(Hypertension. 1997;30:240-246.)
© 1997 American Heart Association, Inc.
Articles |
Renal Hemodynamic Response to an Angiotensin II Antagonist, Eprosartan, in Healthy Men
From the Departments of Medicine and Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.
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Abstract |
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Abstract In view of the vasodilator potential of angiotensin-converting enzyme (ACE) inhibition via prostaglandins and kinins, we asked why renin inhibition induces a larger renal vasodilator response than ACE inhibitors in healthy humans in earlier studies. One possibility was that there was a more complete blockade of the renin system, which could also be achieved by an angiotensin II antagonist, eprosartan. We measured the hormonal and renal hemodynamic responses to eprosartan doses, from 10 to 400 mg in 9 healthy young men in balance on a 10-mmol/d sodium intake. The threshold eprosartan dose to influence renal perfusion was <10 mg, and the 100-mg dose induced a near-maximal vasodilator response of 135±19.7 mL · min-1 · 1.73 m2. When the dose was increased to 400 mg, there was a modest additional increase of 147±57 mL · min-1 · 1.73 m–2. A highly significant dose-related fall in arterial blood pressure occurred (r=-.97; P<.001), with no indication of a maximal response at 400 mg. In 6 additional subjects, we compared responses to eprosartan on a high salt and a low salt diet. The renal response to 200 mg eprosartan on a high salt diet, 26.0±6.6 mL · min-1 · 1.73 m–2, was significantly less than that seen with the low salt diet (P<.001). There was no renal partial agonist angiotensin-like effect of eprosartan. Eprosartan reduced sharply the pressor, renal vascular, and hormonal responses to exogenous angiotensin II. The renal vasodilator response to the angiotensin II antagonist eprosartan closely resembles responses to renin inhibition and exceeds previously reported responses to ACE inhibitors. Thus, eprosartan probably exerted its effect via the angiotensin receptor. More complete blockade of the renin system can be achieved by pharmacological interruption at this level, a finding that could have therapeutic implications.
Key Words: angiotensin II • aldosterone • renin • antihypertensive agents • renal circulation
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Introduction |
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Angiotensin-converting enzyme inhibitors—until recently the only agents available for pharmacological interruption of the RAS in humans—have contributed substantially to our understanding of hypertension, congestive heart failure, and the pathogenesis of kidney injury.1 2 3 4 ACE inhibition blocks an enzyme that is also involved in kinin metabolism and thereby influences the prostaglandin and nitric oxide pathways.5 6 7 8 Thus, ACE inhibition could lead to more renal vasodilation than a renin inhibitor via an added renal vasodilator contribution of kinins and prostaglandins.9 10 11 However, in recent studies that compared ACE and renin inhibition in humans, the renal vasodilator response to renin inhibition was 50% greater.12 13 14 The greater renal response has been attributed to nonspecific vasodilator action, better tissue penetration of these highly lipophilic agents, or a more effective renin system blockade.15 16 17 Our premise was that if an Ang II antagonist18 19 induced a renal vascular response to match that induced by renin inhibitors in earlier studies performed with an identical protocol in healthy persons in balance on a sodium intake of 10 mmol,12 13 14 the response probably reflects reversal of Ang II–induced renal vasoconstriction. The consequence would be that the renal response to ACE inhibitors had underestimated the contribution of Ang II to renal vascular tone. More effective blockade with the newer agents would also introduce the potential for an enhanced therapeutic impact at the renal level.
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Methods |
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Subjects and Protocols
The subjects, 15 healthy men who ranged in age from 24 to 48 years (33.5±1.8 years), were free of cardiovascular, renal, and endocrine diseases, and all were within 20% of ideal body weight (mean body mass index, 25.4±0.6 kg/m2). After an outpatient evaluation, they were admitted to a metabolic ward for a 10-day inpatient study. The protocol was approved by the human subjects committee of the institution, and written informed consent was obtained from each subject.
Our first goal was to assess the relation between the dose of eprosartan, an Ang II antagonist, and changes in renal perfusion in healthy normal subjects. The subjects were in balance on a 10-mmol sodium diet to activate the RAS, a model we have used for more than 20 years to assess renal vascular responses to pharmacological interruption of the renin system.12 13 14 20 Our second goal was to assess the influence of salt intake on the renal vascular response to eprosartan. Our final goal was to assess the influence of the eprosartan dose at the top of the dose-response curve on renovascular, hormonal, and pressor responses to Ang II.
