Biochemical Effects of Losartan, a Nonpeptide Angiotensin II Receptor Antagonist, on the Renin-Angiotensin-Aldosterone System in Hypertensive Patients
Abstract We investigated the effects of angiotensin II (Ang II) type 1 receptor blockade with losartan on the renin-angiotensin-aldosterone system in hypertensive patients (supine diastolic blood pressure, 95 to 110 mm Hg). Qualifying patients (n=51) were allocated to placebo, 25 or 100 mg losartan, or 20 mg enalapril. Blood pressure, plasma drug concentrations, and renin-angiotensin-aldosterone system mediators were measured on 4 inpatient days: end of placebo run-in, after first dose, and 2 and 6 weeks of treatment. Plasma drug concentrations were similar after the first and last doses of losartan. At 6 weeks, 100 mg losartan and 20 mg enalapril showed comparable antihypertensive activity. Four hours after dosing, compared with the run-in day, 100 mg losartan increased plasma renin activity 1.7-fold and Ang II 2.5-fold, whereas enalapril increased plasma renin activity 2.8-fold and decreased Ang II 77%. Both drugs decreased plasma aldosterone concentration. For losartan, plasma renin activity and Ang II increases were greater at 2 than at 6 weeks. Effects of losartan were dose related. After the last dose of losartan, plasma renin activity and Ang II changes were similar to placebo changes by 36 hours. These results indicate that long-term blockade of the feedback Ang II receptor in hypertensive patients produces modest increases of plasma renin activity and Ang II that do not appear to affect the antihypertensive response to the antagonist.
Losartan (DuP 753, MK-954) is an angiotensin II (Ang II) type 1 (AT1)–selective, nonpeptide receptor antagonist1 2 3 administered clinically as the potassium salt (losartan potassium). Its activity as an Ang II antagonist has been characterized in preclinical and clinical models, and reports of its efficacy in clinical hypertension are appearing.1 2 3 4 5 6 7 8 9 10 11 One consequence of Ang II receptor blockade that has been documented in healthy subjects is increased plasma renin activity (PRA) followed by increases in plasma Ang II concentration.4 5 6 Thus, in healthy male volunteers, single and multiple doses of losartan resulted in 4-fold (trough) to 10-fold (peak) increases in PRA and Ang II concentrations.6 The mechanism for these increases is presumed to be a combination of blockade of feedback inhibition of renin release at the juxtaglomerular apparatus and possibly a response to hemodynamic changes produced by the drug. Since losartan and its active metabolite, E-3174, have much longer half-lives than either PRA or Ang II,11 12 it is assumed that drug-induced increases of Ang II will not persist beyond the period of receptor antagonism. Furthermore, completed animal toxicity studies (up to 2 years’ duration) have not shown any findings that would indicate any unexpected effect of such increases in Ang II (Merck Research Laboratories, data on file). However, it is also known that multiple binding sites (ie, AT1 and AT2 receptors) for Ang II have been identified, and losartan and E-3174 antagonize only one of these sites (ie, AT1).2 3 Although no biological activity has been associated with the interaction of Ang II at the AT2 site, it remains a possibility that some biological effect could be manifest during long-term AT1 Ang II blockade, with enhancement of these effects if hypertensive individuals exhibit sustained increases in Ang II during therapy. In addition, it is possible that sustained autonomous secretion of PRA (with consequent generation of Ang II) could, during long-term treatment with losartan, result in loss of antihypertensive activity and rebound hypertension with discontinuation.
Accordingly, we designed this study to assess the biochemical response of hypertensive patients to subchronic (6 weeks) treatment with losartan, compared with placebo and enalapril, an inhibitor of angiotensin-converting enzyme (ACE). The primary hypothesis of this study was that losartan treatment would result in increases in PRA and Ang II compared with baseline and placebo values. Changes in plasma aldosterone and catecholamine concentrations and urinary aldosterone and catecholamine excretions were also measured.
