Hyperactivity in Patients with Chronic Renal Failure

Inge H.H.T. Klein^*, Gerry Ligtenberg^*, P. Liam Oey, Hein A. Koomans^* and Peter J. Blankestijn^*

*Department of Nephrology and Hypertension and Department of Clinical Neurophysiology, University Medical Center Utrecht, The Netherlands.

Correspondence to Peter J. Blankestijn, Department of Nephrology and Hypertension, room F03.226, University Medical Center, PO Box 85500, 3508 GA Utrecht, The Netherlands. Phone: 31-30-2507336; Fax: 31-30-2543492;

	Abstract

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ABSTRACT. The aim of this study was to compare the effects on BP and sympathetic activity of chronic treatment with an angiotensin (Ang)-converting enzyme (ACE) inhibitor and an AngII receptor blocker in hypertensive patients with chronic renal failure (CRF). In ten stable hypertensive CRF patients (creatinine clearance, 46 ± 17 ml/min per 1.73 m²), muscle sympathetic nerve activity (MSNA), plasma renin activity (PRA), baroreceptor sensitivity, and 24-h ambulatory BP were measured in the absence of antihypertensive drugs (except diuretics) after 6 wk of enalapril (10 mg orally) and after 6 wk of losartan (100 mg orally). The order of the three phases was randomized. Normovolemia was controlled with diuretics and confirmed with extracellular fluid volume measurements throughout the study. Both enalapril and losartan reduced MSNA (from 33 ± 10 to 27 ± 13 and 27 ± 13 bursts/min, respectively; P < 0.05) and average 24-h BP (from 141 ± 8/93 ± 8 to 124 ± 9/79 ± 8 and 127 ± 8/81 ± 9 mmHg; P < 0.01). PRA was not different during the treatments. The change in BP and the change in MSNA during the treatments were correlated (r = 0.70 and r = 0.63, respectively; both P < 0.05). Baroreceptor sensitivity was not affected by the treatments. This is the first study to compare the effects of ACE inhibition and AngII blockade on MSNA. In hypertensive CRF patients, enalapril and losartan equally reduced BP and MSNA. Differences in modes of action of the two drugs did not result in differences in effects on MSNA, supporting the view that AngII-mediated mechanisms contribute importantly in the pathogenesis of sympathetic hyperactivity in these patients. E-mail: p.j.blankestijn@azu.nl

	Introduction

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Sympathetic hyperactivity in chronic renal failure (CRF) is caused by mechanisms arising in the failing kidneys (1). The renin system is often activated in hypertensive patients with CRF. There is clear evidence that high circulating angiotensin II (AngII) levels can stimulate central sympathetic outflow by a direct effect on the vasomotor center in the brain stem, which in humans can be quantified as increased muscle sympathetic nerve activity (MSNA) (2). We showed that MSNA is increased in patients with CRF and that this hyperactivity was reduced by chronic angiotensin-converting enzyme (ACE) inhibition (3). These findings support the idea that AngII is involved in the pathogenesis of the sympathetic hyperactivity. However, ACE inhibition did not completely normalize the MSNA in these patients. There is increasing evidence that sympathetic hyperactivity contributes to the cardiovascular risk profile, not only by its effect on BP, but also independent of this effect (4).

The hypothesis in the present study was that AngII receptor blockade in an equally effective antihypertensive regimen more effectively reduces the sympathetic hyperactivity than ACE inhibition. AngII receptor blockers are well accepted as antihypertensive agents in patients with CRF (5–7). Their BP lowering effect is comparable to that of ACE inhibitors (7,8). However, although both classes of drugs primarily interfere with the renin-angiotensin system, their modes of action show distinct and possibly relevant differences. Specific for ACE inhibitors is that they also inhibit the metabolism of kinins, resulting in increased levels of bradykinin (8,9), which may contribute to their BP lowering effect. Inhibition of AngII formation is unavoidably incomplete, because high concentrations of AngI lead to AngII formation through nonACE pathways (10). AngII receptor blockers do not inhibit kinin degradation, but they are presumed to more completely block the renin cascade (8). The BP lowering effect of AngII receptor blockade depends more on the blockade of the AngII pathway, and thus perhaps on inhibition of sympathetic activity. We therefore compared in hypertensive patients with CRF the effects of chronic equally antihypertensive treatment with enalapril and losartan on MSNA in a randomized crossover study.

