(Hypertension. 1997;29:634-640.)
© 1997 American Heart Association, Inc.
Articles |
Additive Effects of Losartan and Enalapril on Blood Pressure and Plasma Active Renin
the Broussais Hospital Clinical Investigation Center, Institut National de la Sante et de la Recherche Medicale (INSERM) et Assistance Publique des Hopitaux de Paris (M.A., T.-T.G., G.C., M.W., J.M.), and INSERM U 367 (J.M.), Paris, France.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
The combination of single oral doses of an angiotensin I–converting enzyme inhibitor (captopril) and a type 1 angiotensin II receptor antagonist (losartan) has additive effects on blood pressure fall and renin release in sodium-depleted normotensive subjects. We planned the present study to determine whether the magnitude of the hemodynamic and hormonal consequences of renin-angiotensin system blockade by such a combination is larger than that obtained by doubling the dose of the angiotensin-converting enzyme inhibitor given alone. In a single-dose, double-blind, randomized, three-way crossover study, 10 mg enalapril, 20 mg enalapril, and the combination of 50 mg losartan and 10 mg enalapril were administered orally to 12 sodium-depleted normotensive subjects. The area under the time curve from 0 to 24 hours (AUC0-24) of the mean blood pressure fall after losartan-enalapril combination intake (-220±91 mm Hg·h) was significantly greater than that of either 10 or 20 mg enalapril (-124±91 and -149±85 mm Hg·h, respectively; P<.05 vs both doses). The combination significantly increased by 2.3±1.2-fold the AUC0-24 of plasma active renin compared with either 10 or 20 mg enalapril given alone (P<.05) but had no additive effect on plasma aldosterone fall. The losartan-enalapril combination is more effective in decreasing blood pressure and increasing plasma active renin than doubling of the enalapril dose.
Key Words: blood pressure • angiotensin-converting enzyme inhibitors • angiotensin II • renin • sodium • drug synergism
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
A flat dose-response curve on BP measured at trough has been reported with most of the ACE inhibitors so far tested in essential hypertensive patients.1 To increase the duration of action of these drugs up to the end of the dosing interval, increases in the once-daily administered dose or twice-daily administration have been proposed.2 The "escape" of BP response to ACE inhibitors 24 hours after drug intake is correlated with a return of plasma Ang II levels toward their initial values because of the conjunction of the progressive fall in the inhibitor plasma levels at the end of the dosing interval and the increase in plasma active renin and Ang I, resulting from the initial interruption of the Ang II–renin feedback.3 During chronic treatment, this persistence of Ang II in plasma reflects an incomplete inhibition of the RAS that may limit the therapeutic results obtained with ACE inhibitors in hypertension and congestive heart failure.4 A non–ACE-dependent production of Ang II may also contribute to the persistence of Ang II during ACE inhibition.5
Because of the potential advantages of a more complete blockade of the hemodynamic and tissue effects of Ang II than that presently achieved with usual doses of ACE inhibitors, it is worthwhile to investigate the biological and hemodynamic effects of the simultaneous blockade of the RAS at the two different sites where it is currently achieved, ACE and AT1 receptors. In a first investigation with a double-blind crossover design, we gave single oral doses of 50 mg captopril, 50 mg losartan, their combination, and matched placebos to 12 normotensive volunteers pretreated with 40 mg furosemide 12 hours before drug intake.6 Compared with losartan and captopril given alone, the combination of both drugs induced a significantly greater decrease in MBP 6 hours after the dose and a significantly greater increase in plasma active renin and plasma Ang I, whereas no additive effect was observed on the fall in plasma aldosterone. Captopril neutralized the losartan-induced rise in plasma Ang II. However, the interpretation of the results was complicated by (1) the difference in the pharmacokinetics of captopril and losartan, and (2) the fact that it was possible that the doses of 50 mg captopril and 50 mg losartan are not maximal for obtaining a complete and long-lasting blockade of the RAS and that, presumably, an increase in dose of one or the other blocker would have effects similar to those of their combination.
