(Hypertension. 1999;34:102-106.)
© 1999 American Heart Association, Inc.
Scientific Contribution |
Role of Sympathetic Nervous System in Cyclosporine-Induced Rise in Blood Pressure
From the Centro de Estudos de Função Autonomica, Hospital S. Joao, Oporto Medical School, Oporto (M.J.C., J.F., O.C., A.F.), Portugal, and the Department of Internal Medicine I, University Hospital Dijkzigt, Erasmus University, Rotterdam (A.H.M., F.B., A.J.M.), The Netherlands.
Correspondence to Dr A.H. van den Meiracker, Department of Internal Medicine I, University Hospital Dijkzigt, Room L253, Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail meirack.{at}mediaport.org
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—To clarify the role of the sympathetic nervous system in the development of cyclosporine A (CsA)-induced rise in blood pressure (BP), the effects of CsA on 24-hour ambulatory BP (ABP) were studied in patients with familial amyloid polyneuropathy (FAP) who underwent a liver transplantation. On the basis of autonomic function tests, patients with absent or mild-to-moderate sympathetic damage (Group A, n=11, age 29 to 43 years, disease duration 2 to 6 years) and patients with severe sympathetic damage (Group B, n=9, age 27 to 38 years, disease duration 3 to 9 years) were identified. Both groups were followed for 1 year. The daily doses of CsA and the CsA whole blood trough levels between the groups did not differ. Pretransplantation values of daytime and nighttime ABP were, respectively, 117±8/76±7 mm Hg and 108±12/68±9 mm Hg in group A and 107±6/66±4 mm Hg (P<0.05 group A versus group B) and 102±6/62±4 mm Hg in group B. In response to CsA, BP increased in all patients, but more so in patients of group B than in patients of group A. One year after transplantation, daytime and nighttime ABP had increased by 6±9/3±11% and 12±10/14±14% in group A and by 12±6/13±10% (P<0.05) and 21±11/27±21% (P<0.01) in group B. In both groups, the increase in nighttime ABP was greater than the increase in daytime ABP, which resulted in an attenuation or, even, a reversal of the diurnal BP rhythm. Because the rise in BP was greater in patients with more advanced sympathetic dysfunction, the sympathetic nervous system appears to counteract the CsA-induced rise in BP rather than causing it. This implies involvement of factors other than sympathetic activation in the pathogenesis of CsA-induced rise in BP in patients with familial amyloid polyneuropathy.
Key Words: amyloid neuropathies • cyclosporine • blood pressure monitoring, ambulatory • transplantation, liver
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Familial amyloid polyneuropathy (FAP) type I is a hereditary autosomal dominant disease of the peripheral nervous system. The biochemical basis of the disease is a point mutation of the plasma protein transthyretin that causes replacement of valine by methionine at position 30.1 This mutant protein is the major component of the deposited amyloid. The first symptoms of FAP type I usually occur in the third or fourth decade of life, and the disease invariably progresses to death within 7 to 15 years.2 The clinical picture of FAP type I is dominated by a sensorimotor polyneuropathy, starting in the distal parts of the limbs, and a progressive failure of the parasympathetic and sympathetic nervous system (SNS).2 3 Because more than 95% of transthyretin is produced by the liver, orthotopic liver transplantation (OLTx) is currently the preferred treatment in FAP patients to halt the progression of the disease by eliminating the production of the mutant protein.4
The use of cyclosporine A (CsA) as the immunosuppressive agent in organ transplantation is associated with a high incidence of posttransplant hypertension. For example, 1 to 2 years after liver transplantation, a 50% to 80% incidence of hypertension has been reported. A large proportion of these patients require antihypertensive medication.5 6 7 It has been well established that the CsA-induced rise in blood pressure (BP) is due to an increase in vascular resistance in both systemic and renal circulation,7 8 9 but the precise pathophysiological mechanisms mediating this increase are unknown.7
Scherrer et al, 10 by measuring muscle sympathetic nerve activity in heart transplant recipients and in patients with myasthenia gravis, found that CsA treatment is accompanied by a sustained activation of the SNS, which suggests that augmented sympathetic activation is involved in CsA-induced hypertension. However, in a number of other human studies using various techniques to assess the activity of the SNS, no evidence for CsA-induced sympathetic activation could be detected.11 12 13 14
A way to obtain more information about a possible pathogenetic role of the SNS in the development of CsA-induced rise in BP is to study the effect of CsA in patients with various degrees of sympathetic dysfunction. We hypothesized that if a normally functioning SNS is critical to the development of the CsA-induced rise in BP, a relatively large increase in BP could be expected to occur in those patients with a less severe impairment of their SNS, and a small or absent increase in BP could be expected in those patients with more severe impairment of their SNS. To test this hypothesis, the response of 24-hour ambulatory BP (ABP) to CsA was studied in FAP patients with more or less severe impairment of their SNS, who had undergone OLTx.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Patients
FAP patients who underwent OLTx in either the in São João Hospital or Santo António Hospital, in Oporto, were studied. The diagnosis of FAP was based on the clinical picture, a positive familial history of FAP, the presence of the abnormal transthyretin in plasma, and a subcutis biopsy positive for amyloid.