	Materials and Methods

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Subjects
We included 13 hypertensive CRF patients. In ten patients (mean age, 45 ± 10 yr; 7 men; body mass index, 26 ± 2 kg/m²; creatinine clearance: between 20 and 70 ml/min, mean value, 46 ± 17 ml/min per 1.73 m², stable during the 3 mo before the study), we were successful in obtaining MSNA measurements in all three study sessions. Clinical characteristics of the excluded patients were not different from the ten in the study group. The causes of the nephropathy were polycystic kidney disease (six), IgA nephropathy (two), interstitial nephritis (one), and obstructive uropathy (one). Patients with clinically manifest heart disease (congestive heart failure, coronary heart disease, or atrial fibrillation) or diabetes mellitus, as well as patients known to have had adverse reactions to ACE inhibitors or AngII receptor blockers were excluded. The patients were selected on the fact that they were hypertensive (BP > 145/90 mmHg) after stopping all antihypertensive medications, in the presence of normovolemia, judged clinically from absence of edema and confirmed with volume measurements (see below). To control this normovolemic state, four patients were maintained on diuretics throughout the study. The data obtained in the patients were compared with data obtained in a historical group of matched healthy subjects (n = 20; 46 ± 9 yr; 15 men; body mass index, 25 ± 2 kg/m²).

Protocol
The institutional committee for studies in humans approved the protocol. All subjects gave their written informed consent. Patients were studied on three occasions, i.e., when taken off antihypertensive medication for more than 2 wk, during chronic (6 wk) 10 mg of enalapril, or during chronic (6 wk) 100 mg of losartan. These dosages are clinically recommended. The order of the treatment phases was randomized. Throughout the study, diuretics were continued to maintain normovolemia. Vitamin D supplements, phosphate binders, and/or HMG-CoA-reductase inhibitors were continued as well.

All subjects underwent an identical set of measurements in supine position in a quiet room with an ambient temperature of 22 to 24°C. All study sessions were done in the morning between 2 and 5 h after drug intake. These measurements included supine BP, heart rate, muscle sympathetic nerve activity (MSNA), baroreflex sensitivity, extracellular fluid volume (ECFV), and plasma renin activity (PRA). BP was measured in a recumbent position with a standard mercury sphygmomanometer. Means of three measurements are presented. During the baroreflex sensitivity assessments, BP was recorded continuously by finger plethysmography (Finapres; Datex-Ohmeda, Louisville, CO). The Finapres device is especially suitable for analysis of changes in BP during short-term interventions (11). MSNA was recorded with a unipolar tungsten microelectrode placed in a muscle nerve fascicle of the peroneal nerve using the technique of Wallin et al. (12), as described by us previously (3). The correct position of the electrode is evaluated by means of a Valsalva maneuver: the patient is asked to blow into a mouthpiece of an aeroid manometer to 40 mmHg for 15 s while BP, heart rate, and MSNA are continuously recorded. The BP overshoot after the restart of breathing is associated with a short pause in neural activity. The neural signal during the BP overshoot is considered to be the background noise. This procedure is done at the beginning and at the end of the study session. Success rate of obtaining an adequate neural signal is approximately 85%. The heartbeat intervals were measured from the ECG. The sample frequency is 200 Hz. An intravenous cannula for infusion and blood sample collection was inserted into an antecubital vein.

After instrumentation, the subjects rested for 20 min. Baseline measurements for BP, heart rate, and MSNA were obtained, blood was sampled for measurement of PRA and bromide, and bromide was injected intravenously for measurement of the ECFV (see below). Next, baroreflex sensitivity was assessed as the response of MSNA and of heart rate to changes in BP induced by subsequent continuous infusion of sodium nitroprusside and phenylephrine. Sodium nitroprusside (333 µg/ml in 5% glucose) was infused starting at a rate of 33 µg/min and individually increased (in 3-min steps) to obtain a reduction of MAP of at least 12 mmHg. After a second 20-min rest period, a continuous infusion of phenylephrine (333 µg/ml in saline 0.9%) was started at a rate of 33 µg/min and individually increased (in 3-min steps), to increase MAP by at least 12 mmHg.

On the day before these studies, 24-h BP was monitored noninvasively using the Spacelabs 90207 device (Spacelabs Inc., Richmond, WA). Recordings were made every 20 min during daytime (7 a.m. to 11 p.m.) and every 30 min during nighttime (11 p.m. to 7 a.m.) on the nondominant arm. During this 24-h period, urine was collected for measurement of sodium and creatinine excretion.

