long-term renoprotective effects of standard versus high doses of telmisartan in hypertensive...
TRANSCRIPT
●
ep(tRpt80t0alde©
Ir
AmImz(etp
oHDS
3
o
SC
sdm
1
Long-Term Renoprotective Effects of Standard Versus High Dosesof Telmisartan in Hypertensive Nondiabetic Nephropathies
Pedro Aranda, MD, Julian Segura, MD, Luis M. Ruilope, MD, Francisco J. Aranda, MD,Miguel A. Frutos, MD, Verónica López, MD, and Eduardo López de Novales, MD
Background: This report describes an open randomized study intended to evaluate the long-term renoprotectiveffects of “standard” (80 mg once daily) versus “high” (80 mg twice daily) doses of telmisartan in hypertensiveatients without diabetes with biopsy-proven chronic proteinuric nephropathies. Methods: We included 78 patientsage, 43.5 � 13.2 years; 71.8% men). After a 4-week wash-out period, patients were randomly assigned toelmisartan, 80 mg once daily (n � 40) or 80 mg twice daily (n � 38), during a mean follow-up of 24.6 � 2.2 months.esults: Baseline characteristics were similar in both groups, including blood pressure, renal function, androteinuria. Blood pressure control did not differ between groups during follow-up. In the group administeredelmisartan, 80 mg once daily, serum creatinine level increased from 1.6 � 0.6 to 2.7 � 0.9 mg/dL (141 � 52 to 239 �0 �mol/L), and estimated creatinine clearance declined from 68 � 30 to 50 � 34 mL/min (1.13 � 0.50 to 0.83 �.57 mL/s), whereas in those administered 80 mg twice daily, serum creatinine (1.6 � 0.7 to 1.6 � 0.8 mg/dL [141 � 62o 141 � 71 �mol/L]) and estimated creatinine clearance values (67 � 38 to 74 � 38 mL/min [1.12 � 0.63 to 1.23 �.63 mL/s]) did not change during the study. The decrease in proteinuria was more pronounced (P < 0.01) in patientsdministered the high dose of telmisartan compared with those treated with the standard dose. Serum potassiumevels and lipid profiles did not change significantly in either group. Conclusion: Long-term administration of highoses of telmisartan seems to improve the efficacy of the drug to decrease proteinuria and slow the progression tond-stage renal failure in nondiabetic hypertensive renal disease. Am J Kidney Dis 46:1074-1079.2005 by the National Kidney Foundation, Inc.
NDEX WORDS: Chronic proteinuric renal diseases; renin-angiotensin system; nephroprotection; angiotensin
eceptor blockers.ibfdAto
AAtmAtctiowwl
luat
CTIVATION OF THE renin-angiotensin sys-tem (RAS) has a major role in the develop-
ent and progression of chronic renal failure.1
nhibition of the effects of angiotensin II, byeans of either an angiotensin-converting en-
yme (ACE) inhibitor or an angiotensin II type 1AT1) receptor blocker (ARB), is necessary tonsure the best degree of renal protection throughheir simultaneous capacity to decrease bloodressure (BP) and control proteinuria.2-4 A grow-
From the Hypertension and Vascular Risk Unit, Nephrol-gy Department, Hospital Regional Universitario Carlosaya, Málaga; and the Hypertension Unit, Nephrologyepartment, Hospital Universitario 12 de Octubre, Madrid,pain.Received April 14, 2005; accepted in revised form August
0, 2005.Originally published online as doi:10.1053/j.ajkd.2005.08.034
n October 26, 2005.Supported in part by a grant from Boehringer Ingelheim,
pain; and a grant from Red temática de Enfermedadesardiovasculares (RECAVA), ISCIII, Madrid, Spain (J.S.).Address reprint requests to Julian Segura, MD, Hyperten-
ion Unit, Hospital Universitario 12 de Octubre, Av Cór-oba s/n, 28041 Madrid, Spain. E-mail: [email protected]© 2005 by the National Kidney Foundation, Inc.0272-6386/05/4606-0009$30.00/0
ndoi:10.1053/j.ajkd.2005.08.034
American Journal of Kidney074
ng body of evidence recently has shown theeneficial effects of ARBs for protection of renalunction, in particular, in patients with type 2iabetic nephropathy.5-8 These good effects ofT1 receptor blockade could be complemented
hrough the effects of angiotensin II at the levelf AT2 receptors.9,10
It was shown that commonly used doses ofRBs could block only approximately 40% ofT1 receptors.11 This could contribute to explain