All patients who participated in this study had sensorimotor polyneuropathy, but they were in good general clinical condition and were able to stand up and walk without support. None of the patients used BP lowering agents or other agents that could interfere with the function of the SNS. Because severe cardiac conduction disturbances occur frequently in FAP, all patients had received a permanent pacemaker before transplantation. In addition, the patients underwent a training session to get accustomed to the various autonomic function tests. Patients were informed about the purpose and procedures of the study, and all gave written informed consent. The study was approved by the ethics review committees of Oporto Medical School and University Hospital Dijkzigt. In this report, the results of investigations on the first 20 consecutive patients who survived the OLTx for at least 1 year are presented.
Evaluation of Cardiovascular Autonomic
Function
All autonomic function tests were performed during the morning
in a temperature-controlled room, before OLTx and for one year after
OLTx. We evaluated cardiovascular autonomic function 30
minutes after insertion of a catheter (Venflon, BOC, Ohmeda AB)
in one of the forearm veins. During the studies, finger BP (Finapres BP
monitor, Ohmeda 2300) and ECG were monitored continuously, and data
were stored in a computer for off-line
analysis.3
Cardiac Parasympathetic Function
Parasympathetic cardiac innervation was assessed by a
deep-breathing test and an intravenous atropine infusion
(0.04 mg · kg-1 ·
min-1 for 10 minutes). For the deep breathing
test, patients were instructed to breathe deeply at 6 breaths per
minute for 1 minute while maintaining a supine position. The maximum
and minimum heart rate (HR) of each breathing cycle was measured, and
the mean of the difference between maximum and minimum HRs for the 6
cycles was used as an index of cardiac parasympathetic function. A
value of 15 bpm or higher is considered to be normal.15
For the atropine infusion, an increase in HR of 40 bpm or higher is
considered to be normal.16
Cardiovascular Sympathetic Function
Cardiovascular sympathetic function was assessed
by a head-up tilt test, a Valsalva maneuver, a
norepinephrine infusion, and the determination of
plasma-norepinephrine concentration. A 10-minute, 60°
head-up tilt test was performed after patients had rested in a supine
position on a tilt-table for 30 minutes. The erect BP (minus the first
2 minutes) and supine BP were averaged and their difference was
calculated. Just before the tilt test, blood was sampled for
determination of plasma-norepinephrine concentration. For
the Valsalva maneuver, patients had to maintain an expiratory pressure
of 40 mm Hg for 15 seconds by blowing through a mouthpiece and
tubing attached to a mercury manometer. Norepinephrine was
infused to assess the sensitivity of vascular 
-adrenoceptors. The
starting dose was 2.5 ng · kg-1 ·
min-1. The dose was doubled every 6 minutes
until mean BP increased by 30 mm Hg.3 In 6
apparently healthy normotensive control subjects (4 men, 2 women) the
mean dose of norepinephrine needed to increase mean BP by
30 mm Hg was 249 ng · kg-1 ·
min-1 (range,
200–300 ng · kg-1 ·
min-1).