Using a similar experimental design, we planned the current study to determine whether the hemodynamic and hormonal effects of 50 mg losartan combined with 10 mg enalapril, an ACE inhibitor with a longer duration of action than captopril, will be of greater magnitude than the effect obtained by increasing the dose of the ACE inhibitor given alone. We selected enalapril instead of captopril because of the similarities in its pharmacokinetics and that of its active metabolite, enalaprilat, with that of losartan and its active metabolite, EXP 3174.7 8
The present study confirms the additive effects of ACE inhibition and Ang II antagonism. The combination of 50 mg losartan and 10 mg enalapril is more effective in decreasing BP and increasing plasma active renin and plasma Ang I than doubling the enalapril dose from 10 to 20 mg. No additive effect of the combination was observed on the fall in plasma aldosterone in this single-dose study. The combination of 10 mg enalapril and 50 mg losartan neutralizes both the fall in plasma Ang II induced by 10 mg enalapril and the rise in plasma Ang II induced by 50 mg losartan.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Study Design
We used a single-dose, double-blind, randomized, three-way crossover study design. Each period was separated by a 2-week washout interval. Treatment assignment was performed according to a Latin square design. Each subject received 10 mg enalapril, 20 mg enalapril and the combination of 50 mg losartan and 10 mg enalapril.
Subjects
Twelve healthy, normotensive (supine BP <140/90 mm Hg) male volunteers aged 18 to 35 years and weighing 74.4±8.4 kg completed the study. Each subject had a medical history taken and underwent a complete physical examination and routine laboratory evaluation, including an electrocardiogram, 14 days before the study. Volunteers gave their written and informed consent to receive 40 mg furosemide followed by 10 mg enalapril, 20 mg enalapril, and the combination of 50 mg losartan and 10 mg enalapril on three separate occasions. The protocol was approved by the "Comite Consultatif de Protection des Personnes se pretant a des Recherches Biomedicales" (Paris-Cochin, France). The procedures followed were in accordance with institutional guidelines.
Drugs
Losartan and enalapril were provided by Merck Research Laboratories as capsules identical in appearance.
Study Protocol
Before each period, all subjects were asked to refrain from smoking, drinking alcoholic beverages, and taking any medication. For each phase, subjects were instructed to arrive at the Broussais Clinical Investigation Center at 6 PM on the prestudy evening (D0), and they remained hospitalized at the center for 36 hours. For induction of mild sodium depletion, subjects were given 40 mg furosemide at 9 PM on D0 and received a sodium-restricted diet (20 mmol/d) during the 36 hours of each phase. Water was given ad libitum. Between each period, volunteers were instructed to follow their regular diet.
On the study day (D1), after a light caffeine- and fat-free breakfast at 7 AM, subjects were comfortably installed in a semirecumbent position on their beds. An indwelling cannula was inserted into a brachial vein for blood sampling. At 9 AM, after subjects had rested 1 hour in the semirecumbent position to allow equilibration of BP, HR, and hormones, they received a single oral dose of each treatment (10 mg enalapril, 20 mg enalapril, or the combination of 50 mg losartan and 10 mg enalapril) with 50 mL water and remained in the same position until 6 hours postdose (3 PM). Fluid intake throughout each study day was unrestricted, and subjects were given a light meal 6 and 12 hours postdose. After the first meal, subjects were allowed to move from their beds. For BP, HR, and hormonal determinations performed 9, 12, and 24 hours postdose, subjects were once again placed in the semirecumbent position 1 hour before sampling.
On each study day (D1), MBP and HR (average of 15 measurements performed every 2 minutes) were monitored with subjects in the semirecumbent position at defined intervals (before and 2, 4, 6, 9, 12, and 24 hours after dosing) with an automatic BP recorder (Press Mate BP 8800, Colin Co). In addition, MBP and HR were determined with subjects in the standing position (mean of three values obtained over 3 minutes) 4 hours postdose.
Blood was sampled before and 2, 4, 6, 9, 12, and 24 hours after dosing for determinations of plasma active renin, Ang I, Ang II, ACE activity, aldosterone, and cortisol. Plasma total renin was determined before and 24 hours after drug intake.
Before oral dosing, subjects voided their bladder to complete a 12-hour urine collection (from 9 PM on D0 to 9 AM on D1). Two further 12-hour urine collections were completed after drug intake (from 9 AM to 9 PM on D1 and from 9 PM on D1 to 9 AM on D2). Urinary electrolytes and creatinine were measured in each urine sample.