Male and female patients (aged 21 to 70 years) with mild to moderate hypertension (supine diastolic blood pressure, 95 to 110 mm Hg after 4 weeks of single-blind placebo) were eligible for this study. Patients were nonblack, in general good health, free of significant concomitant illness or therapy that might influence blood pressure, and compliant with once-daily run-in placebo. Based on study inclusion and exclusion criteria, patients were considered to have essential hypertension. All patients provided written informed consent for the study after review of the protocol and consent form by the Institutional Review Boards of the four participating centers.
This was a multicenter, randomized, double-blind, placebo-controlled, parallel study in patients with mild to moderate hypertension. The design included a 2- to 4-week medication tapering/placebo run-in period followed by a 6-week double-blind treatment period. The daily time of drug dosing was to be 7 to 10 am throughout the study. However, for outpatient visits, patients reported to the clinic before taking their morning dose of medicine. Study treatments included placebo, 25 and 100 mg losartan once daily, and 20 mg enalapril once daily. Fig 1⇓ illustrates the overall design.
The losartan doses used in this study reduced blood pressure in hypertensive patients, with the effect of 25 mg being less than that of 100 mg.10 These doses also resulted in minimal4 and maximal5 inhibition of responses to Ang II injections in healthy volunteers and produced substantial shifts of dose-response curves to Ang I and II in the human forearm.7 After single and multiple doses, these doses also resulted in significant increases in PRA and Ang II in healthy volunteers.4 6 The enalapril dose (20 mg), an active dose in hypertensive patients,10 was expected to result in increases in PRA and decreases in Ang II and to produce blockade of the renin-angiotensin-aldosterone system (RAAS) equivalent to the 100-mg dose of losartan.7
The principal study observations were made during 4 inpatient study days. These visits occurred in association with the end of the placebo baseline period (run-in), the first dose of double-blind therapy, 2 weeks of double-blind therapy, and 6 weeks of double-blind therapy. The first dose visit could follow the run-in visit by 1 to 7 days. For each visit, the patient reported to the clinic the evening before the study day for an overnight stay. From midnight before dosing until after the 1.5-hour measurement, patients remained in bed except to use the toilet and for scheduled standing blood pressure and heart rate measurements. On the morning of the study day (approximately 1 hour before dosing), a butterfly (or other) catheter was inserted into an arm vein for repeated sampling of blood. Within 30 minutes of dosing and after 60 minutes of supine rest, plasma samples were obtained for predose PRA, Ang II, aldosterone, and catecholamine concentrations (and losartan concentrations, when required). Supine and standing blood pressure and heart rate measurements were recorded. Supine blood pressure measurements were made after patients had rested for at least 10 minutes in the supine position. The average of two measurements made with a mercury sphygmomanometer was recorded, followed by heart rate measurement for 1 minute. A single standing blood pressure measurement was made after 2 minutes of upright posture.
For the run-in visit, placebo was administered at 0 hour (approximately 7 to 10 am). For first-dose, 2-week, and 6-week visits, double-blind treatment was administered at the same clock time (±30 minutes). A light breakfast was served after the 1.5-hour measurements, with regular lunch and dinner served after the 5- and 8-hour measurements. A bedtime snack was offered after the 12-hour measurements. On study days the timing of measurements was in relation to the 0 hour administration of the dose. All doses on the 4 study days were administered under direct observation at the clinic.
At these visits, supine and standing blood pressure and heart rate were measured before the dose and frequently for 12 hours. PRA, Ang II, aldosterone, and plasma catecholamines were measured at 0, 4, 4.5, 8 and/or 12, and 24 hours after dosing, with the 4.5-hour sample collected after 30 minutes of ambulation and the other measurements made after 1 hour of supine posture. At each visit, a 24-hour urine collection was made for measurement of aldosterone, catecholamine, and electrolyte excretions. Most patients (80% to 90%) showed 24-hour urinary sodium excretion levels greater than 100 mmol.
Biochemical measurements used to evaluate drug effects in this study were carefully evaluated in the respective central laboratories conducting these assays. These critical study measurements included plasma concentrations of losartan and its active metabolite (E-3174), PRA, plasma Ang II concentration, plasma and urinary aldosterone concentrations, and plasma and urinary norepinephrine and epinephrine concentrations. Briefly, plasma drug concentrations were measured by high-performance liquid chromatography (HPLC with UV detection).13 PRA was measured by radioimmunoassay (RIA) of Ang I after timed incubation of plasma under optimized conditions.6 Plasma and urinary aldosterone were measured by RIA using a commercially available kit.6 Catecholamines were measured by HPLC with electrochemical detection.
