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
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).
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.
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 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.
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.
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.
Six weeks of treatment with losartan also decreased BP without changing heart rate. The increase in PRA was comparable with what was seen using enalapril. Again, kidney function, assessed from plasma creatinine, did not change. Losartan suppressed MSNA comparably to enalapril, to 27 ± 13 bursts/min, thus about halving the surplus of the sympathetic activity. Baroreceptor activity did not change. The change in MSNA induced by losartan correlated with the change in MAP (r = 0.63, P < 0.05). The ECFV remained within normal limits. Effects of enalapril and losartan on MSNA were not different (Figure 3). Urinary sodium excretion during the three study sessions did not differ (baseline, enalapril, and losartan: 126 ± 74, 125 ± 68, and 121 ± 50 mmol/24 h, respectively).
Figure 1 presents the 24-h MAP. The overall decreases induced by enalapril and losartan were comparable. Systolic as well as diastolic arterial pressures during daytime as well as nighttime were equally reduced by both drugs, and the 24-h pattern remained unchanged. The 24-h averages of the arterial pressures decreased from 141 ± 8/93 ± 8 mmHg to 124 ± 9/79 ± 8 mmHg during enalapril (P < 0.01) and to 127 ± 8/81 ± 9 mmHg during losartan (P < 0.01). The averaged 24-h heart rate did not change significantly (79 ± 9 bpm during baseline, 74 ± 12 bpm during enalapril, and 74 ± 10 bpm during losartan).
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.
Dr. Klein was supported by a grant of the Dutch Kidney Foundation (C97–1684).
1. Augustyniak RA, Tuncel M, Zhang W, Toto RD, Victor RG: Sympathetic overactivity as a cause of hypertension in chronic renal failure. J Hypertens 20: 3–9, 2002
2. Matsukawa T, Gotoh E, Minamisawa K, Kihara M, Ueda S, Shionoiri H, Ishii M: Effects of intravenous infusions of angiotensin II on muscle sympathetic nerve activity in humans. Am J Physiol 261: R690–R696, 1991
3. Ligtenberg G, Blankestijn PJ, Oey PL, Klein IHH, Dijkhorst-Oei LT, Boomsma F, Wieneke GH, van Huffelen AC, Koomans HA: Reduction of sympathetic hyperactivity by enalapril in patients with chronic renal failure. N Engl J Med 340: 1321–1328, 1999
4. Mancia G, Grassi G, Giannattasio C, Seravalle G: Sympathetic activation in the pathogenesis of hypertension and progression of organ damage. Hypertension 34: 724–728, 1999
5. Gansevoort RT, de Zeeuw D, Shahinfar S, Redfield A, De Jong PE: Effects of the angiotensin II antagonist losartan in hypertensive patients with renal disease. J Hypertens 12 [suppl 12]: S37–S42, 1994
6. Toto R, Shultz P, Raij L, Mitchell H, Shaw W, Ramjit D, Toh J, Shahinfar S. Efficacy and tolerability of losartan in hypertensive patients with renal impairment. Hypertension 31: 684–691, 1998
7. Schulz E, Bech JN, Pedersen EB, Mu[Combining Circumflex Accent]ller GA: A randomized, double-blind, parallel study on the safety and antihypertensive efficacy of losartan compared to captopril in patients with mild to moderate hypertension and impaired renal function. Nephrol Dial Transplant 14 [suppl 4]: 27–28, 1999
8. Burnier M, Brunner HR: Angiotensin II receptor antagonists. Lancet 355: 637–45, 2000
9. Vaughan D: Pharmacology of ACE inhibitors versus AT1 blockers. Can J Cardiol 16 [Suppl E]: 36E–40E, 2000
10. Hollenberg NK, Fisher ND, Price DA: Pathways for angiotensin II generation in intact human tissue: evidence from comparative pharmacological interruption of the renin system. Hypertension 32: 387–392, 1998