Laboratory Methods
We used heparinized tubes to collect blood for plasma active and total renin, ACE activity, aldosterone, and cortisol determinations. For measurement of plasma angiotensins, blood samples (10 mL) were rapidly collected (within 10 seconds) into prechilled EDTA-K3 Vacutainers, and 0.5 mL of an inhibitor mixture of 62.5 mmol/L EDTA, 100 µmol/L remikiren, and 100 µmol/L enalaprilat was immediately added.9 Blood samples were immediately centrifuged at 3500 rpm at 4°C, and plasma was stored at -80°C until assay.
All methods of measurement have been previously described.6
Statistical Methods
Using a similar experimental design, we have previously shown that with the exception of plasma cortisol and aldosterone, all parameters remained stable during the placebo period.6 Therefore, we did not introduce a placebo period in the present study in order to increase its statistical power by reducing the number of periods. This study had a statistical power of 80% to detect a difference of 5 mm Hg in BP between the losartan-enalapril combination and 20 mg enalapril, with an 
risk of 5%, an SD of BP values of 7 mm Hg, and a correlation coefficient of .63 between BP values of two periods.
AUC versus time was calculated according to the trapezoidal rule for plasma active renin (0 to 24 hours) and aldosterone (0 to 6 hours) and for MBP changes from baseline (0 to 24 hours). To calculate the AUC of MBP changes, we set all positive values obtained after subtracting each MBP level from the baseline level to zero in order to avoid biased estimation of the AUC of MBP fall; positive values (ie, increases in MBP) caused by random fluctuations of BP at the end of the observation period, when drugs are less effective, would induce an underestimation of the AUC of MBP fall. The times to peak effect for MBP fall, plasma active renin rise, and plasma aldosterone decrease were determined graphically for each subject.
Data were analyzed by ANOVA; the crossed factor was the subject, and the within factor was treatment. Since the order of treatment period was randomized for each subject and a 2-week washout period was allowed between each drug administration, it was assumed that there were no carryover effects. Analysis was performed according to the method for repeated measures in a Latin square design. When the F test was significant (P<.05), paired comparisons were performed with Bonferroni correction to avoid type I errors caused by multiple testing. Residual variance of ANOVA was taken for performing pairwise tests. The assumptions of ANOVA (homogeneity of variance and normality) were verified for each variable, and natural logarithmic transformation was applied where appropriate. For all parameters tested, the ANOVA was first performed on the summarized parameter, which is the AUC. When the F test was significant for the AUC (P<.05), additional ANOVAs were performed at peak and 12 and 24 hours after drug intake. The regression line was estimated by the least-squares method.
Calculations were done on an Apple Macintosh computer with StatView II and Superanova statistical software (Abacus Concepts Inc). Data are expressed as mean±SD in the tables and mean±SE in the graphs unless otherwise indicated. A probability value of less than .05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Superimposition of a low sodium diet after 40 mg furosemide induced a sodium-potassium ratio less than 1 in the two postdose collection periods (data not shown). Body weight loss was comparable during the three periods (1.6±1.2, 1.8±1.0, and 1.9±1.1 kg for the first, second, and third periods, respectively). For all results, no period effect was detected; therefore, only treatment effects are reported in text and tables.
BP and HR
The AUC0-24 of the fall in MBP differed significantly among the three periods (F2,20=6.5, P=.007, Table 1
). In paired comparisons, the AUC0-24 of the fall in MBP after losartan-enalapril combination intake (-220±91 mm Hg·h) was significantly greater than that of either 10 or 20 mg enalapril (-124±91 and -149±85 mm Hg·h, respectively; P<.05 versus both doses). The AUC0-24 of the fall in MBP for 20 mg enalapril did not significantly differ from that of 10 mg enalapril.
|
At peak, the combination of 50 mg losartan and 10 mg enalapril produced a significant additional fall in MBP compared with 10 mg enalapril given alone. Doubling enalapril doses from 10 to 20 mg caused a peak MBP effect of a magnitude similar to that induced by the addition of 50 mg losartan to 10 mg enalapril (Table 1
). The kinetics of the fall in MBP were similar during the three periods. The times to peak for the maximum MBP fall were not significantly different (Table 1 and Fig 1).
|
), 20 mg enalapril (
), and a combination of 50 mg losartan and 10 mg enalapril (
).