Ang II was measured by an HPLC-RIA method6 that selectively measures Ang II with high sensitivity (lower limit of detection, 0.3 pg/mL). The method couples an RIA using a reasonably selective antibody (ie, 0.1% and 53% cross-reactivities with Ang I and Ang II, respectively) with reversed-phase HPLC separation of Ang II from other structurally related angiotensin peptides.6 14 This methodology provided the primary measurement of Ang II changes in this study, with samples collected predose and at 4 hours postdose on the study days. In this respect, the predose measurement represents the trough, or presumed minimal, effect during the dosing interval, and the 4-hour time point corresponds to a period of peak plasma drug concentrations and Ang II blockade in an antagonism model in humans.4 5 Measurement of postural effects and monitoring of Ang II after the last dose of study drug were done using a direct RIA method in which Ang II was measured by RIA in plasma that had been partially purified by C8 solid-phase extraction.
PRA, Ang II, aldosterone, and norepinephrine results are reported in conventional units. SI conversions are as follows: aldosterone, ng/dL×27.74=pmol/L; Ang II, pg/mL×1=ng/L; norepinephrine, pg/mL×0.005911=nmol/L; and PRA, ng Ang I/mL per hour×1=μg Ang I/L per hour.
The general strategy for statistical analysis was to compare in a pairwise fashion the results in each treatment group to those observed in each of the other treatment groups. For each response variable, either the change from run-in (blood pressure, aldosterone, catecholamines) or the ratio versus run-in (PRA, Ang II) was calculated at each time point on the 24-hour diurnal curve. Also calculated for some variables were signed area-about-zero on the change curve (AUC) up to a specified hour or signed area-about-ln 1 (0) on the ln ratio curve up to a specified hour. These assessments provided an overview of the treatment effect at each visit for comparison between treatments. The usual trapezoidal rule15 was adapted to account for the direction and (sometimes exact) magnitude of the area-about-ln 1 or 0. Furthermore, the results after the first dose and at weeks 2 and 6 were compared in a time point–by–time point fashion with the results at run-in. The results of weeks 2 and 6 were compared with each other in a similar fashion.
A normal theory randomized complete block analysis of variance (RB-ANOVA) with the main effects clinic (3 df) and treatment (3 df) provided the mean squared error term for the least significant difference procedure,16 which was used to make the six pairwise comparisons between the treatment groups, with the type I error rate set at α=.05. Before statistical analysis, the ratio scaled data were (natural) log transformed. The change data were not transformed. Population marginal (least-squares) means17 were used to summarize and evaluate the data. In the case of the ratio-scaled data, these means were back-transformed to geometric means for presentation in the tables and text. Within–treatment group assessments of changes or ratios were made using two-tailed paired Student’s t test18 on the population marginal means. The type I error rate was set at α=.05 for all comparisons.
Since the patient counts in each treatment group in one of the clinics were small (one to two patients) compared with the counts at the other three clinics (one to five patients), treatment-by-clinic interaction was not formally assessed.
A total of 51 hypertensive patients (35 men, 16 women) ranging in age from 22 to 69 years (median, 53 years) met the inclusion and exclusion criteria and were randomized to treatment. Forty-eight of the patients completed the study. The four treatment groups were of similar age but less balanced with respect to gender (placebo, 6/8 [female/male]; 25 mg losartan, 6/5; 100 mg losartan, 2/12; and 20 mg enalapril, 2/10). Enrollment varied among the four sites (6, 10, 15, and 17 completing patients, respectively).
