(Circulation. 1997;96:3072-3078.)
© 1997 American Heart Association, Inc.
Articles |
Synergistic Effects of ACE Inhibition and Ang II Antagonism on Blood Pressure, Cardiac Weight, and Renin in Spontaneously Hypertensive Rats
From INSERM Unit 367, Paris, France (J.M., M.-F.G.); St Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia (D.J.C.); and Broussais Clinical Investigation Center, Assistance Publique des Hôpitaux de Paris and INSERM, Paris, France (M.A.).
Correspondence to Prof Joël Ménard, Hôpital Broussais, 96 rue Didot, 75674 Paris Cedex 14, France.
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Abstract |
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Background Blockade of type 1 angiotensin (Ang) II receptors combined with ACE inhibition may amplify the efficacy of the renin-angiotensin system blockade because ACE inhibitors do not completely and permanently suppress Ang II production.
Methods and Results Enalapril or losartan (1, 3, 10, and 30 mg/kg) or their combination was administered for 2 to 4 weeks to spontaneously hypertensive rats. The combination of low doses of each agent induced greater reductions in blood pressure (BP) and left ventricular weight/body weight (LVW/BW) ratio than monotherapy with the same or higher doses. When approximately equipotent regimens of enalapril, losartan, and their combination, as judged by BP fall, were compared, there were similar increases in plasma and renal renin and in plasma Ang-(1-7) and Ang I and similar reductions in plasma angiotensinogen. Enalapril alone reduced plasma Ang II levels, and losartan alone increased Ang II levels. The combination of enalapril with losartan prevented or reduced the increase in Ang II levels observed with losartan alone.
Conclusions These findings show that the synergistic interaction between the effects of low doses of enalapril and losartan on BP and LVW/BW ratio is due to more effective inhibition of the renin-angiotensin system by their combination than by either agent alone. When both drugs are given together, the ACE inhibitor–induced fall in plasma Ang II results in modulation of the Ang II antagonist–induced reactive rise in Ang II, thereby lowering the plasma Ang II concentration, which competes with the antagonist for the Ang II receptors.
Key Words: hypertension • blood pressure • angiotensin • enzymes • renin
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Introduction |
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The observation that Ang II and its metabolites are detected in plasma during chronic administration of ACE inhibitors implies that inhibition of the RAS is not complete, and this may limit their efficacy in the treatment of hypertension and congestive heart failure.1 2 3 This continuation of Ang II production with chronic ACE inhibition is due to the concomitant rise in Ang I levels consequent to the rise in plasma renin initially induced by the interruption of the Ang II–renin feedback4 5 and to the progressive dissociation of the ACE inhibitor from the enzyme active sites at the end of the dosing interval.2 6 Ang II present in plasma during chronic ACE inhibition may also be produced by enzymes other than ACE, such as chymase.7 8 If significant levels of Ang II persist during ACE inhibition, there is a rationale to determine whether there are additive effects on BP of adding an Ang II antagonist to an ACE inhibitor.
Indeed, in mildly sodium-depleted healthy volunteers, single oral doses of captopril 50 mg and losartan 50 mg had an additive effect on reducing mean BP.9 The combination of single oral doses of losartan 50 mg with enalapril 10 mg decreased BP and stimulated renin release more than increasing enalapril from 10 to 20 mg did.10 The use of a renin-dependent animal model of hypertension in which BP is reduced by the administration of ACE inhibitors or Ang II receptor antagonists11 12 allows testing of a wider range of doses of an ACE inhibitor and an Ang II receptor antagonist than can be investigated in humans. A factorial design13 was used to investigate dose-related BP, cardiac, and hormonal responses of enalapril, losartan, and their combination in SHRs.
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Methods |
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Animals
Three consecutive experiments were performed on SHRs purchased from Charles Rivers (Saint Aubin les Elbeuf, France) at 10 to 12 weeks of age. Losartan and enalapril were provided by Merck Research Laboratories, Pa.
Experiment 1: pilot study in SHRs. This first factorial
design was planned to test the range of enalapril and losartan
doses that can be administered and tolerated (Fig 1
). Four animals were investigated in
each treated group and 5 in the control group. Animals were killed
after 2 weeks of treatment.
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Experiment 2: factorial design in SHRs. The doses selected
for the main factorial design, avoiding both the noneffective
monotherapy and the lethal doses of combination therapy found during
the pilot study, are shown in Fig 1
. Groups of 8 rats were
investigated, and animals were killed after 4 weeks of treatment.
