(Hypertension. 1995;25:602-609.)
© 1995 American Heart Association, Inc.
Articles |
Short-term and Sustained Renal Effects of Angiotensin II Receptor Blockade in Healthy Subjects
From the Division of Hypertension and Cardiovascular Research Group, Lausanne, Switzerland (M.B., M.H., J.N., J.B., B.W., H.R.B.) and Sanofi Recherche, Montpellier, France (C.A., R.B.).
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Abstract |
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Abstract We investigated the short-term and sustained hormonal and renal effects of angiotensin II (Ang II) receptor blockade in normotensive healthy volunteers. Twenty-four subjects maintained on a fixed sodium diet were randomized to receive for 8 days a placebo or 10 or 50 mg doses of the Ang II antagonist irbesartan (SR 47436, BMS 186295) according to a double-blind, parallel group design. Plasma renin activity, plasma immunoreactive Ang II and aldosterone levels, blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 8 hours after the first and eighth administration of each dose of irbesartan or placebo. Ang II receptor blockade with irbesartan induced a dose-dependent compensatory increase in plasma renin activity and plasma angiotensin levels and a significant decrease in plasma aldosterone levels. The compensatory rise in plasma renin activity and Ang II levels was more pronounced on day 8, reflecting a long duration of the blocking effect of irbesartan. Irbesartan induced small changes in blood pressure and did not significantly modify renal blood flow and glomerular filtration rate. However, a significant decrease in filtration fraction was observed during receptor blockade on days 1 and 8. The tubular effects of irbesartan were characterized by a dose-dependent increase in sodium and chloride excretions. Interestingly, the cumulative natriuretic response to Ang II receptor blockade was similar on days 1 and 8, suggesting that in these subjects, renal Ang II receptors are not blocked over 24 hours during repeated administration even though this antagonist has a long duration of action (t1/2 of 15 to 17 hours). Irbesartan had no significant effect on urinary potassium and uric acid excretions on days 1 and 8. Together, these results demonstrate that in healthy subjects the Ang II receptor antagonist irbesartan decreases filtration fraction and promotes urinary sodium excretion without affecting urinary uric acid excretion and that these renal hemodynamic and tubular effects are maintained during a repeated 8-day administration.
Key Words: receptors, angiotensin • angiotensin II • renal circulation • natriuresis • uric acid
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Introduction |
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The kidney is the major site where sodium and water balance is controlled. For this reason, it plays a pivotal role in the regulation of blood pressure (BP) and for many years has been a target of antihypertensive therapies. Thus, today, all antihypertensive drugs recommended as first-line therapy in essential hypertension act to some degree on the kidney. Diuretics are specifically designed to decrease sodium reabsorption in various segments of the nephron. Renal vasodilation and an increase in urinary sodium excretion have been reported after administration of calcium antagonists and probably contribute to the antihypertensive effect of these agents.1 2 The kidney is also the main source of circulating renin, which determines the plasma concentration of angiotensin II (Ang II). In turn, Ang II exerts an important influence on renal function through its hemodynamic, glomerular, and tubular effects.3 Inhibition of renin secretion is one mechanism whereby ß-blockers lower BP in hypertensive patients.4 Angiotensin-converting enzyme (ACE) inhibitors, which reduce Ang II generation, influence renal function profoundly.5 Indeed, short-term ACE inhibition increases renal blood flow (RBF) without affecting glomerular filtration rate (GFR); hence, filtration fraction decreases. ACE inhibitors also enhance both the absolute and fractional excretions of sodium. Finally, in animals and humans with chronic renal failure, ACE inhibitors exert a renoprotective effect, reducing the deterioration rate of GFR.5 6 7 8 This nephroprotection is seemingly related to a specific ACE inhibitor–induced decrease in glomerular capillary pressure resulting from an attenuation of the action of Ang II on the afferent and efferent arterioles of the glomeruli.6
Blockade of the Ang II type 1 (AT1) receptor is another way to block the renin-angiotensin system. In recent years, several specific, orally active Ang II receptor antagonists have been developed.9 In contrast to the first peptidic Ang II antagonist saralasin, the new nonpeptidic compounds are devoid of any partial agonistic effect. Moreover, these antagonists do not interfere with the metabolism of kinins.10 11 12 So far, the results of most animal and human studies performed with various Ang II antagonists suggest that the renal effects of these compounds are comparable to those of ACE inhibitors.13 But in some circumstances, the renal response to receptor blockade appears to differ from that induced by an ACE inhibitor, implying a role of bradykinin or other peptides in mediating some of the effects of ACE inhibitors.14 15 In a recent study, we have shown that a single administration of the Ang II antagonist losartan induces in healthy subjects an increase in urinary sodium excretion and a marked rise in uric acid excretion, with no significant change in renal hemodynamics.16 The natriuretic response was more pronounced in salt- depleted subjects with a stimulated renin-angiotensin system than in salt-repleted volunteers. So far, nobody has evaluated the long-term renal effects of Ang II receptor antagonists in normotensive subjects or hypertensive patients with a normal renal function. Thus, whether the renal tubular effects of Ang II receptor blockade are maintained after repeated administrations is still unknown.