Scoring the Degree of Sympathetic Damage
To score the degree of sympathetic damage in individual
patients, a composite grading system was developed, taking into account
the response of systolic BP to the head-up tilt test (fall in
systolic BP<5, 5 to 15, or >15 mm Hg; score 0, 1, or
2), the BP response during phase IV of the Valsalva maneuver (overshoot
present, delayed, or absent; score 0, 1, or 2), the dose of
norepinephrine needed to increase mean BP by 30 mm Hg
(>160, 80 to 160, or <80 ng · kg-1
· min-1; score 0, 1, or 2) and the baseline
plasma norepinephrine concentration (>100, 50 to 100, or
<50 pg/mL; score 0, 1, or 2). This composite grading system denotes
absence of sympathetic damage when the sum of scores is 0 and maximal
sympathetic damage when the sum of scores is 8. The combination of the
results of the 4 tests provides a reproducible estimate of sympathetic
damage per patient. In 18 FAP patients with different degrees of
sympathetic dysfunction, the mean difference in score at an interval of
3 months was 0.1±0.7. Based on the grading system, 2 groups of
patients, referred to as group A (score 0 to 4, absent or
mild-to-moderate sympathetic damage) and group B (score 5 to 8, severe
sympathetic damage), were distinguished (Table 1).
|
24-Hour ABP Monitoring
24-Hour ABP monitoring (SpaceLabs 90207, ABP monitor) was
performed before OLTx and at intervals of 3, 6, and 12 months after
OLTx. ABP was measured at 20-minute intervals during the day (8
AM to 11 PM) and at 30-minute intervals during
the night (midnight to 7 AM).
Data Analysis
The BP and HR values stored in the computer were
analyzed beat-by-beat with AT- and MCA-Codas programs (Dataq
Instruments). Plasma norepinephrine concentration was
determined by fluorimetric detection after HPLC
separation.17 In 20 healthy volunteers, matched with
respect to age with the FAP patients, the mean value was 184 (range,
158–210) pg/mL.
Data are presented as mean±SD. For comparison Student paired and unpaired t tests were used. A value of P<0.05 was considered to indicate statistical significance.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Relevant characteristics of the 2 groups of patients are given in Table 2. The 2 groups did not differ with respect to number, age, body weight, supine BP, or serum creatinine concentration. Duration of disease was longer in group B than in group A. All patients in group B had complete cardiac parasympathetic failure as reflected by absent HR responses to the deep breathing test and atropine. In 5 patients in group A, residual cardiac parasympathetic function was present (Table 1). The degree of sympathetic damage and duration of disease were correlated (r=0.46, P<0.05). The degree of sympathetic damage in each individual patient remained stable during the year of follow-up (mean difference±SD of sympathetic score –0.2±0.7)
|
Daytime and 24-hour values of the pretransplantation systolic and diastolic ABP were significantly higher in group A than in group B, but nighttime systolic and diastolic ABP between the 2 groups did not differ (Table 3). As a consequence, the day-night differences of systolic and diastolic BP were larger in patients in group A than in group B, reflecting the more severe sympathetic dysfunction in this latter group. Day, night, and 24-hour values of HR tended to be lower in group B than in group A (Table 3). After OLTx, all patients used CsA and prednisone as immunosuppressive therapy. Azathioprine was also used by 10 patients, 5 in each group. The daily doses of the immunosuppressive agents at 3, 6, and 12 months after OLTx did not differ between groups, and in both groups they were reduced to a similar extent during follow-up (Table 4). CsA whole blood trough levels in groups A and B were similar; values in the 2 groups were, respectively, 331±120 and 299±158 µg/L at 3 months, 245±71 and 256±119 µg/L at 6 months, and 177±44 and 173±80 µg/L at 12 months after transplantation.
|
|
ABP at intervals of 3, 6, and 12 months after OLTx significantly
increased (Figures 1 and 2), but in only 1 patient did daytime
diastolic BP become >90 mm Hg, and none of the
patients required antihypertensive medication. The increase in BP,
especially nighttime BP, was 
2 times larger in group B than in group
A (Figure 2).