Experiment 3. On the basis of the results obtained in experiments 1 and 2, doses of enalapril (20 mg/kg), losartan (30 mg/kg), and their combination (enalapril 3 mg/kg+losartan 3 mg/kg [E3-L3], enalapril 10 mg/kg+losartan 3 mg/kg [E10-L3], and enalapril 3 mg/kg+losartan 10 mg/kg [E3-L10]) were selected to obtain effects on BP and LVW of similar magnitude to characterize the RAS during these treatments by measuring plasma Ang I, Ang-(1-7), and Ang II. Groups of 10 rats were investigated, and animals were killed after 2 weeks of treatment.
Protocol
All experiments were performed in the same manner. Rats were
housed in groups of 4 to 5 animals, and drugs were administered in
their drinking water. Water consumption was measured daily, and the
drug concentration in the drinking water was adjusted to maintain the
scheduled treatment dose.
SBP was measured each week by the tail-cuff method (4 to 8 hours after last drug intake). Blood was taken from the jugular vein under light anesthesia with ketamine-xylazine (15 and 5 mg/kg body weight IP, respectively). This anesthesia did not influence PRC (5.67±4.05 ng Ang I · mL-1 · h-1, n=11 rats) compared with values obtained after decapitation (5.88±3.55 ng Ang I · mL-1 · h-1, n=12 rats), as previously reported,14 whereas ether anesthesia increased it (43.6±11.9 ng Ang I · mL-1 · h-1, n=11 rats).
PRC was measured in all experiments by the in vitro production of Ang I in the presence of an excess of angiotensinogen provided by binephrectomized rat plasma.15 In experiment 3, PRA was measured by a 1-hour incubation of experimental plasma in the absence of exogenous angiotensinogen. Total renin was measured in experiment 3 after trypsin activation of plasma.16 Angiotensinogen was measured by incubating plasma to exhaustion with an excess of pure mouse submaxillary gland renin.17 The left kidney of each rat was frozen in liquid nitrogen. After three consecutive thawings and freezings, it was homogenized and centrifuged. Ang I production was measured after appropriate dilutions of the supernatant and expressed in nanograms Ang I liberated per microgram proteins measured by the method of Bradford.18 Routine biochemical plasma parameters were measured with a Technicon autoanalyzer.
For plasma angiotensin measurements, blood was taken from the aorta of anesthetized rats in a mixture of a rat renin inhibitor (10-4 mol/L) kindly provided by Dr Hiwada,19 MK 422 (10-5 mol/L), and EDTA (10-3 mol/L). Blood was centrifuged at 4°C, and plasma was immediately extracted on a Bondelut column by the method of Nussberger et al.1 Plasma extracts were acetylated and treated with piperidine, then run on high-performance liquid chromatography, and the chromatography fractions were assayed for Ang-(1-7), Ang II, and Ang I with an amino-terminal directed radioimmunoassay as previously described.20
Statistical Methods
Calculations were done with Statview 4.1 statistical software
(Abacus Concepts Inc). Data are expressed as mean±SD in the tables and
mean±SEM in the figures. A value of P<.05 was considered
significant.
The purpose of experiments 2 and 3 was to demonstrate at least an additivity of the combination of enalapril with losartan.21 To avoid multiple testing, no statistical test was performed to compare the effects of each single drug between different doses and the control group. One-way ANOVA was restricted to a single objective: to compare the effects of the combination of enalapril with losartan at low doses (E3-L3) and high doses of enalapril and losartan (10 mg/kg of each drug in experiment 2 and 20 and 30 mg/kg of enalapril and losartan, respectively, in experiment 3). No statistical evaluation was performed on the other groups, for which results are shown to indicate the range of variations that can be observed over a large range of inhibitor doses alone or in combination.
The assumptions of ANOVA (homogeneity of variance and normality) were verified for each variable, and natural logarithmic transformation was applied where appropriate. When the F test was significant (P<.05), paired comparisons were performed with the Scheffé test. The regression line was estimated by the least-squares method.