The purpose of the present study was therefore to evaluate the renal glomerular and tubular effects as well as the hormonal consequences of a sustained blockade of Ang II receptors and in particular to assess the long-term natriuretic response. For this purpose, normotensive volunteers were randomized to receive for 8 days a placebo or one of two doses (10 or 50 mg) of the new Ang II antagonist irbesartan (SR 47436, BMS 186295) according to a double-blind, parallel group design. Irbesartan is a long-acting Ang II antagonist (t1/2 of 15 to 17 hours) that has been shown to block the BP response to exogenous Ang II. With the 50-mg dose, some inhibition of the Ang II response was still present 36 hours after drug intake.17 In healthy subjects, 50 and 100 mg were comparable in terms of Ang II receptor blockade.17 Unlike losartan, irbesartan does not require active metabolite formation for sustained efficacy.
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Methods |
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Twenty-four healthy white male volunteers aged 19 to 39 years (mean, 25.4) weighing 70.3±1.7 kg participated in this study. Each volunteer had a medical history taken and underwent a complete physical examination. Their baseline systolic and diastolic BPs were 114.2±2.0 and 71.9±1.9 mm Hg, respectively. Routine laboratory tests were done before and after drug administration. The nature and purpose of the study had been explained, and written informed consent had been obtained previously from each subject. The protocol was approved by the Hospital Ethics Committee.
Study Design
To reduce intersubject variability, the volunteers were studied
on a fixed sodium diet containing 100 mmol sodium and 3500 calories per
day. The diet was begun 8 days before drug administration and was
maintained during the next 8 treatment days. The diet was provided
under the supervision of a dietitian by the hospital restaurant where
the subjects ate all their meals. Diet compliance was evaluated by
repeated 24-hour urine collections.
On day 1 (after 1 week of diet), the volunteers came to the hospital at 7 AM after an overnight fast to undergo clearance studies. On arrival, they were made comfortable on a bed. They remained supine, except for voiding, and fasted throughout the study procedure. Two intravenous catheters were inserted into antecubital veins, one for the infusion of inulin and p-aminohippurate (PAH) in a glucose/saline solution and a second into the contralateral forearm for blood drawing.
Between 7 and 8 AM, the volunteers drank an oral water load of 5 mL/kg. After a priming dose, the intravenous infusion of inulin and PAH was started; the infusions were calculated to provide plasma concentrations of approximately 400 and 20 µg/mL, respectively. The volunteers were asked to empty their bladders every 60 minutes. After each voiding, a fixed amount of water (200 mL) was given orally to sustain urine output. After a 2-hour equilibration period, baseline measurements were performed until the volunteers were in a steady state. The steady state was reached when the difference in volume of two consecutive urine collections was within 1 mL/min. At the end of the baseline period (T0), the volunteers were randomized to receive in a double-blind fashion placebo (n=8) or 10 mg (n=8) or 50 mg (n=8) of the Ang II antagonist irbesartan.
BP, heart rate, urinary electrolyte excretion, and clearances of inulin and PAH for assessment of GFR and RBF, respectively, were measured at 60-minute intervals for 8 hours after drug intake. BP was obtained with subjects in the supine position and was measured by the conventional auscultatory method. Blood samples for the measurement of electrolytes were also drawn hourly. Blood samples for the determination of plasma renin activity (PRA) and plasma Ang II and aldosterone levels were drawn with subjects in the supine position before and every 2 hours after drug intake.