Blood Pressure Changes and Plasma Drug Concentrations
Under the controlled conditions of this study, it was critical to document the antihypertensive activity of the study treatments and that plasma drug concentrations did not change during the study. Antihypertensive activity is demonstrated in Table 1⇓, which includes a summary of the AUC0-12 h analysis of supine diastolic blood pressure (SuDBP). Fig 2⇓ depicts the mean changes from run-in at the double-blind study days for SuDBP. Significant effects of 100 mg losartan and 20 mg enalapril were apparent, particularly after 2 and 6 weeks of treatment. Qualitatively, decreases in supine systolic blood pressure were similar to changes in SuDBP. Mean changes in supine heart rate were small and did not indicate a clinically meaningful effect. Mean changes in standing blood pressure and heart rate were similar to mean supine changes, with no evidence of clinically significant orthostatic hypotension.
Whereas the blood pressure response to losartan was less after the first compared with the last dose, the plasma concentration versus time profile for losartan and its active metabolite E-3174 did not change to a clinically important degree, as shown by analysis of AUC0-24 h and maximal measured concentrations for losartan and E-3174. Fig 3⇓ summarizes mean concentration versus time profiles. There was no evidence of clinically significant accumulation of losartan or E-3174. Geometric mean AUC ratios (week 6/first dose) and 90% confidence intervals for the 100-mg losartan dose were 1.17 (0.87 to 1.56) and 1.04 (0.98 to 1.11) for losartan and E-3174, respectively.
RAAS Mediators and Norepinephrine Results
The statistical analyses emphasized changes (or ratios) in each study measurement from the run-in visit (placebo baseline) to measurements at the same time of day at the three visits during the double-blind treatment phase: first dose, 2 weeks, and 6 weeks. As a global index of treatment effects, the measured changes (or ln ratios) were used to define a signed area-about-zero change over the 8- or 12-hour daytime period when measurements were collected.
Table 1⇑ summarizes the AUC analysis for SuDBP, PRA, aldosterone, and norepinephrine. Based on this analysis, both 100 mg losartan and 20 mg enalapril were associated with statistically significant increases in PRA that were greater at 2 weeks than after the first dose of either treatment. For losartan, PRA increases were greater at 2 than at 6 weeks. For enalapril, effects at 2 and 6 weeks were not different. Plasma aldosterone was decreased during both losartan and enalapril treatments. Plasma norepinephrine was increased during losartan treatment at week 2 but not at week 6.
From a clinical perspective, it seemed most relevant to focus on measurements and changes in these measurements before dosing on each study day (ie, trough) and 4 hours after dosing (ie, peak). Table 2⇓ summarizes mean measurements 4 hours after dosing at the run-in visit for each RAAS mediator and the mean -fold change from the run-in measurement (ie, ratio) for PRA and Ang II and the mean change for plasma aldosterone. As indicated in this table, the measurements at 4 hours generally reflect the AUC analysis in Table 1⇑.
To further summarize these results, Figs 4⇓, 5⇓, and 6⇓ show the mean predose (hour 0) and peak (hour 4) measurements of PRA, Ang II, and aldosterone, respectively, at run-in and the corresponding mean -fold changes and mean changes at these times after dosing at the double-blind visits. For all three mediators, effects tend to be greater at peak than at trough. This result contrasts with the SuDBP effects of 100 mg losartan and 20 mg enalapril, which varied little from trough to peak (Fig 2⇑). Also apparent for the 100-mg losartan group at the 4-hour time point are the greater increases in PRA and Ang II at week 2 compared with both first dose and week 6. However, suppression of aldosterone at this time point was similar at all three visits.
Fig 7⇓ shows Ang II concentrations 4 hours after dosing on each study day in the patients allocated to receive 100 mg losartan, documenting the range of increases in Ang II in individual patients. Greater increases at 2 weeks compared with first dose and/or 6 weeks were apparent in most patients. Maximal concentrations achieved were less than 5 pg/mL in several patients and ranged from 20 to 62 pg/mL in those with more robust responses. Some patients with low concentrations at run-in showed negligible increases. However, exploratory graphic analyses (not shown) did not indicate clear relations between baseline PRA, Ang II levels, or urinary sodium excretion and increases in PRA or Ang II associated with losartan and/or enalapril in the relatively small numbers of patients included in this study. Furthermore, patients with the greatest increases in PRA did not necessarily show the greatest decreases in blood pressure (not shown).