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Results |
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Experiment 1: Pilot Study in SHRs
After 1 week of treatment, a progressive BW loss occurred between days 8 and 12 in the enalapril 10 mg/kg+losartan 10 mg/kg (E10-L10) group and, to a lesser extent, in the enalapril 30 mg/kg (E30) group, and a decision was made to euthanize all animals. These rats had a major hypotension (E10-L10, 86±9 mm Hg; E30, 107±16 mm Hg). Plasma creatinine and urea were greatly increased in the E30 group (89±22 µmol/L and 35±6 mmol/L, respectively) and in the E10-L10 group (168±49 µmol/L and 42±9 mmol/L, respectively) versus 30±5.6 µmol/L and 5.4±0.4 mmol/L in controls, respectively. There was no hyponatremia or hyperkalemia. SBP was lower in the enalapril 1 mg/kg+losartan 1 mg/kg combination group (166±13 mm Hg) than in the control group (217±18 mm Hg), the enalapril 1 mg/kg group (189±3 mm Hg), and the losartan 1 mg/kg group (202±23 mm Hg). On the basis of these results, subsequent experiments were planned to investigate the range of doses that could be tolerated.
Experiment 2: Dose-Response Curves of the RAS Blockade by
Enalapril, Losartan, and Their Combination in SHRs
In this 4-week experiment, blood sampling under light
anesthesia was performed from the jugular vein at days 8,
16, and 28 (day of euthanasia), and the averages of the three values of
PRC and plasma angiotensinogen observed during the
experiment are shown in Fig 2. The
physical signs observed in the high-dose groups of the pilot experiment
(progressive BW loss, general weakness, and decreased activity) were
not observed. Three animals in the E3-L10 group and 3 animals in the
E10-L3 group had elevated plasma creatinine levels and the
lowest growth rate. Six animals had a pulmonary infection at
autopsy (enalapril 10 mg/kg group, n=1; losartan 3
mg/kg group, n=2; losartan 10 mg/kg group, n=2;
E10-L3 group, n=1) and were excluded from the analysis.
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These results confirmed and amplified the observations made in the
pilot experiment, and the data at the time of euthanasia are shown in
Tables 1 and 2. The combination of losartan
and enalapril significantly increased all the events expected from a
more complete RAS blockade compared with monotherapy. The addition of
losartan or enalapril caused a significantly larger SBP fall,
left ventricular hypertrophy regression,
increase in PRC and RRC, and decrease in plasma
angiotensinogen compared with monotherapy by enalapril or
losartan at similar doses (Figs 2 and 3). The most potent treatment
combinations were E3-L10 and E10-L3. Both combinations were equivalent
in terms of SBP fall, PRC rise, and plasma angiotensinogen
fall.
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The addition of losartan 3 mg/kg to enalapril 3 mg/kg decreased SBP significantly more than increasing the dose of either enalapril or losartan to 10 mg/kg. This combination had significantly larger effects on LVW/BW ratio and RRC than enalapril and losartan 10 mg/kg, whereas for PRC it differed significantly only from enalapril 10 mg/kg. Plasma angiotensinogen did not differ significantly.
Experiment 3: Plasma Levels of Angiotensins
The drug doses selected on the basis of the previous results
achieved the objectives of this experiment (Tables 3 and 4).
As in experiment 2, the E3-L10 and E10-L3 combinations were the most
potent treatments on all tested parameters. The E3-L3
combination achieved either similar or significantly larger SBP fall
and left ventricular hypertrophy regression
compared with monotherapy by enalapril 20 mg/kg or
losartan 30 mg/kg (Table 3). In addition, the E3-L3
combination achieved an RAS blockade similar to that achieved with
enalapril 20 mg/kg or losartan 30 mg/kg, as
attested by similar increases in plasma total renin, PRA, PRC, and RRC
and fall in plasma renin substrate (Table 4).
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Plasma Ang I and Ang-(1-7) levels increased in parallel to PRC and did
not differ significantly between the E3-L3 combination and either
enalapril 20 mg/kg or losartan 30 mg/kg given
singly (Table 5 and Fig 4). In contrast to the BP, renin,
angiotensinogen, and Ang I profiles, plasma Ang II and the
plasma Ang II/Ang I ratio (index of in vivo ACE inhibition) differed
markedly between the groups (Table 5 and Fig 4). As expected, plasma
Ang II levels were very high in the losartan 30 mg/kg
group, whereas they were very low or at an intermediate level when
enalapril was given singly (20 mg/kg) or added to
losartan (3 mg/kg or 10 mg/kg), respectively.
When the data of all groups were pooled, plasma Ang-(1-7) levels were
correlated to plasma Ang I levels but not to plasma Ang II levels (not
shown).
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Discussion |
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These experiments were performed in SHRs to describe, over a wide dose range, the BP and cardiac effects of the combined administration of an ACE inhibitor, enalapril, with an Ang II antagonist, losartan, and to extensively study the changes induced in the RAS.