On study days 2 to 8, the doses of placebo or irbesartan were administered at 8 AM. BP and heart rate were measured with subjects in the supine position before the drug was given. Twenty-four-hour urine collections were repeated on days 2, 4, and 6 during treatment. On day 8, renal clearances were repeated as on day 1.
Drugs and Chemicals
Irbesartan was provided by Sanofi Recherche. Inulin
(Inutest) was purchased from Laevosan Gesellschaft and PAH
(Nephrotest, sodium salt of PAH) from Biologische Arbeitsgemeinschaft
GmbH.
Analytic Methods
Plasma and urinary inulin concentrations were measured by a
microadaptation of a diphenylamine procedure on an autoanalyzer
(Technicon).18 PAH concentrations were determined by
spectrophotometry (model 700, Beckman Instruments).19
Plasma and urinary sodium, potassium, and chloride concentrations were
analyzed with selective electrodes (Hel-ISE, Beckman). Calcium,
phosphate, uric acid, and magnesium were quantified photometrically
(RAXT, Technicon). Endogenous trace lithium was measured by
electrothermal absorption spectrophotometry (atomic absorption
photometer Nr 1100 B, Perkin-Elmer) as described by Magnin et
al20 and Miller et al.21
Aldosterone was measured by a direct radioimmunoassay.22 For the determination of PRA, generated Ang I was trapped and measured by high-affinity antibodies.23 For the measurement of immunoreactive plasma Ang II levels, a new method using monoclonal antibodies against Ang II was used.24
Renal Parameters and Statistical Evaluation
Clearances (C) were calculated by the traditional method using
the formula
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where Ux and Px represent urine and plasma concentrations of x, and V is the urine flow rate in milliliters per minute. Fractional excretion (FEx) was calculated as the clearance of x divided by the clearance of inulin or GFR (Cx/GFR). Plasma concentrations used for clearance determinations were calculated by averaging initial and final values of each clearance period. Filtration fraction was calculated as the ratio of inulin and PAH clearances (GFR/RBF). Absolute distal reabsorption of sodium (ADRNa) was estimated by the difference between the clearances of lithium and sodium multiplied by the plasma concentration of sodium (CLi-CNa) · plasmaNa/100. The absolute rate of proximal reabsorption (PRRNa) of sodium was estimated as (GFR-CLi) · plasmaNa/100.
All results are expressed as mean±1 SEM. The statistical significance of differences was evaluated by ANOVA for repeated measurements, with a value of P<.05 as the minimum level of significance. The 4- and 8-hour areas under the curve (AUC) were also calculated for each parameter followed by Duncan's test. We looked for significant changes within and between groups.
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Results |
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After 8 days of diet, the three groups of volunteers were comparable in terms of age, body weight, systolic and diastolic BPs, and heart rate. The values of the last 24-hour urinary sodium excretion before day 1 were 98.9±8 mmol/d in the placebo group and 101.5±8.9 mmol/d in the 10-mg and 98.6±10.7 mmol/d in the 50-mg irbesartan groups. There were no biochemical or hormonal differences between the groups at baseline. Irbesartan administration was well tolerated by all subjects, and no significant clinical or laboratory side effects were observed.
Short-term and Sustained Hormonal Effects
Fig 1 shows the effects of a single dose of and
8-day treatment with irbesartan on PRA, plasma immunoreactive Ang II,
and aldosterone levels. On day 1, significant and dose-dependent
increases in PRA and immunoreactive Ang II levels were observed with
the two doses of irbesartan, whereas no change was found in the placebo
group. On day 8, PRA and plasma Ang II were already elevated before
drug administration. A further dose-dependent rise occurred on
administration of the Ang II antagonist. In the placebo group, plasma
aldosterone decreased significantly throughout the study on day 1 as
well as on day 8, corresponding to the expected circadian rhythm of
aldosterone secretion (Fig 1). After administration of the first
irbesartan dose (day 1), the fall in plasma aldosterone occurred
earlier than in the control group, with a significant decrease in
aldosterone levels 2 hours after drug intake. In contrast to PRA and
Ang II, aldosterone levels were comparable at time 0 of days 1 and 8.