|
|
Serious events after OLTx did not occur in any of the patients. Serum creatinine increased by 28±13 µmol/L (P<0.001) in group A and by 41±17 µmol/L (P<0.001) in group B, 1 year after transplantation. Body weight at that time increased by 4.0±4.7 (P<0.001) kg in group A and by 1.7±2.1 kg (P=0.046) in group B.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present study shows that CsA in patients with autonomic dysfunction due to FAP is associated with a rise in BP. The rise in BP was more pronounced in the subgroup of patients with more severe sympathetic damage. Our findings, therefore, do not favor the hypothesis that activation of the SNS is critical to the development of CsA-induced rise in BP in patients with FAP but do suggest that the CsA-induced rise in BP is counteracted by the autonomic nervous system. In agreement with previous studies,8 18 19 20 21 CsA, by increasing nighttime BP more than daytime BP, caused an attenuation of the day-night difference in BP. This effect was more pronounced in the group of patients with more severe sympathetic damage.
A characteristic feature of FAP patients is that their BP becomes lower with more advanced disease. In part, this is related to the occurrence of orthostatic hypotension as a result of the progressive insufficiency of their SNS. This explains why daytime ABP, but not nighttime ABP, was considerably lower in the patient group with more severe sympathetic damage. This difference in daytime ABP between the 2 groups disappeared completely after initiation of CsA immunosuppressive therapy because of the greater rise in BP in the patients with more pronounced sympathetic damage.
The greater rise in BP in the patient group with more severe impairment of their SNS could not be explained by differences in immunosuppressive therapy or CsA-induced impairment of renal function. In addition, evaluation of autonomic function 1 year after transplantation revealed a stable degree of sympathetic damage in each individual patient. Therefore, the more severe degree of sympathetic damage in the patients of group B most likely accounted for the observed greater rise in BP in that group. As has been emphasized recently, the baroreflex is crucial to counteract the rise in BP induced by pressure agents.21 If the buffering capacity of the baroreflex is impaired, as was certainly the case in the patients in group B, the sensitivity to agents that increase BP, irrespective of the underlying mechanism, will be augmented. This is in accordance with previous observations, which show that similar doses of CsA were associated with a greater rise in BP in heart transplant recipients than in patients with myasthenia gravis.10 22 Removal of the inhibitory afferent restraint on sympathetic outflow due to interruption of the ventricular-baroreceptor reflex has been mentioned to explain this greater BP rise in cardiac transplant recipients.22
Previous studies have shown that the CsA-induced rise in BP is associated with an attenuation of the nocturnal fall in BP.18 19 20 The simultaneous use of glucocorticoids may contribute to this blunted diurnal BP rhythm.23 As a consequence of their autonomic dysfunction, the diurnal BP rhythm was already attenuated before the start of immunosuppressive therapy in a substantial number of our patients. During immunosuppressive therapy, a further blunting of the diurnal BP rhythm was observed. This effect was more pronounced in the group with more severe impairment of their SNS (Figure 1B). Volume expansion related to CsA-induced renal vasoconstriction and to the use of glucocorticoids is a likely explanation of this blunting of the diurnal BP rhythm.20 23 24 25 Volume expansion will lead to a greater venous return during nighttime recumbency, when extracellular fluid shifts from the periphery to central parts of the body. This greater venous return, through an increase in cardiac output, forces BP to rise. We suggest that in the absence of sympathetic dysfunction, this rise in BP is counterbalanced by the baroreflex, although not completely, as the day-night difference in BP is attenuated during CsA therapy. If the function of the baroreflex is impaired or fails, the rise in BP during the night will be greater than during the day.
Although administration of CsA was associated with a rise in BP,
hypertension, as defined as a daytime ambulatory diastolic
BP of 
90 mm Hg, was observed in only 1 patient and none of the
patients required antihypertensive medication during the 1 year of
follow-up. This extremely low incidence of de novo hypertension
contrasts with the prevalence of CsA-induced hypertension after liver
transplantation observed in other studies.5 6 7 The
question of why hypertension did not develop in our patients is not
easy to answer. The daily doses of CsA and prednisone used by our
patients were similar to those reported for other transplant patient
groups, as were the CsA whole blood trough levels. It is possible that
the deposition of amyloid within the vascular wall and the kidney
prevented the development of hypertension in our patients. Although
after liver transplantation the production of the transthyretin
mutant will stop, it is not to be expected that the already formed
amyloid will disappear quickly.26 27 Indeed,
autonomic function tests 1 year after transplantation showed no
evidence of either improvement or progression of autonomic dysfunction
in our population.