The results obtained in experiments 2 and 3 with the 3 mg/kg combination clearly demonstrate that combination treatment with low doses of both drugs are either as effective as or more effective than higher doses of each compound on all tested parameters (SBP, LVW/BW, PRC, and plasma angiotensinogen). Similar results on BP22 23 and biochemical effects24 have been reported after a single administration of the combination of a renin inhibitor with either an ACE inhibitor or an Ang II antagonist. On the contrary, losartan at 10 mg/kg IV lowered BP to a normotensive level in renal hypertensive rats, and captopril at 3 mg/kg IV did not cause a further decrease.25 When the RAS is blocked by an ACE inhibitor or a type 1 Ang II receptor antagonist, there is competition between the inhibitor or the antagonist, which is progressively cleared from the body, and the available substrate (Ang I) or agonist (Ang II). Ang I or Ang II production is very dependent on the sensitive feedback between Ang II and renin release, which is permanently operational, as suggested by the colocalization of type 1 Ang II receptors and renin in the juxtaglomerular cells.4 When the inhibitor dissociates from the enzyme active sites, ACE starts again to generate Ang II in the presence of a high level of plasma and interstitial Ang I, which is always in competition with the inhibitor. At that time, the concurrent administration of Ang II antagonist will protect the type 1 Ang II receptor from newly produced agonist. Reciprocally, when less Ang II antagonist is present at the type 1 receptors, an ACE inhibitor will reduce the amount of Ang II available to compete with the antagonist. An alternative to this internal counterregulation of the RAS would be that an Ang II antagonist added to an ACE inhibitor blocks the effects of Ang II generated by pathways others than renin and ACE.7 8 Whatever the interpretation, low doses of an Ang II antagonist and an ACE inhibitor are more effective at reducing BP than high doses of a single drug. On the basis of these experiments, 3 mg/kg of enalapril combined with 3 mg/kg of losartan produced the same BP fall in SHRs as monotherapy with 20 mg/kg enalapril or 30 mg/kg losartan.
The use of a factorial study design has made it possible to show that equivalent effects in terms of BP fall, renin release, and plasma angiotensinogen fall can be obtained by appropriate selection of RAS blocker doses, independently of the step in which the RAS is interrupted. With the exception of work performed by Campbell et al,26 27 very few investigations have analyzed in depth the dose-response curves of RAS blockade in animal models. Campbell et al described dose-dependent changes of the plasma and tissue RAS parameters and bradykinin peptides in normal Sprague-Dawley rats during 7 days of oral administration of the ACE inhibitor perindopril (from 0.006 to 12.6 mg/kg). In experimental models of cardiac failure28 and glomerulosclerosis,29 as well as in patients with congestive heart failure,30 it has been reported that the outcome improved with increasing doses of ACE inhibitors. In many experiments designed to compare the effects of ACE inhibition and Ang II antagonism in animal models, the absence of quantification of the intensity of the RAS blockade certainly explains part of the difficulties encountered in attributing effects of different kinds of RAS blockade on target organs such as blood vessels, heart, and kidneys to the fall in BP and/or to the local consequences of angiotensin neutralization or bradykinin accumulation.
The plasma angiotensin profiles were different between the
different monotherapies or combinations despite similar levels of BP
reductions. The dose-dependent rises in PRC, plasma total renin, Ang I,
and Ang-(1-7) occurred in parallel. All these parameters
investigated the reactive rise in renin release induced by the blockade
of Ang II effects at the level of the juxtaglomerular
cells, either by a decrease in local Ang II levels, an inhibition of
its binding to type 1 receptors, or both. RAS blockade was achieved
with similar efficacy by either combined administration of enalapril
and losartan (E3-L3) or enalapril or losartan given
singly (20 or 30 mg/kg, respectively) despite contrasting Ang II
levels in plasma. Plasma Ang II levels are dependent on both the
magnitude of the rise in plasma Ang I and the intensity of ACE
inhibition, according to the selected dose of enalapril, as shown in
Fig 4. ACE inhibition by enalapril dose-dependently prevented the Ang
II rise induced by losartan when the two drugs were given in
combination. This experiment shows that by selecting the appropriate
doses of either an ACE inhibitor, an Ang II
antagonist, or a combination of various doses of the two,
it is possible to induce similar levels of plasma renin, Ang I, and
Ang-(1-7) and that these equipotent blockades of the RAS induce similar
falls in BP and LVW. The three methods of RAS inhibition do not induce
the same plasma levels of Ang II, from low (ACE inhibition) to normal
(combined blockade) or high levels (Ang II antagonism).