Protocol A
Nine subjects were placed on a low salt isocaloric diet with a
daily sodium intake of 10 mmol. Daily dietary potassium (100
mmol) and fluid intake (2500 mL) were constant. Twenty-four-hour urine
samples were collected daily and analyzed for sodium,
potassium, and creatinine. When 24-hour urine sodium
matched sodium intake, the first study was initiated.
On each study day, an intravenous catheter was placed in each arm of each subject, one for infusion and the other for blood sampling. The subjects were supine and had been fasting for at least 8 hours. Subjects were given successively greater single ascending oral doses of eprosartan, from 10 to 400 mg. Each subject received three different doses, one on each of 3 experimental days, each separated by a rest day. Each study day began at about 7 AM with a bolus and then a 60-minute baseline infusion of PAH and inulin before drug administration, which continued for 5 to 6 hours after drug administration. Hormonal and triplicate RPF measurements were made at baseline and at six to eight time points over 5 to 6 hours.
Protocol B
Another 6 subjects were studied when in balance on a low salt
and again on a high salt (200 mmol sodium) diet to compare renal
vascular and hormonal responses to eprosartan. A second objective in
Protocol B was to examine the influence of eprosartan on renal
vascular, pressor, and hormonal responses to Ang II. There were three
study days, two when balance had been achieved on a low salt diet and
one when balance had been achieved on a high salt diet. In 3 of the 6
subjects a high salt diet was employed first, followed by the low salt
study. In the other 3, who were selected randomly, the sequence was
reversed. When the latter sequence was employed, the transition from
the low salt to the high salt state was facilitated by the infusion of
2 L of normal (0.9%) saline at the beginning of the transition. This
maneuver returns renal vascular responses to the state associated with
high salt balance in about 4 hours.21
On one of the two low salt days and on the high salt day after baseline measurements of hormone profile and hemodynamics, the subjects received a single 200-mg eprosartan dose. On the other low salt day, the subjects received a matching placebo tablet. After the hemodynamic and hormonal responses to the Ang II antagonist had been evaluated for 135 minutes, the blockade of Ang II was assessed on the two low salt study days by the infusion of graded Ang II doses of 1 and 3 ng · kg-1 · min-1 for 45 minutes each. The rationale for the selection of dose and duration of these infusions of Ang II (Hypertensin, Ciba-Geigy) has been described in detail.22 23
Blood pressure was recorded during each infusion using an automatic recording device (Dinamap, Critikon) at 5-minute intervals during the treatments; during the Ang II infusion, recordings were made every 2 minutes. All blood pressure data are expressed as the mean of three readings surrounding a time point. The electrocardiogram was monitored continuously.
Renal Clearance Studies
PAH (Merck Sharp and Dohme) and inulin (Inutest Polyfructosan;
Laevosan-Gesellschaft) clearances were assessed after
metabolic balance had been achieved. A control blood sample
was obtained, and then loading doses of PAH (8 mg/kg) and inulin
(50 mg/kg) were given. A constant infusion of PAH and inulin was
initiated immediately at a rate of 12 mg/min for PAH and 30
mg/min for inulin with an IMED pump (IMED Corp) to achieve
plasma PAH concentration in the middle of the range in which tubular
secretion dominates excretion. Basal PAH and inulin clearances were
calculated from their plasma levels and infusion rates for each
substance. Plasma samples reflecting the control clearances were
obtained 60 minutes after the start of the PAH-inulin infusion, when a
steady state had been achieved, and at 45-minute intervals
thereafter.
Laboratory Procedures
Blood samples were collected on ice and spun immediately, and
the plasma was frozen until assay. Serum and urinary sodium and
potassium levels were measured using flame photometry. Serum
creatinine, PAH, and inulin were measured using an
autoanalyzer. PRA, cortisol, and aldosterone were
assayed by radioimmunoassay techniques as described.24 25
To limit selection bias, data review was made without reference to
dose, time, or specific protocol.