Laboratory Analyses
Bromide distribution volume, as an index of extracellular fluid volume, was calculated from plasma bromide concentration in blood samples obtained at 90, 120, and 150 min after injection of 4 g of sodium bromide. Plasma bromide was measured colorimetrically at 440 nm by the gold bromide technique and corrected for plasma bromide before injection. The distribution volume was corrected for bromide penetration into erythrocytes for plasma water content and for the Donnan equilibrium effect and expressed as ml/kg lean body mass (13). Plasma bromide levels range between 1 and 3 mmol/L, which is well below the therapeutic and toxic levels (13). Lean body mass, estimated from weight and height, is the most suitable index for normalization of body fluid volumes in humans and allows comparison between men and women (14). The normal range in our laboratory is 273 to 334 ml/kg of lean body weight. PRA was measured by RIA (15).

Data Analyses
Data are given as mean ± SD unless indicated otherwise. MSNA was expressed as the number of bursts of sympathetic activity per minute or as the number of bursts per 100 heart beats to correct for differences in heart rate. Intraobserver and interobserver reproducibility are 4.5 ± 0.5% and 6.2 ± 0.7%. During the sodium nitroprusside and phenylephrine infusion, MSNA was counted for 1 min during each infusion step. The results of the continuous registration of MAP and heart rate were averaged per minute. Baroreflex sensitivity was expressed as changes in MSNA and heart rate versus BP. It was calculated for each subject by least square analysis of the linear part of the baroreflex curves that included the baseline value and expressed as the number of bursts per minute per millimeter of mercury and the number of beats per minute per millimeter of mercury, respectively.

Statistical Analyses
PRA was analyzed after logarithmic transformation. Baseline characteristics of patients and controls were compared by unpaired t test. Differences between different occasions of patients were examined by repeated measure analyses of variance. If variance reached statistical significance, the means were analyzed using a Student Newman-Keuls test in parametric variables and Kruskal-Wallis ANOVA on ranks in nonparametric variables. Pearson correlation product was calculated to assess correlations. A P value of <0.05 was considered to be statistically significant.

	Results

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When untreated, BP in the patients was clearly elevated above normal (Table 1 and Figure 1). PRA and MSNA were also elevated. The ECFV was within normal limits, and the baroreceptor sensitivity was normal. Six weeks of treatment with enalapril decreased BP without changing heart rate. The PRA increased. Renal function, assessed from the plasma creatinine, did not change. MSNA decreased from 33 ± 10 bursts/min to 27 ± 13 bursts/min (P < 0.05). Although the latter value was not significantly higher than the reference value of 21 ± 3 bursts/min, this effect of enalapril in fact corresponded with suppressing about half of the surplus of sympathetic activity. Although MSNA decreased, the baroreceptor activity was not affected (Figure 2). The change in MSNA induced by enalapril correlated with the change in MAP (r = 0.70; P < 0.05). ECFV remained within normal limits.

View larger version (23K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Twenty-four–hour BP profiles without antihypertensive treatment and during 6 wk of enalapril or losartan.

View larger version (19K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. Baroreflex response to changes in mean arterial pressure in patients with chronic renal failure without antihypertensive treatment and during 6 wk of enalapril or losartan. Changes in muscle sympathetic nerve activity and heart rate are plotted against changes in mean arterial pressure.

View larger version (18K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 3. Individual results in ten patients with chronic renal failure of the changes from baseline in muscle sympathetic nerve activity during chronic treatment with enalapril and with losartan.

	Discussion

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This study extends the present knowledge on the role of sympathetic hyperactivity in CRF (1). It confirms that normovolemic hypertensive CRF patients have an activated renin and sympathetic nervous system and that in these patients ACE-inhibition with enalapril can effectively lower BP and ameliorate the sympathetic hyperactivity. News in our study is that losartan, in a dosage with a comparable BP lowering effect, also reduces the sympathetic hyperactivity, not, however, better than enalapril.

Hypertension is a common problem in CRF patients. Fluid overload is considered to contribute importantly in the pathogenesis. It has long been recognized that in patients with CRF the renin-angiotensin system is "inappropriately" activated in relation to the fluid status (16). This contributes to the hypertension, and explains why hypertension may persist even after correction of the fluid overload. The role of the sympathetic nervous system is less clear. Our data show that in these patients the MSNA is often increased as well, confirming the limited available data on this issue in CRF patients (3,17). As a consequence of these findings, the logical treatment of these patients should be aimed at normalization of the fluid status and of the renin and sympathetic overactivity.