This second observation does not support a participation of type 2 Ang
II receptor stimulation by high levels of Ang II when BP and LVW of
SHRs are reversed by a type 1 Ang II antagonist. It also
eliminates Ang II as an important source of
Ang-(1-7).31 32 Ang-(1-7) is increased by the three
methods of RAS inhibition, and it has been proposed as a participant in
the antihypertensive effect of RAS
inhibitors.33 Investigation of renin
inhibitors will be necessary to solve this issue.
On the basis of clinical investigation performed in renin-dependent normotensive subjects9 10 and this experimental investigation in SHRs, we conclude that the combination of low doses of an Ang II antagonist and an ACE inhibitor is more effective on BP than higher doses of each individual inhibitor. The choice between increasing the dose of either drug or combining lower doses of both drugs in human beings will be more influenced by the tolerability of each therapeutic strategy than by their efficacy. The choice between these two strategies will also depend on whether the demonstration of specific consequences at the tissue level of each method of RAS inhibition, especially concerning the effects of bradykinin accumulation and stimulation of type 2 Ang II receptors, is accompanied by significant differences in beneficial or detrimental consequences on target organs such as heart, blood vessels, and kidneys.34 35 36 37 38 Our results do not support these hypotheses and outline the crucial need for investigating in experimental studies large dose ranges of ACE inhibitors and Ang II antagonists when the objective of an experiment is to look for differences between the consequences of the RAS inhibition at different sites.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants from INSERM and Association Claude Bernard. The help of Than-Tam Guyene, Athena Kladis, and Sible Krüithof, who performed the angiotensin measurements, is gratefully acknowledged. We thank Prof Trefor Morgan for his contribution to the presentation of the paper and Dr Gilles Chatellier for his advice on statistics.
Received March 4, 1997; revision received June 13, 1997; accepted June 14, 1997.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Nussberger J, Brunner DB, Waeber B, Brunner HR. True versus immunoreactive angiotensin II in human plasma. Hypertension. 1985;7(suppl I):I-11-I-17.
2.
Juillerat L, Nussberger J, Ménard J, Mooser V,
Christen Y, Waeber B, Graf P, Brunner HR. Determinants of
angiotensin II generation during converting enzyme
inhibition. Hypertension. 1990;16:564-572.
3. Van Den Meiracker AH, Man in't veld AJ, Admiraal PJJ, Ritsema Van Eck HJ, Boomsma F, Derkx FHM, Schalekamp MADH. Partial escape of angiotensin converting enzyme (ACE) inhibition during prolonged ACE inhibitor treatment: does it exist and does it affect the antihypertensive response? J Hypertens. 1992;10:803-812.[Medline] [Order article via Infotrieve]
4.
Gasc JM, Monnot C, Clauser E, Corvol P.
Co-expression of type 1 angiotensin II receptor
(AT1R) and renin mRNAs in juxtaglomerular cells
of the rat kidney. Endocrinology. 1993;132:2723-2725.
5.
Ménard J, Guyene TT, Chatellier G, Kleinbloesem
CH, Bernadet P. Renin release regulation during acute renin
inhibition in normal volunteers. Hypertension. 1991;18:257-265.
6.
Wei L, Clauser E, Alhenc-Gélas F, Corvol
P. The two homologous domains of human angiotensin I
converting enzyme interact differently with competitive
inhibitors. J Biol Chem. 1992;267:13398-13405.
7. Okunishi H, Miyazaki M, Toda N. Evidence for a putatively new angiotensin II-generating enzyme in the vascular wall. J Hypertens. 1984;2:277-284.[Medline] [Order article via Infotrieve]
8.
Urata H, Healy B, Stewart RW, Bumpus FM, Husain
A. Angiotensin II forming pathways in normal and
failing human hearts. Circ Res. 1990;66:883-890.
9.
Azizi M, Chatellier G, Guyene TT, Murieta-Geoffroy D,
Ménard J. Additive effects of combined
angiotensin converting enzyme inhibition and
angiotensin II antagonism on blood pressure and renin
release in sodium-depleted normotensives.
Circulation. 1995;92:825-834.
10.
Azizi M, Guyene TT, Chatellier G, Wargon M,
Ménard J. Additive effects of losartan and
enalapril on blood pressure and plasma active renin.
Hypertension. 1997;29:634-640.