Statistics
Group means are presented with the SEM as the index of
dispersion. Aldosterone values for one patient in protocol
B were deleted from analysis by Chauvenet's
criterion.26 ANOVA was used to assess dose-response
relationships. The Wilcoxon rank sum test was used to compare
renal hemodynamic responses on different salt diets in
similar subjects. For renal clearance data, the predrug value was
calculated as the average of two determinations at baseline, and we
defined the peak renal vascular response as the average of the two
highest sequential values for PAH clearance.
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Results |
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Baseline renal sodium excretion and the state of the renin-angiotensin-aldosterone system followed changes in sodium intake as anticipated (Table 1
). Sodium excretion was less than
25 mmol/d in each subject studied on a low salt diet and
exceeded 150 mmol/d in those on the high salt diet. There
were no differences in baseline parameters in the two
groups when they were studied on low salt diets, and there were no
significant baseline hormonal and renal hemodynamic
status fluctuations on different days of the study.
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Low Salt Diet
Hemodynamics
RPF rose significantly, and in a dose-related manner, with the Ang
II antagonist eprosartan (Fig 1). The threshold response was below 10
mg, and the response was progressive to a maximum increase of 147±57
mL · min–1 · 1.73 m–2 at the
400-mg dose. The renal vasodilator response was very near maximum at
100 mg (135±19.7 mL · min–1 · 1.73
m–2) and 200 mg (137±17.2 mL ·
min–1 · 1.73 m–2). The Ang II
antagonist had no effect on inulin clearance (Table 2), so a dose-related decrease in
filtration fraction was noted (P=.0006).
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The mean arterial blood pressure nadir was usually achieved
within 135 minutes after eprosartan administration, and the change at
this time was used as the index of the response. Eprosartan induced a
highly significant dose-related fall in blood pressure
(r=-.97; F=266; P<.001). The threshold was
above 10 mg, and there was no indication that a maximal response had
been achieved with the highest eprosartan dose used (Fig 1
).
Hormone Responses
The administration of the Ang II antagonist eprosartan
in the subjects in balance on a low salt diet led to an anticipated
increase in PRA and a decrease in plasma aldosterone levels
(Table 3). Peak renin values were reached
in about 2.5 hours, and by 24 hours PRA had returned to baseline.
Baseline measurements of PRA indicated that there was no cumulative
effect of the drug. The smallest dose used, 10 mg, had no effect on
PRA. There was a significant correlation between eprosartan dose and
the increase in PRA concentration for doses between 50 and 200 mg
(r=.93; F=22.3; P<.01). In the 6 subjects who
received placebo while in low salt balance, PRA was unchanged between
baseline 1.1±0.3 ng · L-1 · s-1
(4.0±1.2 ng Ang I · mL-1 · h-1) and 135
minutes 1.1±0.3 ng · L-1 · s–1
(4.0±1.1 ng Ang I · mL–1 ·
h-1); conversion for PRA is nanograms of Ang I per
milliliter per hourx0.2778=nanograms per liter per second. However,
when the same subjects received eprosartan (200 mg), PRA increased
significantly from baseline 0.9±0.2 ng · L–1
· s–1 (3.2±0.8 ng Ang I · mL–1
· h–1) to 135 minutes 5.5±3.4 ng ·
L–1 · s–1 (19.7±12.2 ng Ang I
· mL–1 · h–1; P=.03).
Plasma aldosterone concentration did not fall significantly
with placebo, 705±136 (25.4±4.9) versus 621±92 pmol/L
(22.4±3.3 ng/dL); conversion for aldosterone is nanograms per
deciliterx27.74=picomoles per liter. Conversely, plasma
aldosterone concentration fell significantly at 135 minutes
from 721±100 (26.0±3.6) to 372±64 pmol/L (13.4±2.3
ng/dL; P=.002) in the presence of 200 mg
eprosartan.
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Natriuretic Responses
After the subjects had achieved balance on the low salt diet, the
50-mg eprosartan dose caused a natriuresis of 25±6 mmol during
the 24-hour period. Sodium excretion returned to baseline (9±4
mmol) on the following day. With rechallenge, the 100-mg eprosartan
dose increased urinary sodium excretion to 30±9 mmol, again
followed by a return to 8±3 mmol on the following nonstudy day.
The largest response attained was 40±15 mmol at the 400-mg
eprosartan dose. The eprosartan dose–natriuretic response
relationship was highly correlated (r=.96;
P<.001). This study was not designed to evaluate the time
course of the natriuretic effects of eprosartan.