Twelve hours after drug intake, the losartan-enalapril combination induced a decrease in MBP that was significantly greater than that produced by either 10 or 20 mg enalapril given alone (F2,20=5.7, P<.01, Fig 1). Twenty-four hours after drug intake, no significant difference between the two doses of enalapril or the losartan-enalapril combination could be detected.
For quantification of the average gain in MBP fall produced either by doubling the enalapril dose or by adding 50 mg losartan to 10 mg enalapril, the weighted fall in MBP during the 10 mg enalapril phase was subtracted from the respective weighted falls in MBP for 20 mg enalapril and the losartan-enalapril combination. For each period, the weighted fall in MBP was calculated as the ratio of its AUC0-24 of MBP fall to its 24-hour duration. An additional weighted fall in MBP fall was observed after addition of 50 mg losartan to 10 mg enalapril, whereas doubling the enalapril dose did not increase the MBP fall (-5±4 versus -1±4 mm Hg, respectively, P=.02).
The two doses of enalapril and the losartan-enalapril combination did not significantly modify HR (not shown).
The relative MBP and HR changes when subjects assumed the standing position 4 hours postdose were similar during the three periods (not shown). Two mild episodes of dizziness and postural hypotension when the upright position was assumed 4 hours after drug intake (10 mg enalapril, two episodes; 20 mg enalapril and combination, none) were resolved in the supine position without requiring any specific treatment.
Plasma Renin Parameters
At baseline, plasma active renin and prorenin levels did not differ significantly among the three periods. Both enalapril doses significantly increased plasma active renin levels from their respective baselines (Fig 2). They remained at a plateau level from 4 to 9 hours after drug intake, thereafter decreasing progressively until 24 hours. After intake of the losartan-enalapril combination, plasma active renin rapidly increased toward a peak value (10.4±4.8-fold of the baseline level), thereafter decreasing progressively until hour 24 of the experiment (Fig 2).
|
Doubling of the enalapril dose did not significantly increase the AUC0-24 of plasma active renin versus time (Table 1).The effect of losartan-enalapril combination was additive on plasma active renin levels, significantly increasing the AUC0-24 of plasma active renin versus time compared with each enalapril dose given alone. The maximum increase in plasma active renin levels did not significantly differ between the two enalapril doses (10 mg: 4.6±2.1-fold the baseline level; 20 mg: 5.9±2.9-fold; P=NS), whereas the combination of losartan and enalapril significantly increased the maximum plasma active renin compared with each enalapril dose given alone (Table 1 and Fig 2). Plasma active renin levels were significantly higher 12 and 24 hours after losartan-enalapril dosing than those measured after either 10 or 20 mg enalapril (F2,20=13.5, P<.001, and F2,20=19.7, P<.001, respectively [Fig 2]). Twenty-four hours after drug intake, plasma active renin levels remained higher than their respective baseline levels for all three treatments.
At baseline, plasma prorenin levels were 270±82, 272±118, and 258±73 pg/mL for 10 mg enalapril, 20 mg enalapril, and the losartan-enalapril combination, respectively (P=NS). Twenty-four hours after drug intake, both enalapril doses increased plasma prorenin levels to a similar extent, whereas prorenin was significantly higher during the losartan-enalapril period (10 mg enalapril: 499±136 pg/mL; 20 mg enalapril: 541±226; losartan-enalapril combination: 808±257; F2,20=9.3, P<.001).
Plasma Ang I and Ang II
The plasma Ang I profile after intake of the losartan-enalapril combination or of each enalapril dose followed exactly the same pattern as that of plasma active renin levels (Fig 3), and both measurements were significantly correlated (r=.84, n=12, P<.001). Similar to what was observed for plasma active renin levels, the losartan-enalapril combination significantly increased both the magnitude of the plasma Ang I rise and the AUC0-24 of plasma Ang I versus time compared with each enalapril dose given separately (Table 1). The differences in AUC values between 10 and 20 mg enalapril were not statistically significant.
|
Enalapril at 10 and 20 mg and the losartan-enalapril combination decreased plasma Ang II levels from their respective baselines (Fig 3). The losartan-induced rise in plasma Ang II did not occur after administration of the losartan-enalapril combination.6 The plasma Ang II profile was close to that observed after 10 mg enalapril given alone, even though the AUC0-24 of plasma Ang I for the losartan-enalapril combination was 2.4±1.5 times that for 10 mg enalapril given alone (Fig 3). The AUC0-24 of plasma Ang II levels versus time was significantly higher after the losartan-enalapril combination than after either 10 or 20 mg enalapril given alone (Table 1). Twenty-four hours after drug intake, 20 mg enalapril maintained significantly lower levels of plasma Ang II than 10 mg enalapril given either alone or in combination (F2,20=20.5, P<.001).