The drug-induced changes in plasma aldosterone were also similar on
days 1 and 8.
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indicates placebo (n=8); 
, 10 mg
irbesartan (n=8); and 
, 50 mg irbesartan (n=8).
*P<.05, **P<.01 vs time 0 of the same day;
#P<.05 vs time 0 of day 1.
Short-term and Sustained Systemic and Renal Hemodynamic Effects
Table 1 shows short-term and sustained variations
in systemic and renal hemodynamics. On day 1, a significant decrease in
systolic, diastolic, and mean BP values was found with 50 mg
irbesartan. Systolic BP decreased by -3.4±1.3 mm Hg at 2 hours
(P=.03 versus T0) and by -5.9±2.5 mm Hg at 5
hours (P=.05 versus T0). Similarly, diastolic BP
decreased by -4.2±1.5 mm Hg at 2 hours (P=.029 versus
T0) and by -9.9±1.3 mm Hg at 5 hours
(P=.0001). No significant change in BP was found with the
low dose of irbesartan or with placebo. The comparison between the
three groups using a statistical analysis of the 8-hour AUC
demonstrated that only the decrease in systolic BP observed after 50 mg
irbesartan was significantly different from placebo. No change in heart
rate was observed with either dose. On T0 of day 8,
systolic and diastolic BPs were slightly but not significantly lower
than on T0 of day 1 (-3.63±2.3 and -1.56±3.4 mm Hg for
systolic and diastolic BPs, respectively). After the eighth
administration, neither 10 nor 50 mg irbesartan reduced BP in these
normotensive volunteers.
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Decreases in GFR were observed after administration of placebo as well as after the two doses of the Ang II antagonist and were similar on days 1 and 8. Although, the fall in GFR tended to be more pronounced with the 50-mg dose of irbesartan, the comparative analysis of the AUCs demonstrated no significant difference between the three groups (Table 1). On day 1, RBF did not vary in response to the placebo or to the 10- and 50-mg doses of irbesartan. On day 8, however, RBF increased significantly with the 50-mg dose (P=.03) compared with the 10-mg dose and placebo. Owing to the slight decrease in GFR and the simultaneous increase in RBF, filtration fraction was significantly reduced by the Ang II antagonist. After the first administration, the reduction in filtration fraction was significant with the 50-mg dose only (P=.03), whereas on day 8, a statistical significance was achieved for both the 10- and 50-mg doses of irbesartan (P=.02) (Fig 2).
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Short-term and Sustained Effects on Fluid and Solute Excretions
Table 2 summarizes the renal tubular effects of
irbesartan. The Ang II antagonist had no diuretic action. However, as
shown in Fig 3, irbesartan had a significant and
dose-dependent natriuretic effect on day 1. The peak natriuresis was
obtained 2 hours after drug intake. The effect persisted for several
hours but was not different from placebo 8 hours after administration.
Between days 1 and 8, body weight did not change significantly in the
placebo group (from 72.1±1.9 to 72.7±2.8 kg) or in the 10-mg (from
70.3±4.0 to 68±3.6 kg) and 50-mg (from 66.4±3.1 to 65.9±3.0 kg)
irbesartan groups. As shown in Table 3, 24-hour urinary
sodium excretion values during treatment on days 2, 4, and 6 were not
significantly different between the three groups although a
dose-independent increase in natriuresis was found on day 2. On day 8,
the short-term natriuretic response to irbesartan was still present
and exhibited the same time profile as on day 1. Although it appears to
be blunted compared with day 1, the cumulative 8-hour sodium excretion
was comparable on days 1 and 8 (Fig 3). Similarly to urinary sodium
excretion, the fractional excretion of sodium increased significantly
in a dose-related manner after irbesartan administration, whereas no
change was found with placebo (Table 2).