he good results obtained by combining recom-ended doses of an ARB and high doses of anCE inhibitor.12 Adequate uptitration to greater
han the recommended dose of an ARB thenould obtain similar or even better results thanhose obtained in combination with an ACEnhibitor.11 Our aim was to compare the renalutcome of nondiabetic hypertensive patientsith chronic proteinuric nephropathies treatedith standard or high doses of telmisartan, a
ong-acting ARB.13
METHODS
This is a randomized open-label study intended to analyzeong-term effects on BP, estimated creatinine clearance,rinary protein excretion, and clinical and biochemical toler-bility of 2 doses, 80 mg once daily (standard) or 80 mgwice daily (high), of telmisartan in patients with chronic
ondiabetic proteinuric nephropathies.Diseases, Vol 46, No 6 (December), 2005: pp 1074-1079
otoebtpiSdt6d
bu2uhtwPtte
Hllawce
S
dgawcdlc(
sd
(v
NASIM
F
NSDBHF
(
HIGH DOSES OF TELMISARTAN AND RENOPROTECTION 1075
We included 78 patients (56 men; 71.7%) aged 18 years orlder with biopsy-proven nondiabetic proteinuric nephropa-hies and signed informed consent. Patients were maintainedn the antihypertensive therapy that they were receiving,xcept for ACE inhibitors or ARBs, for a 4-week periodefore randomization. Patients were consecutively assignedo 1 of the 2 doses of telmisartan contemplated in therotocol. Any other antihypertensive therapy could be addedf required to attain a BP goal less than 130/80 mm Hg.tandard or high doses of telmisartan were administereduring a follow-up period of 24.6 � 2.2 months. During thisime, all patients were advised to follow moderate salt (4 to
g/d) and protein restrictions (0.7 to 0.8 g/kg/d) in theiet.14
Fig 1. Changes in systolic
Table 1. Baseline Characteristics of Patients
Telmisartan80 mg Once
Daily
Telmisartan80 mg Twice
Daily
o. of patients 40 38ge (y) 43.6 � 12.6 43.4 � 13.9ex (men) 28 (70.0) 28 (73.7)
gA nephropathy 17 (42.5) 17 (44.1)embranousglomerulonephritis 11 (27.5) 9 (23.7)
ocal segmentalglomerulosclerosis 4 (10.0) 4 (10.5)ephrosclerosis 8 (20.0) 8 (21.1)ystolic BP (mm Hg) 134.3 � 13 138.1 � 13iastolic BP (mm Hg) 87.1 � 10 84.8 � 8ody mass index (kg/m2) 27 � 2.4 24.8 � 2.0eart rate (beats/min) 76.8 � 5 74.5 � 5ollow-up (mo) 24.1 � 2.9 24.8 � 2
NOTE. Values expressed as mean � SD or numberpercent). All P not significant.
SBP) and diastolic BP (DBP)alues during follow-up.
BP values (mean of 3 readings per visit), heart rate, andody mass index, as well as blood samples and 24-hourrine samples, were obtained at baseline and 6, 12, 18, and4 months of follow-up. Fasting values for serum glucose,ric acid, creatinine, potassium, lipid profile, hematocrit,emoglobin, and, in 24-hour urine samples, urea and pro-ein, were determined at every visit. Creatinine clearanceas estimated by using the Cockcroft-Gault equation.15
atients visited the office in the morning, before administra-ion of antihypertensive agents. Clinical tolerability andreatment compliance (by means of pill counting) werevaluated at every visit.
Arterial hypertension is defined as systolic BP of 140 mmg or greater and/or diastolic BP of 90 mm Hg or greater or
ess under antihypertensive therapy.16 Intended BP goal wasess than 130/80 mm Hg.3 Concomitant antihypertensivegents were prescribed according to clinical daily practiceithout a prespecified protocol, but included, in most cases,
ombined therapy. This study was approved by the localthics committee of the Hospital Carlos Haya, Malaga, Spain.
tatistical AnalysisResults are expressed as mean � SD. The significance of
ifferences in categorical and continuous variables betweenroups was examined by means of Pearson chi-square testnd t-test, respectively. Analyses of variance (ANOVAs)ith repeated measures (serum creatinine levels, estimated
reatinine clearance, and proteinuria) were performed toetermine differences within groups and between groups. Pess than 0.05 is considered statistically significant. Statisti-al analyses were performed using SPSS, version 10.0SSPS Inc, Chicago, IL).