In Vitro and In Vivo ACE Activity
As expected, after administration of enalapril given either alone or in combination, in vitro plasma ACE activity levels (measured by Cushman's assay) decreased in a dose-dependent manner toward a nadir 4 hours after drug intake and began to increase from 9 hours postdose onwards, so that by 24 hours after drug intake, plasma ACE activity was 77±9%, 76±15%, and 89±7% of the respective baseline levels for 10 and 20 mg enalapril and the losartan-enalapril combination (P=NS, Fig 4). At peak, 10 and 20 mg enalapril and the losartan-enalapril combination induced an inhibition of in vitro ACE activity of 74±8%, 83±7%, and 68±10%, respectively (Fig 4).
|
The plasma Ang II–Ang I ratio decreased similarly toward very low levels after either enalapril or losartan-enalapril administration (Fig 4). The analysis of relative changes in the plasma Ang II–Ang I ratio, which represents the in vivo endothelial and plasma ACE activity, showed that in vivo ACE activity was much more inhibited than the level that can be detected in vitro by Cushman's assay (peak inhibition of 97±2%, 98±2%, and 96±2% for 10 mg enalapril, 20 mg enalapril, and the losartan-enalapril combination, respectively, Fig 4). Twenty-four hours after dosing, the plasma Ang II–Ang I ratio remained very low compared with baseline, and a remaining inhibition of 71±15%, 80±12%, and 75±11% of ACE persisted after 10 mg enalapril, 20 mg enalapril, and the losartan-enalapril combination, respectively.
Plasma Cortisol, Aldosterone, and Aldosterone-Cortisol Ratio
The plasma cortisol profile followed its circadian cycle and was not influenced by any of the active drugs (Table 2). Plasma aldosterone also followed the same circadian cycle,10 decreasing toward a nadir 12 hours after drug intake and thereafter increasing until 24 hours after dosing (Table 2). To differentiate the fall in plasma aldosterone caused by RAS blockade from that caused by its circadian cycle, we analyzed the plasma aldosterone-cortisol ratio profile. The plasma aldosterone-cortisol ratio decreased during the first 6 hours after active drug intake and increased thereafter (Table 2). Therefore, we studied the influence of RAS blockade on plasma aldosterone levels during the first 6 hours after dosing. The time to peak for the plasma aldosterone-cortisol ratio during the three periods was similar (Table 1). At peak, the relative fall in plasma aldosterone was similar after the intake of either 10 or 20 mg enalapril (56±27% and 59±19%, respectively; P=NS). The AUC0-6 for plasma aldosterone versus time did not significantly differ between the two enalapril doses (Table 1). Contrary to the effect observed on plasma active renin and Ang I levels, the losartan-enalapril combination had no additive effect on the magnitude of plasma aldosterone fall compared with 10 mg enalapril given separately (62±17%, P=NS; Table 1) or on the AUC0-6 of the plasma aldosterone fall.
|
Summary Results on MBP and Plasma Active Renin
Fig 5 shows a plot of the mean values of the AUC0-24 of the fall in MBP versus the respective AUC0-24 of the rise in plasma active renin after RAS blockade under the influence of the different monotherapies or combinations of treatments that have been tested by the same experimental protocol. Fig 5 combines the results of the present study and those of the comparison of 50 mg captopril, 50 mg losartan, and their combination.6 AUC values were calculated by using only the times of MBP and active renin measurements common to both studies. AUC0-24 is a composite and integrated parameter that takes into account both the magnitude and duration of the effect. Fig 5 shows an inverse relationship between the fall in MBP (expressed by its AUC0-24 as negative values) and the rise in plasma active renin; the greater the decrease in MBP, the higher the plasma active renin. It shows that the rise in plasma active renin and fall in MBP were of similar magnitude when the RAS was blocked by either 50 mg losartan or 10 mg enalapril. Doubling of the enalapril dose had no detectable effect, and the effects of enalapril at either 10 or 20 mg could not be differentiated from those of 50 mg losartan. The additive effects on MBP fall and active renin rise of the combination of 50 mg losartan with either 10 mg enalapril or 50 mg captopril were found in both studies, and these effects were greater than those produced either by each treatment given alone (50 mg captopril, 10 mg enalapril) or by doubling of the enalapril dose. When the combination was used, a full additive effect was observed on renin release, whereas in this experimental model of sodium depletion in normotensive subjects, a partially additive effect on MBP fall was present.