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The clearance of endogenous lithium was determined as an index of proximal sodium reabsorption. No significant variation in lithium clearance or fractional excretion of lithium was observed with placebo or 10 mg irbesartan (Table 2). However, with the 50-mg dose of irbesartan, which induced the most significant change in sodium excretion, a decrease in the proximal rate of sodium reabsorption was found, with no change in absolute distal reabsorption of sodium, suggesting an effect on the proximal tubule with no compensation from the distal segments (Fig 4). On day 8, the decrease in proximal reabsorption was still observed after administration of 50 mg irbesartan.
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The pattern of changes in chloride excretion in response to irbesartan was very similar to that of sodium excretion. Indeed, the Ang II antagonist induced a significant and dose-dependent increase in urinary chloride excretion on days 1 and 8, with a peak effect at 2 hours. A transient increase in potassium excretion was observed during the first 2 hours after irbesartan administration, but the changes did not reach statistical significance even at peak effect (Table 2). No significant change in uric acid excretion was observed after administration of the antagonist (Table 2). Irbesartan induced a transient nonsignificant increase in calcium excretion but only after the first administration. Urinary phosphate excretion tended to increase in all three groups. However, the changes in phosphaturia were never significant from baseline with placebo, whereas they increased significantly with the two doses of the antagonist. There was no clear dose dependency as the phosphate response to 10 mg irbesartan was as large if not larger than that observed with 50 mg (Table 2).
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Discussion |
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The results of the present study demonstrate that the Ang II receptor antagonist irbesartan given acutely decreases BP and filtration fraction and increases urinary sodium excretion. The changes in filtration fraction and the natriuretic response to irbesartan were still present after a repeated 8-day administration, suggesting a persistence of the renal effects of the Ang II antagonist. In contrast to losartan, this new receptor antagonist had no effect on renal uric acid and potassium excretions.
Hormonal Effects
As expected from the results of earlier studies conducted with the
peptidic analogue saralasin or the nonpeptide antagonist
losartan,16 25 26 27 irbesartan induced a dose-dependent
compensatory increase in PRA and immunoreactive Ang II levels. The
rises in PRA and plasma Ang II levels were not only dose dependent but
also time dependent. The compensatory increase appears to be more
pronounced on day 8 than on day 1. Yet the percent increases in PRA and
Ang II are comparable on days 1 and 8. More importantly, during
repeated administration, PRA and plasma immunoreactive Ang II were
clearly increased before the last dose of the antagonist. This pattern
of hormonal response probably reflects the long duration of the
blocking effect of irbesartan.17 It could also indicate a
"turning on" of the renin synthesis over the 8-day treatment
period caused by a drug-induced salt depletion. A decrease in plasma
aldosterone levels during Ang II receptor blockade has been sometimes
difficult to demonstrate in human subjects.26 27 In the
present evaluation, a clear decrease in plasma aldosterone levels
that was not present in the placebo group was observed 2 hours
after irbesartan administration. This suggests that irbesartan reduces
plasma aldosterone and that this effect is more pronounced with the
50-mg than the 10-mg dose.
Hemodynamic Effects
In contrast to previous studies with other Ang II antagonists,
irbesartan decreased systolic and diastolic BPs in our normotensive
subjects after the first administration.26 27 This fall in
BP was observed only with the 50-mg dose of irbesartan and was
surprising. Indeed, in our hands, blockade of the
renin-angiotensin-aldosterone system of normotensive subjects with ACE
inhibitors or Ang II receptor antagonists is generally associated with
hardly any change in BP. There are two potential explanations of why
this BP reduction was observed. The first concerns the technical
aspects of the study. As in previous protocols, BP was always measured
with subjects in the supine position. However, in contrast to most
studies, the subjects were maintained on a fixed, moderately
salt-restricted diet (100 mmol sodium/d). Moreover, the water load
given in the morning of the study day has been considerably reduced (5
mL/kg). The degree of volume expansion might be an important factor
modulating the BP response during salt depletion. Indeed, in a previous
study, we found that losartan caused no reduction in BP in
salt-depleted subjects (50 mmol sodium/d) studied under
water-loaded conditions (12 mL/kg water load), whereas other
researchers have reported a fall in BP after administration of the same
dose of losartan to salt- and water-depleted
volunteers.16 28
The second possible explanation for the short-term hypotensive effect of irbesartan at the high dose may reside in its efficacy. In vitro studies have shown that the affinity of irbesartan for the Ang II receptor is of the same order of magnitude as that of saralasin but 10-fold higher than that of the mother compound of losartan (DuP 753).29 30 In conscious dogs and monkeys, irbesartan was also more potent in antagonizing the Ang II pressor response than DuP 753.30 Thus, the short-term effect of irbesartan on BP may be linked to a higher efficacy in blocking the renin-angiotensin system. Surprisingly, the hypotensive response to irbesartan did not persist during repeated administration and was not observed on day 8. This would imply that compensatory mechanisms had been activated to maintain BP. Heart rate did not increase during repeated administration of the Ang II antagonist and therefore did not contribute to offsetting the fall in BP. As will be discussed below, alterations in the renal response to Ang II receptor blockade may perhaps explain the lack of long-term BP changes.