As activation of the SNS appears not to be critical to the development of CsA-induced rise in BP in our patients, other factors should be investigated. There is evidence that the use of CsA is associated with an inhibition of vasodilator pathways and an activation of vasoconstrictor pathways leading to an increase in vascular resistance.7 13 22 28 CsA-induced renal vasoconstriction, especially with the concomitant use of glucocorticoids, promotes fluid retention, which likely contributes to the development of the rise in BP.24 25 In the present study, some deterioration in renal function and an increase in body weight were found. These findings favor renal vasoconstriction and fluid retention as pathogenetic mechanisms in the observed rise in BP.
Received October 2, 1998; first decision November 4, 1998; accepted March 15, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Saraiva MJM, Costa PP, Goodman DS. Biochemical marker in familial amyloidotic polyneuropathy, Portugese type: family studies on the transthyretin (pre-albumin)-methionine 30 variant. J Clin Invest. 1985;76:2171–2177.
2.
Andrade CA. A peculiar form of peripheral
neuropathy: familial atypical generalized amyloidosis with
special involvement of peripheral nerves. Brain. 1952;75:408–427.
3. Carvalho MJ, van den Meiracker AH, Boomsma F, Man in `t Veld AJ, Freitas J, Costa O, Falcao de Freitas A. Improved orthostatic tolerance in familial amyloidotic polyneuropathy with unnatural noradrenaline precursor L-threo-3,4-dihydroxyphenylserine. J Auton Nerv Syst. 1997;62:63–71.[Medline] [Order article via Infotrieve]
4. Holmgren G, Ericzon BG, Groth CG, Steen L, Suhr O, Andersen O, Wallin BG, Seymour A, Richardson S, Hawkins PN. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet. 1993;341:1113–1116.[Medline] [Order article via Infotrieve]
5. Starzl TE, Demeteris AJ, Van Tiel D. Liver transplantation. N Engl J Med. 1989;321:1014–1022.[Medline] [Order article via Infotrieve]
6. Taler SJ, Textor SC, Ganzanello VJ, Schwartz L, Porayko M, Wiesner RH, Krom RA. Role of steroid dose in hypertension early after liver transplantation with tacrolimus (FK506) and cyclosporine. Transplantation. 1996;62:1588–1592.[Medline] [Order article via Infotrieve]
7.
Textor SC. De novo hypertension after liver
transplantation. Hypertension. 1993;22:257–267.
8. Frist WH, Stinson EB, Oyer PE, Baldwin JC, Shumway NE. Long-term hemodynamic results after cardiac transplantation. J Thorac Cardiovasc Surg. 1987;94:685–693.[Abstract]
9.
Greenberg ML, Uretsky BF, Reddy PS, Bernstein RL,
Griffith BP, Hardesty RL, Thompson ME, Bahnson HT. Long-term
hemodynamic follow-up of cardiac transplant patients
treated with cyclosporine and prednisone.
Circulation. 1985;71:487–494.
10. Scherrer U, Vissing SF, Morgan BJ, Rollins JA, Tindall RSA, Ring S, Hanson P, Mohanty PK, Victor RG. Cyclosporine-induced sympathetic activation and hypertension after heart transplantation. N Engl J Med. 1990;323:639–699.
11.
Kaye D, Thompson J, Jennings G, Esler M.
Cyclosporine therapy after cardiac transplantation causes
hypertension and renal vasoconstriction without sympathetic activation.
Circulation. 1993;88:1101–1109.
12. Floras JS, Legault L, Morali GA, Hara K, Blendis LM. Increased sympathetic outflow in cirrhosis and ascites: direct evidence from intraneural recordings. Ann Intern Med. 1991;114:373–380.
13.
Stein CM, He H, Pincus Th, Wood AJJ.
Cyclosporine impairs vasodilation without increased
sympathetic activity in humans. Hypertension. 1995;26:705–710.