RESULTS
Baseline characteristics, including mean age,ex, anthropometric parameters, type of renalisease, mean time since diagnosis of renal dis-
esg
fps
apT
E
lttDc(0w0Awc50
gimAwswmtgdpbpcw
agn
A
N
O
s
ARANDA ET AL1076
ases, and arterial hypertension, did not showtatistically significant differences between the 2roups (Table 1).Figure 1 shows changes in BP values during
ollow-up. Values were similar in the 2 groups ofatients. Heart rate and body mass index showedimilar levels at baseline and during follow-up.
Data about concomitant antihypertensivegents and other therapies used in the 2 groups ofatients during follow-up are listed in Table 2.he 2 groups of patients behaved similarly.
volution of Renal Function and Proteinuria
Figure 2 shows changes in serum creatinineevels, estimated creatinine clearance, and pro-einuria in the 2 groups of patients. All parame-ers were similar at baseline in both groups.uring follow-up, mean creatinine values in-
reased from 1.6 � 0.6 to 2.7 � 0.9 mg/dL141 � 53 to 239 � 80 �mol/L; ANOVA, P �.01) in patients treated with 80 mg of telmisartan,hereas they remained stable (1.6 � 0.7 to 1.6 �.8 mg/dL [141 � 62 to 141 � 71 �mol/L];NOVA, P � not significant) in patients treatedith 80 mg twice daily. Conversely, estimated
reatinine clearance decreased from 68 � 30 to0 � 34 mL/min/1.73 m2 (1.13 � 0.50 to 0.83 �
Table 2. Concomitant Therapies
Telmisartan80 mg Once
Daily
Telmisartan80 mg
Twice Daily
ntihypertensive therapyDiuretic 21 (52.5) 22 (57.9)�-Blocker 8 (20.0) 8 (21.1)Dihydropyridine calcium
channel blocker 17 (42.5) 11 (28.9)Nondihydropyridine
calcium channel blocker 12 (30.0) 14 (36.8)�-Blocker 16 (40.0) 12 (31.6)o. of antihypertensive drugs1 4 (10.0) 8 (21.1)2 8 (20.0) 4 (10.5)3 16 (40.0) 20 (52.6)�4 12 (30.0) 6 (15.8)ther therapiesStatins 34 (85.0) 30 (79.0)Allopurinol 12 (30.0) 12 (31.6)Antiplatelet 19 (47.5) 14 (36.8)
NOTE. Values expressed as number (percent). All P notignificant.
.57 mL/s/1.73 m2; ANOVA, P � 0.01) in thecb
roup administered 80 mg once daily, whereas itncreased from 67 � 38 to 74 � 38 mL/min/1.73
2 (1.12 � 0.63 to 1.23 � 0.63 mL/s/1.73 m2;NOVA, P � not significant) in those treatedith 80 mg twice daily. We also observed a
tatistically significant decrease in proteinuriaith both therapeutic regimens (telmisartan, 80g once daily; ANOVA, P � 0.01); however,
his decrease was significantly greater in theroup administered telmisartan, 80 mg twiceaily (ANOVA, P � 0.001). The percentage ofatients attaining control of proteinuria to valueselow 0.3 g/24 h that was significantly less inatients administered 80 mg of telmisartan (15%)ompared with those administered a double dose,hich attained control in 40%. Serum potassium
Fig 2. Changes in serum creatinine, estimated cre-tinine clearance, and proteinuria values in the 2roups of patients during follow-up. To convert creati-ine in mg/dL to �mol/L, multiply by 88.4; creatinine
2 2
learance in mL/min/1.73 m to mL/s/1.73 m , multiplyy 0.01667.
vg
ulmctps
e1c
tsrRAtitucastAbea
t
attpefdriu(
sdpaatttgssapwB
pnattbT
THLGUHH
0m
HIGH DOSES OF TELMISARTAN AND RENOPROTECTION 1077
alues did not change significantly in eitherroup throughout the study.Table 3 lists mean serum values for glucose,
ric acid, hematocrit, and hemoglobin, as well asipid profile, at inclusion and the end of 24onths of follow-up. No statistically significant
hange was observed in these parameters be-ween the 2 groups. Urinary urea values (gramser liter) were similar in both groups, as expres-ion of a moderate protein restriction diet.