Blockade of the renin-angiotensin system with ACE inhibitors or Ang II antagonists generally results in an increase in RBF with no change in GFR unless subjects or animals are salt depleted.16 31 32 33 In the present study, irbesartan caused a slight increase in RBF with no significant change in GFR. This might suggest that there is a difference between the hemodynamic and tubular response to Ang II receptor blockade. It is very unlikely that this is the case, and technical aspects must be considered to explain the apparent discrepancy between the hemodynamic and natriuretic response. Indeed, determination of GFR and RBF is subject to a large interindividual variability and this variability is greater than that observed with sodium excretion. Thus, because of the small number of volunteers in each group, the changes in GFR and RBF did not reach statistical significance. Yet irbesartan has a direct effect on renal hemodynamics, as demonstrated by the significant drug-induced changes in filtration fraction. This latter effect occurred simultaneously with the changes in sodium excretion and was maintained during long-term administration. In this respect, these results indicate that the renal response to Ang II receptor blockade in normotensive subjects is comparable to that obtained in previous studies with ACE inhibitors. In a recent study, Gansevoort et al34 have also found a decrease in filtration fraction in patients with chronic renal failure treated with losartan. These results are in accordance with the observation that Ang II antagonists are able to block both the afferent and efferent vasoconstrictor responses to Ang II.35 The decrease in filtration fraction caused by the Ang II antagonist might have important clinical implications in terms of renal protection as it might contribute to a decrease in proteinuria in patients with diseased kidneys.
Tubular Effects
Several studies have demonstrated that the short-term
administration of an ACE inhibitor or an Ang II receptor antagonist is
associated with a transient increase in urinary sodium
excretion.16 36 37 38 39 Yet whether this natriuretic response
persists during sustained blockade of the renin-angiotensin system has
never been investigated in humans. The results of the present study
confirm this general observation, as the first administration of
irbesartan induced a dose-dependent natriuresis. This natriuretic
response achieved its peak at approximately 2 hours. Six to 8 hours
after drug intake, sodium excretion was still increased compared with
baseline but was not different from placebo, thereby suggesting that
the effect is only transient. As observed in previous studies, the
changes in sodium excretion appear to result from direct tubular
effects of the receptor antagonist, as no increase in GFR was
observed.
A priori, one would expect that the natriuretic response decreases during repeated administration as the subjects enter into a new sodium balance. To our surprise, the changes in urinary sodium excretion caused by irbesartan were similar on days 8 and 1, suggesting a persistence of the tubular effects during long-term administration. Under treatment, on days 2 to 8, 24-hour urinary sodium excretion was not different between the three groups although a slight but not significant increase in natriuresis was found on day 2. This observation leads to several important comments. First, if the subjects respond to each daily administration of irbesartan by an increase in sodium excretion, this increase should result in either a fall in BP or decrease in body weight as the volunteers become progressively salt depleted. In fact, this was not the case because neither body weight nor BP varied during sustained Ang II receptor blockade. This lack of change almost necessarily implies that the subjects went through sodium-retaining phases after the daily natriuretic responses. Sodium retention might have occurred during the night. This may indicate that the kidney somehow escapes to the blockade of Ang II receptors and regulates sodium excretion by Ang II–independent mechanisms to preserve sodium balance or that blockade of renal Ang II receptors does not last throughout the day.