|
When the same analysis was performed 2 hours after drug intake, a synergistic effect of the losartan-enalapril combination was observed on both the fall in BP and rise in plasma renin. Twenty-four hours after drug intake, no significant fall in BP was observed, whereas the rise in plasma active renin persisted, with an additive effect of the combinations (Fig 6).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The model of mild sodium depletion in normotensive volunteers provides an experimental condition in which BP is consistently dependent on the RAS.11 By contrast to the heterogeneity of the RAS of hypertensive patients, sodium-depleted normotensive volunteers have homogeneous levels of plasma active renin, and all have a diuretic-induced BP renin dependency.6 12 This is actually shown by the reproducibility of the model, in which baseline plasma active renin, Ang II, and aldosterone values have been similar in seven consecutive investigations performed on two groups of 12 volunteers (7 among them participated in both studies at a time interval of 6 months).6 These experimental conditions make it possible for one to build dose-response curves on two indexes of RAS blockade: the fall in BP and the rise in plasma renin. As shown by our investigation, both indexes change in parallel, although the precision in the assessment of their variation is not similar. The in vitro renin measurement is much less sensitive to external factors than the assessment of a BP fall. In addition, the range of renin changes (1 to 10 times) is much larger than the range of BP changes (10 to 20 mm Hg). With a more substantial sodium depletion it would be possible to induce larger falls in BP and theoretically to better discriminate the BP effects of different doses or combinations of RAS blockers. However, it has been shown in normotensive subjects that after a sodium depletion induced by larger doses of furosemide that increase plasma renin by fivefold, blockade of the RAS may occasionally induce symptomatic orthostatic hypotension and a significant fall in glomerular filtration rate.12
Our results confirm the initial observations made on the combination of captopril and losartan.6 They show that doubling the dose from 10 to 20 mg of an ACE inhibitor such as enalapril does not significantly increase the intensity of RAS blockade, which is in accordance with the prediction of the pharmacokinetic-pharmacodynamic studies of Meredith et al2 in hypertensive patients. Alternatively, if instead of doubling the dose of an ACE inhibitor, the RAS is blocked at the AT1 receptor, the effects on BP and renin release are significantly increased, although concurrently no additive effect on plasma aldosterone level is observed. Twenty-four hours after drug intake, the rise in plasma prorenin is proportional to the intensity and duration of the RAS blockade. The higher value of plasma prorenin observed after the combination of 50 mg losartan and 10 mg enalapril in conjunction with the rise in active renin reflects a persistent increase in the rate of enzyme biosynthesis and an augmented secretion by both the regulated and constitutive pathways.13 All these results confirm that neither the first dose of 50 mg losartan nor 10 or 20 mg enalapril achieves a maximum blockade of the RAS. They reinforce the conclusions of the losartan-captopril study,6 showing an additive effect in terms of renin release and MBP fall of the combined administration of losartan and enalapril, two drugs with similar pharmacokinetics.
An informative summary of the results of the present study and the losartan-captopril study is provided in Figs 5 and 6. They show that the BP and renin effects of a single oral administration of RAS blockers depend highly and in a time-dependent manner on the intensity of the RAS blockade. Fig 5 shows that the 24-hour effects of 50 mg losartan are equal to those of 10 or 20 mg enalapril in terms of both MBP and renin responses. These results are in accordance with those reported in two different phase II controlled trials in hypertensive patients, in which the BP effects of 50 mg losartan did not significantly differ from either those of 10 mg enalapril OD administered for 5 days or those of 20 mg enalapril OD administered for 8 weeks.14 15 The losartan-enalapril combination is the most effective on BP and plasma active renin over 24 hours. On the contrary, the limited BP efficacy of the single oral dose of 50 mg captopril is explained by its shorter duration of action on BP, although it is still effective on plasma active renin 24 hours after its intake. When the same analysis is performed 2 hours after drug intake, losartan is not yet converted to EXP 3174, nor is enalapril to enalaprilat, and both drugs are minimally effective. In contrast, at that time, the losartan-enalapril combination has synergistic effects on BP and plasma renin.