Percentages of patients showing clinical sideffects were similar in both groups (15% versus3.2%). No patient discontinued the study as aonsequence of adverse events.
DISCUSSION
Beneficial renoprotective effects of blockinghe RAS on renal outcome were shown in aeries of clinical trials recently reviewed.3,4 Ouresults reinforce the concept that more effectiveAS inhibition achieved by greater doses of anRB results in more effective proteinuria reduc-
ion and stabilization of renal function. The BP-ndependent effect of ACE inhibitors and ARBsriggered the concept that uptitration beyond thesually recommended antihypertensive dosesould be considered preferential to attain a betterntiproteinuric effect.17 Forclaz et al11 recentlyhowed that the usual dose (80 mg once daily) ofelmisartan blocks only approximately 40% ofT1 receptor activity, but by doubling that dose,lockade increased to approximately 57%, orven more (64%) if the dose of telmisartan wasdministered twice daily.
The majority of large trials showed that, within
Table 3. Mean Values of
Telm
Base
riglycerides (mg/dL) 147 �igh-density lipoprotein cholesterol (mg/dL) 51 �ow-density lipoprotein cholesterol (mg/dL) 146 �lucose (mg/dL) 90.9 �ric acid (mg/dL) 6.56 �ematocrit (%) 41.6 �emoglobin (g/dL) 13.9 �
NOTE. Not statistically significant changes between grou.01129; cholesterol in mg/dL to mmol/L, multiply by 0.025g/dL to �mol/L, multiply by 59.48.
he recommended limits, the greater the dose of d
n ACE inhibitor or ARB, the better the antipro-einuric effect.1,3,4,12 The possibility of uptitratinghe dose of a drug able to inhibit the RAS isarticularly feasible with ARBs because of theirxcellent tolerability, which did not seem to varyrom that of placebo, even passing recommendedoses.18 In this regard, in patients with chronicenal failure treated with these agents, an increasen serum potassium level rarely is seen with glomer-lar filtration rates greater than 30 mL/min/1.73 m2
�0.50 mL/s/1.73 m2).19-21
Therefore, although several studies12,22,23
howed better reductions in proteinuria and retar-ation of progression of chronic renal failure inatients treated with the combination of an ARBnd ACE inhibitor than with either componentlone, examination of the capacity of an upti-rated dose of an ARB has remained to be inves-igated. Our data indicate that administration ofelmisartan, 80 mg twice daily, causes a muchreater decrease in urinary protein excretion as-ociated with significantly better preservation oferum creatinine and estimated creatinine clear-nce values compared with the standard antihy-ertensive dose of 80 mg once daily. This effectas observed in the presence of unusually goodP control.These results are not in agreement with 3
ublished studies of patients with type 2 diabeticephropathy and proteinuria, contemplating thentiproteinuric capacity of uptitration of losar-an22-25 and candesartan.26 Uptitration of losar-an from 100 to 150 mg/d was not accompaniedy an additional decrease in proteinuria or BP.22,25
he same result was seen when candesartan
iochemical Parameters
80 mg Once Daily Telmisartan 80 mg Twice Daily
24 Months Baseline 24 Months
149 � 56 166 � 68 153 � 6046 � 10.5 47 � 12 46 � 11
130 � 28 134 � 30 132 � 3289 � 4.9 96.6 � 10 92.5 � 86.3 � 1.73 7.08 � 1.18 6.51 � 0.93
35.1 � 3.9 40.5 � 5.1 40.1 � 4.510.9 � 1.2 13.6 � 1.7 13.4 � 1.6
convert serum triglycerides in mg/dL to mmol/L, multiply bycose in mg/dL to mmol/L, multiply by 0.05551; uric acid in
Other B
isartan
line
831533781.3862
ps. To86; glu
osage was uptitrated from 16 to 32 mg/d.26 As
sciAhmitAidnitbcittt
tFewct
tdrpwpeacfi
dt
ti2
O2
t2
Rdd
ttN
lw8
Ett3
dfC
st
Bb2
Ttnc
Is3
iH
c
StJ
Hbp
a(s2
VtI
ARANDA ET AL1078
hown by Forclaz et al11 in their report, 200 mgompared with 150 mg of losartan was able toncrease in a significant manner the degree ofT1 receptor activity blockade, mainly whenalf this dose is administered twice daily. Evenore, that dose of losartan showed a capacity to
nhibit RAS activity similar to that attained withhe combination of an ACE inhibitor plus anRB in conventional doses.11 Conversely, more
ntense and complete blockade of AT1 receptorsuring the nighttime in patients who used to beondippers could facilitate better BP control dur-ng the nighttime.27 Nighttime BP has been showno facilitate urinary albumin excretion,28 andetter control of nocturnal BP could enhanceontrol of proteinuria. In addition to greaternhibition of AT1 receptors, uptitration of theelmisartan dose also could potentiate the posi-ive renal effects mediated through AT2 recep-ors.29-31
This study has some limitations, partly relatedo its design, based on daily clinical practice.irst, sample size and follow-up period were notstablished “a priori.” Second, office BP valuesere used as the main variable to evaluate BP
ontrol during follow-up, and data about night-ime BP were not available.