In this respect, the second important point is the apparent discrepancy between the long duration of action of the Ang II antagonist (t1/2 of 15 to 17 hours) and the transient pattern of the natriuretic response.17 As such, these results are very similar to those obtained with losartan, another Ang II antagonist with a long duration of action, which induces only a transient increase in sodium excretion.16 26 This discrepancy seems to be even more evident during repeated administration when Ang II receptor blockade is apparently maximal. The natriuretic effect on day 8 is most likely explained by a further blockade of some or all renal Ang II receptors, implying again that renal Ang II receptors are not blocked over 24 hours even during repeated administration. In accordance with this hypothesis is the observation that filtration fraction, which decreases on administration of the antagonist on day 1, is not decreased before administration of the eighth dose of the antagonist. If this hypothesis holds true, PRA and plasma Ang II levels would not be accurate indexes of the actual degree of blockade of renal Ang II receptors.
Recent in vitro and animal studies have suggested that the renal tubular effects of Ang II antagonists are due to decreased fluid and sodium reabsorption in the proximal segments of the nephron.36 37 Yet the postproximal nephron segments may also contribute to the natriuretic response induced by the blockade of the renin-angiotensin system, as Ang II receptors have been localized in the outer medulla.40 Moreover, decreases in plasma aldosterone levels may contribute to enhancing sodium excretion in the distal tubule.
In humans, the localization of the natriuretic effect within the nephron has been more difficult to determine with precision. Using endogenous lithium as the best actual marker of proximal sodium reabsorption, we have recently shown that losartan enhances sodium excretion mainly via an effect on postproximal tubules, but a proximal effect could not be ruled out because subjects received an important water load.16 In the present study, the subjects were given only a moderate water load, which increased urine output to 5 to 6 mL/min. With this protocol, the Ang II antagonist irbesartan decreased the proximal reabsorption rate of sodium on the first and last days of treatment, indicating an effect on the proximal tubule. However, because of the rather small number of subjects in each group and the large variability between volunteers, this effect was significant only with the highest dose of irbesartan, which caused the more pronounced change in sodium excretion. In accordance with a proximal tubular effect, a concomitant increase in urinary phosphate excretion was found after administration of 50 mg irbesartan.
As reported with losartan, postproximal segments of the nephron appear to contribute to the natriuretic response to Ang II receptor blockade.16 Indeed, if sodium reabsorption decreases in the proximal tubule, sodium delivery into the distal segments increases and should lead to a compensatory rise in distal sodium reabsorption. In the present study, no compensatory increase in the absolute distal reabsorption of sodium was found. This is compatible with a contribution of postproximal nephrons to the natriuretic response to Ang II receptor blockade.
In contrast to losartan, irbesartan had no influence on urinary uric acid and potassium excretions.16 41 The lack of a uricosuric effect of irbesartan further supports the general idea that the increase in uric acid excretion induced by losartan is not directly linked to the inhibition of the renin-angiotensin system and rather represents a direct tubular effect of the mother compound losartan. Regarding potassium excretion, a transient nonsignificant increase in urinary potassium was observed during the first hours after irbesartan administration. This transient change in potassium handling most likely results from the increased sodium delivery into the distal tubule.
Taken together, these results demonstrate that in healthy subjects, the Ang II receptor antagonist irbesartan decreases filtration fraction and promotes urinary sodium excretion without affecting urinary potassium and uric acid excretions. These renal hemodynamic and tubular effects are maintained during a repeated 8-day administration. This latter observation suggests that although irbesartan has a long duration of action, renal Ang II receptors are perhaps not blocked throughout the day. The daily natriuretic response to the Ang II receptor may therefore be blunted by daily compensatory phases of sodium retention. Whether higher doses of irbesartan would provide renal Ang II blockade for the entire day was not assessed in this study and should be investigated. In addition, for evaluation of the clinical relevance of the repeated natriuretic response to Ang II receptor blockade, similar studies should be conducted in hypertensive patients in whom alterations of renal sodium handling have been reported.42
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Acknowledgments |
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This work was supported by Sanofi Recherche, Montpellier, France.
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Footnotes |
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Reprint requests to M. Burnier, MD, Division of Hypertension, CHUV, Av P Decker, 1011 Lausanne, Switzerland.
Received August 1, 1994; first decision September 23, 1994; accepted December 21, 1994.
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