Despite a 97% inhibition of ACE by 10 mg enalapril at peak (assessed by the Ang II–Ang I ratio), the blockade of AT1 receptors by losartan gives an additional effect, at least detectable at the level of the AT1 receptors that regulate renin release by the juxtaglomerular cells, confirming that the small amounts of residual Ang II produced through ACE or other pathways are still effective on unblocked AT1 receptors and may limit the full effect of an ACE inhibitor, even at peak.
The additive effects of the combined treatments remain now to be validated during repeated administration to patients with hypertension or congestive heart failure.
Such a combined blockade of the RAS is different from what has been clinically tested so far. Besides a more intensive blockade of AT1 receptor functions, it induces bradykinin accumulation, as do ACE inhibitors, and does not stimulate potentially functioning AT2 receptors, contrary to AT1 receptor antagonists given alone. The consequences of a stimulation of AT2 receptors are unknown and have equal chances to be beneficial,16 17 18 deleterious,19 20 or neutral. For all these reasons, the consequences of the combined blockade of the RAS requires appropriate testing in animal models and further clinical investigation, after the present demonstration in normotensive volunteers of the mutual reinforcement of the effects of losartan and enalapril or captopril.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This work was supported by a grant from Merck Research Laboratories, West Point, Pa, and Association Claude Bernard. The authors wish to thank the nursing staff of the Clinical Investigation Center at the Broussais Hospital (Daniele Menard, Jeanne Meunier, Olivier Picart, and Michele Godeau) who ran the protocol. The technical contribution of Christiane Dollin who performed the assays was also much appreciated. The authors acknowledge William Grossman and Charles Sweet for their support and editorial help.
|
Footnotes |
|---|
Reprint requests to Dr Michel Azizi, Clinical Investigation Center, Broussais Hospital, 96 rue Didot, 75674 Paris Cedex 14, France.
Received July 11, 1996;
first decision July 31, 1996;
first decision August 26, 1996;
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Lees KR. The dose-response relationship with angiotensin converting enzyme inhibitors: effects on blood pressure and biochemical parameters. J Hypertens. 1992;10(suppl 5):S3-S11.
2. Meredith PA, Donnelly R, Elliott HL, Howie CA, Reid JL. Prediction of the antihypertensive response to enalapril. J Hypertens. 1990;8:1085-1090.[Medline] [Order article via Infotrieve]
3.
Juillerat L, Nussberger J, Menard 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.
4. 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]
5.
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.
6.
Azizi M, Chatellier G, Guyene TT, Murieta-Geoffroy D, Menard 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.
7. Weisser K, Schloos J, Lehmann K, Dusing R, Vetter H, Mutschler E. Pharmacokinetics and converting enzyme inhibition after morning and evening administration of oral enalapril to healthy subjects. Eur J Clin Pharmacol. 1991;40:95-99.[Medline] [Order article via Infotrieve]
8. Ohtawa M, Takayama F, Saitoh K, Yoshinaga T, Nakashima M. Pharmacokinetics and biochemical efficacy after single and multiple oral administration of losartan, an orally active nonpeptide angiotensin II receptor antagonist, in humans. Br J Clin Pharmacol. 1993;35:290-297.[Medline] [Order article via Infotrieve]
9. Nussberger J, Brunner DB, Waeber B, Brunner HR. In vitro renin inhibition to prevent generation of angiotensins during determination of angiotensin I and II. Life Sci. 1988;42:1683-1688.[Medline] [Order article via Infotrieve]
10. Quinn SJ, Williams GH. Regulation of aldosterone secretion. Annu Rev Physiol. 1988;50:409-426.[Medline] [Order article via Infotrieve]
11. McGregor GA, Markandu ND, Smith SJ, Sagnella GA, Morton JJ. Maintenance of blood pressure by the renin-angiotensin system in normal man. Nature. 1981;291:329-331.[Medline] [Order article via Infotrieve]
12. Doig JK, MacFadyen RJ, Sweet CS, Lees KR, Reid JL. Dose-ranging study of the angiotensin type I receptor antagonist losartan (DuP753/MK954), in salt-deplete normal man. J Cardiovasc Pharmacol. 1993;21:732-738.[Medline] [Order article via Infotrieve]
13. Toffelmire EB, Slater K, Corvol P, Menard J, Schambelan M. Response of plasma prorenin and active renin to chronic and acute alterations of renin secretion in normal subjects: studies using a direct immunoradiometric assay. J Clin Invest. 1989;83:679-687.