In summary, our data indicate that doublinghe standard dose of telmisartan from 80 mg onceaily to 80 mg twice daily is more effective in theeduction of proteinuria, as well as in slowing therogression of chronic renal failure in patientsithout diabetes with chronic proteinuric ne-hropathies. These results are associated withxcellent clinical and biochemical tolerabilitynd took place in the presence of adequate BPontrol. Additional studies are required to con-rm these data, which look very promising.
REFERENCES1. Remuzzi G, Ruggenenti P, Perico N: Chronic renal
iseases: Renoprotective benefits of renin-angiotensin sys-em inhibition. Ann Intern Med 136:604-615, 2002
2. National Kidney Foundation: K/DOQI Clinical Prac-ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease. Am J Kidney Dis 43:S1-S290,004 (suppl 1)3. Weir MR: Progressive renal and cardiovascular disease:
ptimal treatment strategies. Kidney Int 62:1482-1492,002
4. Schieppatti A, Remuzzi G: The future of renoprotec-ion: Frustrations and promises. Kidney Int 64:1974-1955,
003 A5. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis, Andersen S, Arner P: The effect of irbesartan on theevelopment of diabetic nephropathy in patients with type 2iabetes. N Engl J Med 345:870-878, 20016. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renopro-
ective effect of the angiotensin-receptor antagonist irbesar-an in patients with nephropathy due to type 2 diabetes.
Engl J Med 345:851-860, 20017. Brenner BM, Cooper ME, de Zeeuw D, et al: Effects of
osartan on renal and cardiovascular outcomes in patientsith type 2 diabetes and nephropathy. N Engl J Med 345:861-69, 20018. Barnett AH, Bain SC, Bouter P, et al, for the Diabetics
xposed to Telmisartan and Enalapril Study Group: Angio-ensin-receptor blockade versus converting-enzyme inhibi-ion in type 2 diabetes and nephropathy. N Engl J Med51:1952-1961, 20049. Levy BI: Can angiotensin II type 2 receptors have
eleterious effects in cardiovascular disease? Implicationsor the therapeutic blockade of the renin-angiotensin system.irculation 109:8-13, 200410. Carey RM, Jin XH, Siragy HM: Role of the angioten-
in AT2 receptor in blood pressure regulation and therapeu-ic implications. Am J Hypertens 14(6 Pt 2):98S-102S, 2001
11. Forclaz A, Maillard M, Nussberger J, Brunner HR,urnier M: Angiotensin II receptor blockade: Is there truly aenefit of adding an ACE inhibitor? Hypertension 41:31-36,00312. Nakao N, Yoshimura A, Morita H, Takada M, Kayano
, Ideura T: Combination treatment of angiotensin-II recep-or blocker and angiotensin-converting enzyme inhibitor inon-diabetic renal disease (COOPERATE): A randomisedontrolled trial. Lancet 361:117-124, 2003
13. Stangier J, Su C-APF, van Heinningen PNM, et al:nhibitory effect of telmisartan on the blood pressure re-ponse to angiotensin II challenge. J Cardiovasc Pharmacol8:672-685, 200114. Lentine K, Wrone EM: New insights into protein
ntake and progression of renal disease. Curr Opin Nephrolypertens 13:307-312, 200415. Cockcroft DW, Gault MH: Prediction of creatinine
learance from serum creatinine. Nephron 16:31-41, 197616. Chobanian AV, Bakris GL, Black HR, et al: The