Both enalapril and losartan exerted a profound and comparable antihypertensive effect without altering the 24-h BP profile and without effect on heart rate, baroreceptor sensitivity, or kidney function. Indeed, these agents are effective and safe in CRF patients (5–7). Few studies have evaluated the effect of ACE inhibitors on MSNA. In essential hypertension, there was no effect (18), but MSNA was reduced when both renin and sympathetic activity were activated, such as in CRF or heart failure (3,19). The present study shows that an AngII receptor blocker also reduces MSNA in CRF patients. The findings support the idea that AngII-mediated mechanisms contribute to the pathogenesis of sympathetic nervous overactivity (1). However, our hypothesis that the AngII receptor blocker would be more effective in reducing sympathetic overactivity than the ACE inhibitor could not be confirmed, at least not in the dosages used in this study. This hypothesis was based on the widely accepted notion that AngII receptor blockade provides a more selective and complete blockade of the renin-angiotensin axis than ACE inhibition (8). The BP lowering effect of ACE inhibitors, instead, may also depend on the inhibited metabolism of kinins and the resulting elevated levels of bradykinin (8,9). Bradykinin is supposed to increase sympathetic activity through vasodilation as well as through a central action (20). Nonetheless, enalapril and losartan equally suppressed the sympathetic overactivity, whereas their BP lowering action was also similar. Stimulation of MSNA by AngII concerns an interaction in the central nervous system. Based on our observations, we have to assume that both drugs interfered equally with the central action of AngII. Interestingly, both drugs also equally increased the PRA, suggesting an identical blockade of the circulating renin-angiotensin system as well.

The background of our study was our previous observation that ACE inhibition with enalapril could only partially suppress the increased sympathetic overactivity in CRF patients, whereas complete normalization would be preferred. Both enalapril and losartan lowered the average BP to levels that are acceptable according to WHO criteria, but BP was still slightly higher than in the healthy control subjects. Recent studies lead to the notion that stronger lowering of BP may be helpful to slow progression of renal failure and reduce the cardiovascular risk further (21). We found a clear relation between the fall in BP and MSNA, and MSNA was still somewhat above normal during treatment; therefore, it seems indeed important to suppress this activity to entirely normal levels. This is also preferable because there is increasing evidence that sympathetic activity contributes to the increased cardiovascular risk, also independent on its effect on BP (4). To obtain complete suppression, several options need to be considered. We purposely investigated the effect of chronic treatment with the recommended dosage of each compound (22,23). It is possible that higher dosages, in particular of AngII receptor blockers, may reduce sympathetic activity further. On theoretical grounds, one can assume that the combination of ACE inhibition and AngII receptor blockade induces a stronger inhibition of the renin-angiotensin system than either drug alone. This appears, for instance, from the observation of higher plasma renin levels and better BP control obtained with the combination than with either ACE inhibition or AngII receptor blockade alone (24,25). Therefore, it is also possible that the combination of both classes of compounds may have a stronger sympatho-inhibitory effect. Finally, use of specific centrally acting blockers of sympathetic output, alone or in combination with renin-angiotensin inhibiting drugs, is an option to be studied.

This study has several limitations. MSNA is the sympathetic activity to the resistance vessels, which is an important determinant of BP (26). There is evidence that the degree of sympathetic activity to various organs differs (27). Consequently, the present data do not assess sympathetic activity to other organs, for instance to the heart. By means of the ¹²³I-metaiodobenzylguanidine-technique, it has been shown that an ACE inhibitor reduced cardiac sympathetic activity, whereas a calcium channel blocker did not (28). This parallels our previous findings in CRF patients that enalapril reduced MSNA and amlodipine did not (3). No studies comparing the effects of an ACE inhibitor and AngII receptor blocker on cardiac sympathetic activity are available at present. AngII also has a peripheral effect on sympathetic activity, as it enhances neuronal noradrenaline release through a prejunctional mechanism (29). In human atria, sympathetic nerve–stimulated noradrenaline release is inhibited more effectively by EXP-3174, the active metabolite of losartan, than by captopril (30). Therefore, we cannot rule out the possibility that treatment with AngII receptor blocker and ACE inhibitor have different sympathetic activity effects on tissue level, even though changes in MSNA are comparable. However, the finding that BP and heart rate were not different during the treatments argues against a major difference in this respect.

In conclusion, the study shows that enalapril and losartan in usually applied dosages are equally effective in reducing the increased BP and sympathetic activity in normovolemic hypertensive patients with CRF. Differences in modes of action do not result in different effects on sympathetic activity. Both agents control the sympathetic hyperactivity only partially. Other strategies have to be tried to completely normalize the sympathetic hyperactivity and further eliminate its contribution to hypertension and the cardiovascular risk in patients with CRF.

	Acknowledgments

 
Dr. Klein was supported by a grant of the Dutch Kidney Foundation (C97–1684).

	References

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