11. Giudicelli JF, Freslon JL, Glasson S, Richer C. Captopril and hypertension development in the SHR. Clin Exp Hypertens. 1980;2:1083-1096.
12.
Wong PC, Price WA, Chiu AT. Hypotensive action
of DUP 753, an angiotensin II antagonist in
spontaneously hypertensive rats. Hypertension. 1990;15:459-468.
13. Goldberg MR, Offen WW, Rockhold FW. Factorial design: an approach to the assessment of therapeutic drug interactions in clinical trials. J Clin Res Drug Dev. 1988;2:215-225.
14. Miller ED, Longnecker DE, Peach MJ. The regulatory function of the renin-angiotensin system during general anesthesia. Anesthesiology. 1978;48:399-403.[Medline] [Order article via Infotrieve]
15.
Ménard J, Catt KJ. Measurement of renin
activity concentration and substrate in rat plasma by radioimmunoassay
of angiotensin I. Endocrinology. 1972;90:422-430.
16. Véniant M, Whitworth CE, Ménard J, Sharp MGF, Gonzalez MF, Bruneval P, Mullins JJ. Developmental studies demonstrate age-dependent elevation of renin activity in TGR(mRen2)27 rats. Am J Hypertens. 1995;8:1167-1176.[Medline] [Order article via Infotrieve]
17.
Clauser E, Bouhnik J, Gonzales MF, Corvol P,
Ménard J. Influence of converting-enzyme inhibition on rat
des-angiotensin I-angiotensinogen.
Am J Physiol. 1984;246:E129-E133.
18. Bradford H. A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248-254.[Medline] [Order article via Infotrieve]
19. Ii Y, Kitami Y, Hiwada K. Effect of a rat renin inhibitor on renal renin synthesis on spontaneously hypertensive rats. Hypertens Res. 1992;15:99-104.
20.
Campbell DJ, Kladis A, Duncan AM. Nephrectomy,
converting enzyme inhibition, and angiotensin
peptides. Hypertension. 1993;22:513-522.
21. Greco WR, Bravo G, Parsons JC. The search for synergy: a critical review from a response surface perspective. Pharmacol Rev. 1995;47:332-385.
22. Fossa AA, DePasquale MJ, Ringer LJ, Winslow RL. Synergistic effect on reduction in blood pressure with coadministration of a renin inhibitor or an angiotensin-converting enzyme inhibitor with an angiotensin II receptor antagonist. Drug Dev Res. 1994;33:422-428.
23.
Mento PF, Holt WF, Murphy WR, Wilkes BM.
Combined renin and converting enzyme inhibition in rats.
Hypertension. 1989;13:741-748.
24. Chauveau D, Guyenne TT, Cumin F, Chatellier G, Corvol P, Ménard J. Investigation of the biochemical effects of renin inhibition in normal volunteers treated by an ACE inhibitor. Br J Clin Pharmacol. 1992;33:253-260.[Medline] [Order article via Infotrieve]
25. Wong PC, Price WA, Chiu AT, Duncia JV, Carini DJ, Wexler RR, Johnson AL, Timmermans PBMWM. In vivo pharmacology of Dup 753. Am J Hypertens. 1991;4:288s-298s.
26.
Campbell DJ, Lawrence AC, Towrie A, Kladis A, Valentijn
A. Differential regulation of angiotensin peptide
levels in plasma and kidney of the rat.
Hypertension. 1991;18:763-773.
27.
Campbell DJ, Kladis A, Duncan AM. Effects of
converting enzyme inhibitors on angiotensin and
bradykinin peptides. Hypertension. 1994;23:439-449.
28.
Wollert KC, Studer R, Von Bülow B, Drexler
H. Survival after myocardial infarction in the rat: role of
tissue angiotensin-converting enzyme inhibition.
Circulation. 1994;90:2457-2467.
29. Ikoma M, Kawamura T, Kakinuma Y, Fogo A, Ichikawa I. Cause of variable therapeutic efficiency of angiotensin converting enzyme inhibitor on glomerular lesions. Kidney Int. 1991;40:195-202.[Medline] [Order article via Infotrieve]
30. Nussberger J, Fleck E, Bahrmann H, Delius W, Schultheiss HP, Brunner HR, for the Study Group on Neurohormonal Regulation in Congestive Heart Failure. Dose-related effects of ACE inhibition in man: quinapril in patients with moderate congestive heart failure. Eur Heart J. 1994;15(suppl D):113-122.