14. Lucini D, Milani RV, Ventura HO, Mehra MR, Messerli FH, Murgo JP, Regenstein F, Copley B, Malliani A, Pagani M. Cyclosporine-induced hypertension: evidence for maintained baroreflex circulatory control. J Heart Lung Transplant. 1997;16:615–620.[Medline] [Order article via Infotrieve]
15. Ewing DJ, Clarke BF. Autonomic neuropathy: its diagnosis and prognosis. Clin Endocrinol Metab. 1985;15:855–888.
16. Bannister R, Mathias C. Testing autonomic reflexes in autonomic failure. In: Bannister R, ed. A Textbook of Clinical Disorders of the Autonomic Nervous System. 2nd ed. Oxford, UK: Oxford Medical Publications; 1988:289–307.
17. van den Hoorn FAJ, Boomsma F, Man in `t Veld AJ, Schalekamp MADH. Determination of catecholamines in human plasma by high performance liquid chromatography: comparison between a new method with fluorescence detection and an established method with electrochemical detection. J Chromatogr. 1989;487:17–27.[Medline] [Order article via Infotrieve]
18.
Reeves RA, Shapiro AP, Thompson ME, Johnsen AM.
Loss of nocturnal decline in BP after cardiac transplantation.
Circulation. 1986;73:401–408.
19.
Idema RN, van den Meiracker AH, Balk AHHM, Bos E,
Schalekamp MADH, Man in `t Veld AJ. Abnormal diurnal variation of
blood pressure, cardiac output and vascular resistance in cardiac
transplant patients. Circulation. 1994;90:2797–2803.
20.
Van den Dorpel MA, van den Meiracker AH, Lameris TW,
Boomsma F, Levi M, Man in `t Veld AJ, Weimar W, Schalekamp MADH.
Cyclosporine A impairs the nocturnal blood pressure fall in
renal transplant recipients. Hypertension. 1996;28:304–307.
21.
Shannon JR, Jordan J, Black BK, Costa F, Roberson D.
Uncoupling of the baroreflex by NN-cholinergic
blockade in dissecting the components of cardiovascular
regulation. Hypertension. 1998;32:101–107.
22. Sander M, Lyson T, Thomas GD, Victor RG. Sympathetic neural mechanisms of cyclosporine-induced hypertension. Am J Hypertens. 1996;9:121S–138S.[Medline] [Order article via Infotrieve]
23. Van de Borne P, Leerman M, Primo G, Degaute J-P. Reappearance of a normal circadian rhythm of blood pressure after cardiac transplantation. Am J Cardiol. 1992;69:794–801.[Medline] [Order article via Infotrieve]
24. Bantle JP, Boudreau RJ, Ferris TF. Suppression of plasma renin activity by cyclosporine. Am J Med. 1987;83:59–64.[Medline] [Order article via Infotrieve]
25. Ciresi DL, Lloyd MA, Sandberg SM, Heublein DM, Edwards BS. The sodium retaining effect of cyclosporine. Kidney Int. 1992;41:1599–1605.[Medline] [Order article via Infotrieve]
26.
Bergethon PR, Sabin TD, Lewis D, Simms RW, Cohen
AS, Skinner M. Improvement in the polyneuropathy
associated with familial amyloid polyneuropathy after
liver transplantation. Neurology. 1996;47:944–951.
27. Pomfret EA, Lewis WD, Jenkins RL, Bergethon P, Dubrey SW, Reisinger J, Falk RH, Skinner M. Effect of orthotopic liver transplantation on the progression of familial amyloidotic polyneuropathy. Transplantation. 1998;65:918–925.[Medline] [Order article via Infotrieve]
28. Richards NT, Poston L, Hilton PJ. Cyclosporine A inhibits endothelium-dependent, prostanoid-induced relaxation in human subcutaneous resistance vessels. J Hypertens. 1990;8:159–163.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  G. LIGTENBERG, R. J. HENÉ, P. J. BLANKESTIJN, and H. A. KOOMANS Cardiovascular Risk Factors in Renal Transplant Patients: Cyclosporin A Versus Tacrolimus J. Am. Soc. Nephrol., February 1, 2001; 12(2): 368 - 373. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. J. Carvalho, A. H. van den Meiracker, F. Boomsma, M. Lima, J. Freitas, A. J. M. i.’t Veld, and A. Falcao de Freitas Diurnal Blood Pressure Variation in Progressive Autonomic Failure Hypertension, April 1, 2000; 35(4): 892 - 897. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||