11. Bos WJ, Imholz BP, van Goudoever, Wesseling KH, van Montfrans GA: The reliability of noninvasive continuous finger blood pressure measurement in patients with both hypertension and vascular disease. Am J Hypertens 5: 529–535, 1992
12. Vallbo AB, Hagbarth KE, Torebjork HE, Wallin BG: Somatosensory, proprioceptive and sympathetic activity in human peripheral nerves. Physiol Rev 59: 919–57, 1979
13. Snel YE, Brummer RJ, Bol E, Doerga ME, Zelissen PM, Zonderland ML Boer P, Koomans HA, Koppeschaar HP: Direct assessment of extracellular water volume by the bromide-dilution method in growth hormone-deficient adults. Eur J Clin Invest 25: 708–714, 1995
14. Boer P: Estimated lean body mass as an index for normalization of body fluid volumes in humans. Am J Physiol 247: F632–F636, 1984
15. Boer P, Sleumer JH, Spriensma M: Confirmation of the optimal pH for measuring renin activity in plasma. Clin Chem 31: 149–150, 1985
16. Schalekamp MA, Beevers DG, Briggs JD, Brown JJ, Davies DL, Fraser R, Lever AF, Medina A, Morton JJ, Robertson JI, Tree M: Hypertension in chronic renal failure. Am J Med 55: 379–390, 1973
17. Converse RL, Jacobson TN, Toto RD, Jost CMT, Cosentino F, Fouad-Tarazi F, Victor RG: Sympathetic overactivity in patients with chronic renal failure. N Engl J Med 327: 1912–1918, 1992
18. Grassi G, Turri C, Dell’Oro R, Stella ML, Bolla GB, Mancia G: Effect of chronic angiotensin converting enzyme inhibition on sympathetic nerve traffic and baroreflex control of the circulation in essential hypertension. J Hypertens 16: 1789–1796, 1998
19. Grassi G, Cattaneo BM, Seravalle G, Lanfranchi A, Pozi M, Morganti A, Carugo S, Mancia G: Effects of chronic ACE inhibition on sympathetic nerve traffic and baroreflex control of circulation in heart failure. Circulation 96: 1173–1179, 1997
20. Schwieler JH, Hjemdahl P: Influence of angiotensin-converting enzyme inhibition on sympathetic neurotransmission: Possible roles of bradykinin and prostaglandins. J Cardiovasc Pharmacol 20 [suppl 9]: S39–S46, 1992
21. Mailloux LU, Haley WE: Hypertension in the ESRD patient: pathophysiology, therapy, outcomes, and future directions. Am J Kidney Dis 32: 705–719, 1998
22. Sica DA, Lo MW, Shaw WC, Keane WF, Gehr TWB, Halstenson CE, Lipschutz K, Furtek CI, Ritter MA, Shahinfar S: The pharmacokinetics of losartan in renal insufficiency. J Hypertens 13 [Suppl 1]: S49–S52, 1995
23. Davies RO, Gomez HJ, Irvin JD, Walker JF: An overview of the clinical pharmacology of enalapril. Br J Clin Pharmacol 18: 215S–229S, 1984
24. Azizi M, Guyene TT, Chatellier G, Wargon M, Ménard J: Additive effects of losartan and enalapril on blood pressure and plasma active renin. Hypertension 29: 634–640, 1997
25. Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, Cooper ME for the CALM Study Group: Randomised cotrolled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. B Med J 321: 1440–1444, 2000
26. Vissing SF, Scherrer U, Victor RG: Relation between sympathetic outflow and vascular resistance in the calf during perturbations in central venous pressure. Circ Res 65: 1710–1717, 1989
27. Esler M, Jennings G, Korner P, Blombery P, Sacharias N, Leonard P: Measurement of total and organ specific norepinephrine kinetics in humans. Am J Physiol 245: E21–E28, 1984
28. Sakata K, Shirotani M, Yoshida H, Kurata C: Comparison of effects of enalapril and nitrendipine on cardiac sympathetic nervous system in essential hypertension. J Am Coll Cardiol 32: 438–443, 1998
29. Rump LC: Advantages of Ang II receptor blockade over ACE inhibition with respect to suppression of sympathetic activity: Heartening news for the kidney? Nephrol Dial Tranplant 14: 556–559, 1999
30. Rump LC, Oberhauser V, Schwertfeger E, Schollmeyer P: Experimental evidence to support ELITE. Lancet 351: 644, 1998