31. Welches WR, Santos RA, Chappell MC, Brosnihan KB, Greene LJ, Ferrario CM. Evidence that prolyl endopeptidase participates in the processing of brain angiotensin. J Hypertens. 1991;9:631-638.[Medline] [Order article via Infotrieve]
32. Welches WR, Brosnihan KB, Ferrario CM. A comparison of the properties and enzymatic activities of three angiotensin processing enzymes: angiotensin converting enzyme, prolyl endopeptidase and neutral endopeptidase 24.11. Life Sci. 1993;52:1461-1480.[Medline] [Order article via Infotrieve]
33. Benter IF, Diz DI, Ferrario CM. Cardiovascular actions of angiotensin (1-7). Peptides. 1993;14:679-684.[Medline] [Order article via Infotrieve]
34. Fernandez LA, Caride VJ, Strömberg C, Nävery L, Wicke JD. Angiotensin AT2 receptor stimulation increases survival in gerbils with abrupt unilateral carotid ligation. J Cardiovasc Pharmacol. 1994;24:937-940.[Medline] [Order article via Infotrieve]
35.
Nakajima M, Hutchinson HG, Fujinaga M, Hayashida W,
Morishita R, Zhang L, Horiuchi M, Pratt RE, Dzau VS. The
angiotensin II type 2 (AT2) receptor antagonizes the growth
effects of the AT1 receptor: gain-of-function study using gene
transfer. Proc Natl Acad Sci U S A. 1995;92:10663-10667.
36. Stoll M, Steckelings UM, Paul M, Bottari SP, Metzger R, Unger T. The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest. 1995;95:651-657.
37. Kerins DM, Hao Q, Vaughan DE. Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV. J Clin Invest. 1995;96:2515-2520.
38. Levy BI, Benessiano J, Henrion D, Caputo L, Heymes C, Duriez M, Poitevin P, Samuel JL. Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin II on the rat vascular structure. J Clin Invest. 1996;98:418-425.[Medline] [Order article via Infotrieve]
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 M. Azizi and J. Menard Combined Blockade of the Renin-Angiotensin System With Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Antagonists Circulation, June 1, 2004; 109(21): 2492 - 2499. [Full Text] [PDF]
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P. Trongtorsak, T. O Morgan, and L. M. Delbridge Combined renin-angiotensin system blockade and dietary sodium restriction impairs cardiomyocyte contractility Journal of Renin-Angiotensin-Aldosterone System, December 1, 2003; 4(4): 213 - 219. [Abstract] [PDF]
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J. Segura, M. Praga, C. Campo, J. L Rodicio, and L. M Ruilope Combination is better than monotherapy with ACE inhibitor or angiotensin receptor antagonist at recommended doses Journal of Renin-Angiotensin-Aldosterone System, March 1, 2003; 4(1): 43 - 47. [Abstract] [PDF]
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 S. Kim, Y. Izumi, Y. Izumiya, Y. Zhan, M. Taniguchi, and H. Iwao Beneficial Effects of Combined Blockade of ACE and AT1 Receptor on Intimal Hyperplasia in Balloon-Injured Rat Artery Arterioscler. Thromb. Vasc. Biol., August 1, 2002; 22(8): 1299 - 1304. [Abstract] [Full Text] [PDF]
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 F. J. Haddy, D. J. Campbell, W. E. Cayley Jr., J. C. Forfar, S. Munir, J. N. Cohn, and G. Tognoni Valsartan in Chronic Heart Failure N. Engl. J. Med., April 11, 2002; 346(15): 1173 - 1174. [Full Text] [PDF]
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T. Morgan, C. Griffiths, and L. Delbridge Interaction of ACE inhibitors and AT1-receptor blockers on maximum blood pressure response in spontaneous hypertensive rats Journal of Renin-Angiotensin-Aldosterone System, March 1, 2002; 3(1): 16 - 18. [Abstract] [PDF]
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 J. L. Wilkinson-Berka, N. J. Gibbs, M. E. Cooper, S. L. Skinner, and D. J. Kelly Renoprotective and anti-hypertensive effects of combined valsartan and perindopril in progressive diabetic nephropathy in the transgenic (mRen-2)27 rat Nephrol. Dial. Transplant., July 1, 2001; 16(7): 1343 - 1349. [Abstract] [Full Text] [PDF]
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 L. H. Opie and M. N. Sack Enhanced Angiotensin II Activity in Heart Failure : Reevaluation of the Counterregulatory Hypothesis of Receptor Subtypes Circ. Res., April 13, 2001; 88(7): 654 - 658. [Abstract] [Full Text] [PDF]
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E. Abro, C. D Griffiths, T. O Morgan, and L. M. Delbridge Regression of cardiac hypertrophy in the SHR by combined renin-angiotensin system blockade and dietary sodium restriction Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S148 - S153. [Abstract] [PDF]