14. Nelson E, Merill D, Sweet CS, Bradstreet T, Panebianco D, Byyny R, Herman T, Lasseter K, Levy B, Lewis G, McMahon FG, Reeves R, Ruff S, Shepherd A, Weidler D, Irvin G. Efficacy and safety of oral MK-954 (DuP753), an angiotensin receptor antagonist, in essential hypertension. J Hypertens. 1991;9(suppl 6):s468-s469. Abstract.
15.
Gradman AH, Arcuri KE, Goldberg AI, Ikeda LS, Nelson EB, Snavely DB, Sweet CS. A randomized, placebo-controlled, double-blind, parallel study of various doses of losartan potassium compared with enalapril maleate in patients with essential hypertension. Hypertension. 1995;25:1345-1350.
16. Fernandez LA, Caride VJ, Stromberg C, Navery 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]
17. 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.
18.
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.
19. 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.
20. 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]
This article has been cited by other articles:
 |
|
 |
|
  M. J Brown Renin: friend or foe? Heart, September 1, 2007; 93(9): 1026 - 1033. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Tsouli, E. N. Liberopoulos, D. N. Kiortsis, D. P. Mikhailidis, and M. S. Elisaf Combined Treatment With Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers: A Review of the Current Evidence Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2006; 11(1): 1 - 15. [Abstract] [PDF]
|
|
|
|
 |
|
 A. W.J.H. Dielis, M. Smid, H. M.H. Spronk, K. Hamulyak, A. A. Kroon, H. ten Cate, and P. W. de Leeuw The Prothrombotic Paradox of Hypertension: Role of the Renin-Angiotensin and Kallikrein-Kinin Systems Hypertension, December 1, 2005; 46(6): 1236 - 1242. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M.A. van de Wal, D. J. van Veldhuisen, W. H. van Gilst, and A. A. Voors Addition of an angiotensin receptor blocker to full-dose ACE-inhibition: controversial or common sense? Eur. Heart J., November 2, 2005; 26(22): 2361 - 2367. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. K. Jacobsen Review: Preventing End-Stage Renal Disease in Diabetic Patients -- Dual Blockade of the Renin-Angiotensin System (Part II) Journal of Renin-Angiotensin-Aldosterone System, June 1, 2005; 6(2): 55 - 68. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Azizi, J. Menard, A. Bissery, T.-T. Guyenne, A. Bura-Riviere, S. Vaidyanathan, and R. P. Camisasca Pharmacologic Demonstration of the Synergistic Effects of a Combination of the Renin Inhibitor Aliskiren and the AT1 Receptor Antagonist Valsartan on the Angiotensin II-Renin Feedback Interruption J. Am. Soc. Nephrol., December 1, 2004; 15(12): 3126 - 3133. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 G. Picciotto, A. Sargiotto, M. Petrarulo, C. Rabbia, P. G. De Filippi, and D. Roccatello Reliability of Captopril Renography in Patients Under Chronic Therapy with Angiotensin II (AT1) Receptor Antagonists J. Nucl. Med., October 1, 2003; 44(10): 1574 - 1581. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. H.H.T. Klein, G. Ligtenberg, P. L. Oey, H. A. Koomans, and P. J. Blankestijn Enalapril and Losartan Reduce Sympathetic Hyperactivity in Patients with Chronic Renal Failure J. Am. Soc. Nephrol., February 1, 2003; 14(2): 425 - 430. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Forclaz, M. Maillard, J. Nussberger, H. R. Brunner, and M. Burnier Angiotensin II Receptor Blockade: Is There Truly a Benefit of Adding an ACE Inhibitor? Hypertension, January 1, 2003; 41(1): 31 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
D. A Sica Review: The practical aspects of combination therapy with angiotensin receptor blockers and angiotensin-converting enzyme inhibitors Journal of Renin-Angiotensin-Aldosterone System, June 1, 2002; 3(2): 66 - 71. [Abstract] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||