High Salt Diet
On the high salt diet, the RAS was suppressed as reflected in
lower PRA and plasma aldosterone concentrations (Table 1).
Despite RAS suppression, PRA concentration rose in response to
eprosartan from a basal value of 0.07±0.01 (0.25±0.04) to a peak of
0.1±0.003 ng · L–1 · s–1
(0.4±0.009 ng Ang I · mL–1 ·
h–1; P=.0599). The renal vasodilator response
of 19.2±9.3 mL · min–1 · 1.73
m–2 to the 200-mg dose of eprosartan on a high salt diet
significantly exceeded the placebo response (1.7±7.9 mL ·
min–1 · 1.73 m–2; P<.04).
As anticipated, the renal vasodilator response was enhanced
substantially on the low salt diet (P<.001).
Eprosartan and Responses to Ang II
RPF was unchanged during placebo treatment (584±26 versus 589±28
mL · min–1 · 1.73 m–2) from
baseline to 135 minutes. Thereafter, the Ang II infusion induced a
dose-related decrease in RPF (P=.001; Fig 2). Eprosartan increased RPF from 582±31
to 661±38 mL · min–1 · 1.73
m–2 in the 135 minutes after administration
(P=.005). When subjects were studied during the low salt
placebo phase, their mean arterial pressure rose from 78±4
to 85±4 mm Hg (P=.03) during Ang II infusion (3
ng · kg–1 · min–1). The renal
vascular response was more substantial, averaging -56.8±18.5 mL
· min–1 · 1.73 m–2 at an Ang II dose
of 1 ng · kg–1 · min–1 and
-96±16 mL · min–1 · 1.73 m–2
with an increase in Ang II dose to 3 ng · kg–1
· min–1 (Fig 2) during the placebo phase of the study.
During the eprosartan phase, renal vascular and pressor responses to
Ang II were both blunted (Fig 2). Indeed, the pressor and renal
vascular responses to Ang II at the lower dose, 1 ng ·
kg–1 · min–1, were both abolished
completely. The renal vascular and pressor responses to the higher Ang
II dose were reduced by more than 50%. The residual renal
vasoconstrictor response was -46±10 mL ·
min–1 · 1.73 m–2, less than half the
response during the placebo phase.
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Eprosartan also blocked the hormonal responses to Ang II (Fig 3). The 6 placebo-treated subjects had a
significant decrease in PRA when given an Ang II infusion, 1.1±0.3 to
0.5±0.2 ng · L–1 · s–1 (4±1.1
to 1.8±0.7 ng Ang I · mL-1 · h-1;
P=.009), which was blocked by 200 mg of eprosartan. Plasma
aldosterone concentration in the placebo group increased
from 621±92 to 1248±319 pmol/L (22.4±3.3 to 45±11.5
ng/dL) in response to exogenous Ang II. This rise was also
prevented by eprosartan.
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Discussion |
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Our primary goal was to identify the maximal renal hemodynamic response to eprosartan, and our underlying objective was to ascertain whether the maximal renal response would resemble that defined for renin inhibitors in an identical protocol.12 13 14 Our additional goals were to assess the influence of salt intake on the renal vascular response to eprosartan and to relate those effects to blockade of responses to Ang II. These objectives were achieved. In the subjects on a low salt diet, we identified a dose-related increase in RPF that evolved over an order of magnitude of eprosartan doses. The threshold was below 10 mg, and the 100-mg eprosartan dose achieved a renal vascular response within 8% of peak. Thereafter, a fourfold increase in dose induced little or no further increase in RPF. The pattern for blood pressure response to eprosartan, on the other hand, differed strikingly. There was a highly significant dose-related fall in blood pressure with a striking correlation between dose and response. As opposed to the renal hemodynamic response, however, there was no clear indication that the top of the depressor dose-response relationship had been achieved with the 400-mg eprosartan dose. Eprosartan also had the anticipated influence on hormonal profile, increasing PRA and reducing plasma aldosterone concentration. There was a significant correlation between dose and PRA response for doses of 50 mg and greater.