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T. Morgan Review: Effect of combining angiotensin receptor blockers and ACE inhibitors on cardiovascular disease Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S223 - S226. [PDF]
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S. Kim, M. Yoshiyama, Y. Izumi, H. Kawano, M. Kimoto, Y. Zhan, and H. Iwao Effects of Combination of ACE Inhibitor and Angiotensin Receptor Blocker on Cardiac Remodeling, Cardiac Function, and Survival in Rat Heart Failure Circulation, January 2, 2001; 103(1): 148 - 154. [Abstract] [Full Text] [PDF]
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 H. Kawai, S. Y. Stevens, and C.-S. Liang Renin-angiotensin system inhibition on noradrenergic nerve terminal function in pacing-induced heart failure Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H3012 - H3019. [Abstract] [Full Text] [PDF]
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 Z. Cao, M. E. Cooper, L. L. Wu, A. J. Cox, K. Jandeleit-Dahm, D. J. Kelly, and R. E. Gilbert Blockade of the Renin-Angiotensin and Endothelin Systems on Progressive Renal Injury Hypertension, October 1, 2000; 36(4): 561 - 568. [Abstract] [Full Text] [PDF]
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M. S Weinberg, A. J Weinberg, and D. H Zappe Effectively targetting the renin-angiotensin-aldosterone system in cardiovascular and renal disease: rationale for using angiotensin II receptor blockers in combination with angiotensin-converting enzyme inhibitors Journal of Renin-Angiotensin-Aldosterone System, September 1, 2000; 1(3): 217 - 233. [PDF]
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S. Hanon, P. Vijayaraman, E. H Sonnenblick, and T. H Le Jemtel Persistent formation of angiotensin II despite treatment with maximally recommended doses of angiotensin converting enzyme inhibitors in patients with chronic heart failure Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 147 - 150. [PDF]
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 S. Kim and H. Iwao Molecular and Cellular Mechanisms of Angiotensin II-Mediated Cardiovascular and Renal Diseases Pharmacol. Rev., March 1, 2000; 52(1): 11 - 34. [Abstract] [Full Text] [PDF]
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S. Kim, Y. Zhan, Y. Izumi, and H. Iwao Cardiovascular Effects of Combination of Perindopril, Candesartan, and Amlodipine in Hypertensive Rats Hypertension, March 1, 2000; 35(3): 769 - 774. [Abstract] [Full Text] [PDF]
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 E. Cerbai, A. Crucitti, L. Sartiani, P. De Paoli, R. Pino, M. L. Rodriguez, G. Gensini, and A. Mugelli Long-term treatment of spontaneously hypertensive rats with losartan and electrophysiological remodeling of cardiac myocytes Cardiovasc Res, January 14, 2000; 45(2): 388 - 396. [Abstract] [Full Text] [PDF]
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L. M. Ruilope Is it wise to combine an ACE inhibitor and an angiotensin receptor antagonist? Nephrol. Dial. Transplant., December 1, 1999; 14(12): 2855 - 2856. [Full Text] [PDF]
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 S. M. Brabant, M. Bertrand, D. Eyraud, P.-L. Darmon, and P. Coriat The Hemodynamic Effects of Anesthetic Induction in Vascular Surgical Patients Chronically Treated with Angiotensin II Receptor Antagonists Anesth. Analg., December 1, 1999; 89(6): 1388 - 1388. [Abstract] [Full Text] [PDF]
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M. Tanimura, V. G. Sharov, H. Shimoyama, T. Mishima, T. B. Levine, S. Goldstein, and H. N. Sabbah Effects of AT1-receptor blockade on progression of left ventricular dysfunction in dogs with heart failure Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1385 - H1392. [Abstract] [Full Text] [PDF]
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B. Pitt Regression of Left Ventricular Hypertrophy in Patients With Hypertension : Blockade of the Renin-Angiotensin-Aldosterone System Circulation, November 10, 1998; 98(19): 1987 - 1989. [Full Text] [PDF]
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C. Richer, P. Bruneval, J. Menard, and J.-F. Giudicelli Additive Effects of Enalapril and Losartan in (mREN-2)27 Transgenic Rats Hypertension, February 1, 1998; 31(2): 692 - 698. [Abstract] [Full Text] [PDF]
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