eventh Report of the Joint National Committee on Preven-ion, Evaluation and Treatment of High Blood Pressure: TheNC 7 Report. JAMA 289:2560-2571, 2003
17. Segura J, Christiansen H, Campo C, Ruilope LM:ow to titrate ACE inhibitors and angiotensin receptorlockers in renal patients: According to blood pressure orroteinuria? Curr Hypertens Rep 5:426-429, 200318. Weinberg AJ, Haneiwich R, Weinberg MS: The safety
nd efficacy of supramaximal doses of candesartan cilexetil160 mg) in chronic renal disease patients’ naïve to angioten-in receptor blockade therapy. Am J Hypertens 16:103A,003 (abstr)19. Bakris GL, Siomos M, Richardson D, et al: for the
AL-K Study Group: ACE inhibition or angiotensin recep-or blockade: Impact on potassium in renal failure. Kidneynt 58:2084-2092, 2000
20. Jacobsen P, Andersen S, Jensen BR, Parving HH:
dditive effect of ACE inhibition and angiotensin II recep-
tn
Rbdt
Zm
Lid
tvre1
Hn
Btb1
tp2
nu
as
ro1
af
HIGH DOSES OF TELMISARTAN AND RENOPROTECTION 1079
or blockade in type 1 diabetic patients with diabeticephropathy. J Am Soc Nephrol 14:992-999, 200321. Rossing K, Jacobsen P, Pietraszek L, Parving HH:
enoprotective effects of adding angiotensin II receptorlocker to maximal recommended doses of ACE inhibitor iniabetic nephropathy: A randomized double-blind crossoverrial. Diabetes Care 26:2268-2274, 2003
22. Laverman GD, Navis G, Henning RH, de Jong PE, deeeuw D: Dual renin-angiotensin system blockade at opti-al doses for proteinuria. Kidney Int 62:1020-1025, 200223. Segura J, Praga M, Campo C, Rodicio JL, Ruilope
M: Combination is better than monotherapy with ACEnhibitor or angiotensin receptor antagonist at recommendedoses. J Renin Angiotensin Aldosterone Syst 4:43-47, 200324. Weinberg MS, Weinberg AJ, Zappe DH: Effectively
argeting the renin-angiotensin-aldosterone system in cardio-ascular and renal disease: Rationale for using angiotensin IIeceptor blockers in combination with angiotensin-convertingnzyme inhibitors. J Renin Angiotensin Aldosterone Syst:217-233, 200025. Andersen S, Rossing P, Juhl TR, Deinum J, Parving
H: Optimal dose of losartan for renoprotection in diabetic
ephropathy. Nephrol Dial Transplant 17:1413-1418, 2002 s26. Rossing K, Christensen PK, Hansen BV, Cartensen, Parving HH: Optimal dose of candesartan for renoprotec-
ion in type 2 diabetic patients with nephropathy: A doublelind randomised crossover study. Diabetes Care 26:150-55, 200327. Hermida RC, Calvo C, Ayala DE, et al: Administra-
ion time-dependent effects of valsartan on ambulatory bloodressure in hypertensive subjects. Hypertension 42:283-290,00328. Lurbe E, Redon J, Kesani A, et al: Increase in
octurnal blood pressure and progression to microalbumin-ria in type 1 diabetes. N Engl J Med 347:797-805, 200229. Horiuchi M, Akishita M, Dzau V: Recent progress in
ngiotensin II type 2 receptor research in the cardiovascularystem. Hypertension 33:613-621, 1999
30. Cao Z, Bonnet F, Candido R: Angiotensin type 2eceptor antagonism confers renal protection in a rat modelf progressive renal injury. J Am Soc Nephrol 13:1773-787, 200231. Hollenberg NK, Fisher ND, Price DA: Pathways for
ngiotensin II generation in intact human tissue: Evidencerom comparative pharmacological interruption of the renin-
ystem. Hypertension 32:387-392, 1998