Postural increases in Ang II (and PRA) were apparent during the run-in day. Thus, after 30 minutes of ambulation from 4 to 4.5 hours after dosing, geometric mean Ang II (direct RIA) increased 14% and PRA increased 49%. At first dose, 2 weeks, and 6 weeks, postural increases in PRA and Ang II in the 100-mg losartan group and PRA in the enalapril group were not statistically significantly different from these values. PRA and Ang II (direct RIA) were also measured during the 72 hours after the last dose of double-blind study drug. By 36 hours after the last dose of either drug, PRA and Ang II in the treated groups were not different from the placebo group.
Plasma norepinephrine tended to increase during losartan treatment at the 2-week visit (Table 1⇑). By the 6-week visit, plasma norepinephrine changes in the active treatment groups were not statistically significantly different from changes in the placebo group or during the run-in day. Fig 8⇓ shows the trough and peak plasma norepinephrine concentrations at the run-in visit and the mean changes at these times during double-blind treatment. Mean changes on the other days are less than 50% of the run-in measurements, suggesting that these apparent changes are probably of little clinical significance. In support of this conclusion, the largest mean difference from run-in was 88 pg/mL in the 100-mg losartan group at 0 hours of the first dosing day, ie, before administration of losartan. Plasma epinephrine values were too often below detection limits to permit analysis.
As indicated in Fig 6⇑ and Tables 1⇑ and 2⇑, plasma aldosterone was decreased during treatment with both losartan and enalapril, particularly at 4 and 8 hours after dosing. For determination of whether a more integrated measure of aldosterone production was altered by losartan or enalapril, 24-hour urine collections for aldosterone excretion were also measured. Table 3⇓ summarizes these results and results of 24-hour urine measurement of norepinephrine. Twenty-four–hour urinary aldosterone excretion tended to be decreased by 100 mg losartan and 20 mg enalapril; but these effects were not as consistent as the changes in plasma aldosterone. Trends seen in plasma norepinephrine were also apparent in the 24-hour urine results, with little evidence of effect at 6 weeks.
Clinical Safety and Laboratory Results
Study treatments were generally well tolerated. However, three patients discontinued the study because of an adverse experience. One patient in the 100-mg losartan group demonstrated symptomatic orthostatic hypotension after the first dose of losartan. No predisposing condition that might account for this dramatic response was detected; pretreatment PRA values in this patient were less than 0.5 ng Ang I/mL per hour. One patient in the placebo group had an exacerbation of coronary artery disease; another patient in this group discontinued because of arm pain and elevated blood pressure.
We also examined 24-hour urinary excretions of sodium, potassium, protein, and creatinine for trends of potential clinical significance. No such trends were discovered. Similarly, serum sodium did not change. Serum potassium tended to increase within the enalapril treatment group (0.3 and 0.5 mmol/L at weeks 2 and 6, respectively; P<.01) but not in the 100-mg losartan group (0.0 and 0.2 mmol/L increases at 2 and 6 weeks, P<.05, versus enalapril at week 6).
The principal objective of this study was to investigate the effects of losartan on the RAAS compared with enalapril and placebo in hypertensive patients. Of primary interest were changes in the more proximate mediators of the RAAS, renin and Ang II. Of secondary interest were changes in aldosterone, an adrenal steroid under the control of Ang II, and catecholamines, a possible index of sympathetic nervous system activation in response to RAAS inhibition.
In planning this study, we considered a number of prior observations. In studies in hypertensive patients, it had been shown that losartan doses of 50 to 150 mg/d reduced blood pressure and increased PRA.8 10 11 Furthermore, in healthy subjects, losartan administration was associated with increases in plasma Ang II sufficiently high (40 to 50 pg/mL 6 hours after dosing ) to be considered to be active in the absence of angiotensin blockade.16 We therefore designed this study to explore these phenomena in hypertensive patients, with sampling conditions highly controlled to assure the accuracy of the assay results.
Under the conditions of this study, the plasma concentration versus time profiles for both losartan and its active metabolite were nearly identical after the first dose and 6-week administration, indicating that any changes in pharmacodynamic effects over the course of the study were unlikely to be a result of changes in circulating levels of Ang II antagonist. These results confirmed results of earlier studies in healthy subjects11 (Merck Research Laboratories, data on file). Furthermore, clinically important antihypertensive effects of the study treatments were clearly demonstrated. Focusing on SuDBP, 100 mg losartan and 20 mg enalapril showed similar efficacy at 2 and 6 weeks of treatment. At 6 weeks, both of these treatments showed clinically and statistically significant effects at trough. The 25-mg dose of losartan was less active than the 100-mg dose. The supine systolic blood pressure response to the study treatments was qualitatively similar to the SuDBP response. The average supine heart rate did not change to a clinically important degree.
Several characteristics of the SuDBP response to the 100-mg dose of losartan are worth noting, particularly compared with the response to the 20-mg dose of enalapril. The initial antihypertensive response to losartan was less pronounced than that to enalapril but was established by 2 weeks. The basis for the more gradual onset of effect of the receptor antagonist is unclear but probably represents a combination of several factors, including time to form the active metabolite (although losartan itself is a potent AT1 antagonist), distribution (possibly influenced by high protein binding19 ) of both losartan and its metabolite to the active site, the complexity of the antihypertensive effect (eg, vasodilator and antialdosterone effects, etc), and complex interactions with the receptor, so-called insurmountable antagonism.20 21 The 20-mg dose of enalapril showed a slightly greater antihypertensive effect than losartan. The mechanism of this difference is not defined, although enhancement of vasodilator effects of kinins by ACE inhibitors have been postulated but never clearly demonstrated to contribute to their antihypertensive activity. Clinically, it is unclear whether these differences in activity will result in different long-term outcomes. The less dramatic first-dose effect could make losartan a better tolerated drug, although one patient in this study did demonstrate an exaggerated first-dose response to 100 mg losartan. After the last dose of study treatment, there was no evidence of rebound hypertension.
Both losartan and enalapril produced the expected increases of PRA. These effects are most likely a result of blockade of the feedback receptor in the renal juxtaglomerular apparatus, as patients with greater antihypertensive responses to any of the study treatments did not demonstrate markedly enhanced PRA increases. For losartan, changes were dose related. Effects of losartan and enalapril on PRA were greater after 2 weeks of treatment than after the first dose.
One concern in planning this study was that blockade of the feedback receptor might result in structural changes in the juxtaglomerular apparatus that could lead to sustained, autonomous renin secretion. However, there was little evidence that usual mechanisms for control of renin release other than the feedback receptor were not operational during treatment with losartan or enalapril. A clear daily rhythm of PRA, coincident with peak and trough drug concentrations, was apparent during treatment with both drugs at 2 and 6 weeks. Autonomous secretion might be expected to result in more sustained increases of PRA during the dosing interval. In addition, during the washout period after the last dose of double-blind drug, PRA rapidly decreased to values no different from those in the placebo group. During treatment with losartan, the PRA effect actually attenuated from 2 to 6 weeks. Last, during both losartan and enalapril treatment, postural effects on PRA were still apparent.
We used highly specific6 14 HPLC-RIA methodology to measure Ang II. Losartan increased Ang II, particularly at 4 hours after dosing, with a time course qualitatively similar to that for changes in PRA: small effect after the first dose, large effect at 2 weeks, and attenuation of the effect at 6 weeks. A perspective on these results can be developed from comparing the increases achieved in this study with studies using Ang II infusions in which Ang II concentrations (by direct RIA) and responses were measured simultaneously. Thus, in our study at 6 weeks and 4 hours after dosing, the mean Ang II concentration had increased approximately 2.5-fold from a baseline of 2.6 pg/mL, an average near the threshold for pressor effects of Ang II described in earlier studies.22 23 24 Although some individuals demonstrated increases to concentrations that might be associated with more definite effects, only a single patient showed increases to a concentration that would be expected to be associated with a pressor effect of more than 10 mm Hg (ie, ≥50 pg/mL24 ). Furthermore, in this latter study, such increases in Ang II were associated with an approximate doubling of aldosterone concentration. Since the depressor response to losartan was similar at 2 and 6 weeks and since aldosterone concentrations were decreased at the times Ang II concentrations were greatest, it is reasonable to conclude that the AT1 receptor was effectively antagonized. If clinically relevant effects of AT2 receptor stimulation are identified and concentration-effect relations are defined for Ang II with respect to these effects, the current data will permit an assessment of the potential for clinical consequences of stimulation of this unblocked Ang II receptor. Expected reductions in Ang II associated with enalapril administration were also demonstrated at peak and trough after 6 weeks of treatment. Interestingly, as previously reported,25 ACE inhibition did not result in complete suppression of plasma Ang II.
It is noteworthy that the PRA and Ang II responses to losartan attenuated from 2 to 6 weeks. The mechanism for this observation is not obvious, particularly because effects of enalapril on PRA, which are presumably caused by the same mechanism as losartan, were similar at 2 and 6 weeks. One possibility is that endogenous substrate could be depleted.26 27 This hypothesis is being evaluated in a subsequent study. Regardless of mechanism, these data indicate that during long-term treatment with usual doses of losartan, hypertensive patients demonstrate limited increases in plasma Ang II concentrations. An open question remains as to whether Ang II changes at other sites of formation parallel changes in the plasma with respect to both extent of elevation and time course.
The magnitude of the increases in Ang II and PRA in this study was less than increases noted previously in healthy, young male subjects using the same methodology.6 These differences could be related to intrinsic differences between normotensive and hypertensive individuals, with hypertensive patients showing less effective feedback inhibition of renin release, hence less effect of inhibition of the feedback mechanism. This phenomenon has been demonstrated in “non-modulating” hypertensive patients.28 In addition, patients were considerably older than the healthy male volunteers, and it has been shown that resting PRA and Ang II tend to be reduced in older compared with younger volunteers.29 Furthermore, subjects in the prior study6 were modestly sodium restricted, which could have enhanced baseline and stimulated PRA.30 Nonetheless, it was somewhat reassuring that mean 10-fold increases in Ang II were not noted in the hypertensive patients who were maintained on their usual diet and who demonstrated a reasonable antihypertensive response to 100 mg losartan.
Both doses of losartan and enalapril resulted in a decrease in plasma aldosterone concentration. After 6 weeks of treatment with 100 mg losartan, as well as 20 mg enalapril, plasma aldosterone concentration measured 4 hours after dosing was reduced approximately 50%, with lesser effect at the 25-mg losartan dose. Decreases in trough concentrations were also apparent. Twenty-four–hour urinary aldosterone excretion tended to decrease during the study in the 100-mg losartan and 20-mg enalapril groups. However, changes in urinary aldosterone excretion were not as apparent as changes in plasma aldosterone. Thus, it appears that under the conditions of this study, the RAAS played only a partial role in the regulation of aldosterone secretion. Perhaps had the patients been more clearly renin dependent, eg, on a low salt diet, diuretic therapy, etc, blockade of the RAAS would have resulted in greater decreases in plasma aldosterone concentration, and urinary aldosterone excretion would have been more clearly reduced.
In conclusion, results of this study confirm the tolerability and antihypertensive activity of losartan, a selective, orally active AT1 receptor antagonist. The 100-mg dose of losartan and 20 mg enalapril are clinically equivalent in antihypertensive effect, whereas the 25-mg dose of losartan is less active. As expected, both losartan and enalapril increase PRA and decrease plasma aldosterone and have opposite effects on plasma Ang II. On the average, in these patients, even at the 100-mg dose of losartan, increases in Ang II are modest and insufficient to alter the effects of the drug on blood pressure or plasma aldosterone. There was no evidence for autonomous secretion of PRA during losartan or enalapril.
This study was supported by clinical grants from Merck Research Laboratories. The authors acknowledge Kathleen Lonergan and Sue Ann Duffy for preparing the data from this study for analysis; Nora Sene, Laura Coffey, and Ruth Swithenbank for programming the analyses; and Betty Jean Miller for assistance in typing the manuscript.
- Received June 20, 1994.
- Revision received August 10, 1994.
- Accepted September 20, 1994.
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