The effect of eprosartan may be different in different responding systems because the relationship between eprosartan dose and influence on hormonal, blood pressure, and renal vascular responses was not uniform. The threshold eprosartan dose for a renal vasodilator response was below 10 mg, a dose that influenced neither blood pressure nor hormonal profiles. For the renal blood supply, an eprosartan dose of 100 mg was very near the top of the dose-response relationship but not for either blood pressure or hormonal profile. The renal specificity may reflect preferential local accumulation, perhaps related to filtration of the native compound, concentration in the tubular system, and subsequent reabsorption during acidification of the urine. The lipophilicity of the compound is pH dependent; eprosartan is more lipophilic under acidic conditions.
The substantial fall in blood pressure was not anticipated. The subjects were normotensive, and the study involved a single dose during recumbency. In our earlier studies, responses to ACE and renin inhibitors in an identical model, when a blood pressure fall occurred, were rather more modest.12 13 14 15 Although there was no reason to anticipate a priori a larger response to the Ang II antagonist, the close relationship between eprosartan dose and depressor response suggests a causal relationship.
Responses to exogenous Ang II were blunted by the 200-mg eprosartan dose. The response to eprosartan is compatible with its action as an Ang II receptor antagonist: The renal responses clearly indicated a parallel shift, supporting in vitro data to indicate that the agent acts as a competitive antagonist.
Reports on renal hemodynamic and functional responses to Ang II antagonists in humans have been limited.27 28 29 30 31 32 33 34 35 Our study design differed from those reported previously in several ways. We attempted to define a specific relationship between dose of the Ang II antagonist and response over a range of doses designed to identify the maximum. The study was performed on a highly restricted salt intake to activate the renin system, a method we have used in the past.12 13 14 20 21 22 23 Although such a model might be considered artificial, since few healthy human beings subsist on such a diet, the model has several advantages. First, the activation of the RAS thus achieved facilitates the assessment of angiotensin-mediated control mechanisms. Activation of the RAS system makes it possible to define a relationship between dose of a blocking agent and the renal vasodilator response14 as confirmed in this study with eprosartan. With one exception, other studies with Ang II antagonists, conversely, have failed to identify a renal vasodilator response perhaps because of diet and dose.28 29 In the exception35 patients were maintained on a diet of 100 mmol sodium per day, and the Ang II receptor antagonist losartan induced a renal vasodilator response similar to that of the ACE inhibitor enalapril in patients with proteinuria caused by disease other than diabetes mellitus. Second, the renal vascular response to pharmacological interruption of the system in normotensive subjects on a low salt diet resembles the response in some patients with hypertension and in patients with diabetes mellitus, in which it is thought that the disease process might activate the renal renin system.1 36 37 38 Thus, this model might predict more effectively the renal response to pharmacological interruption of the renin system in disease.
This study confirmed the natriuretic effects of eprosartan documented in earlier studies with other Ang II antagonists.27 28 29 A natriuretic response occurred with each dose, and the magnitude of the response followed a dose-response relationship. The peak natriuretic response was probably underestimated because collections were made over 24 hours.
Early in the development of new drug classes there is substantial interest in uncovering evidence that might point to the absence of specificity of action. To date, the Ang II antagonists appeared to be highly specific drugs, with the possible exception of the uricosuric effect of losartan.28 32 What evidence do we have that the striking renal vasodilator and depressor responses seen in the subjects in balance on a low salt diet are actually caused by a specific action? Both the renal vasodilator and the blood pressure responses were highly dependent on salt intake. Moreover, the peak renal vasodilator response requires interpretation in the context of responses to pharmacological interruption of the renin system in an identical model.12 13 14 The peak response in this study, an increase in the range of 135 to 147 mL · min–1 · 1.73 m–2, was remarkably similar to the renal response to renin inhibition and exceeded substantially the response anticipated for ACE inhibition.13 A similar response to two different classes of agent that interrupt the renin system suggests that the contribution of angiotensin to renal hemodynamics in healthy humans on a low salt diet is indeed reflected in the value of about 140 mL · min–1 · 1.73 m–2. A summary of our experience with ACE inhibitors, renin inhibitors, and now with the Ang II antagonist eprosartan shows that the peak renal vasodilator response to ACE inhibition averaged about 90 mL · min–1 · 1.73 m–2 and that the renal vasodilator responses to the renin inhibitor and Ang II antagonist both averaged about 140 mL · min–1 · 1.73 m–2. Although all studies were performed under identical conditions, with the exception of the pharmacological agent and study subjects, the interpretation must be considered speculative.
Why should the use of ACE inhibitors have led to an underestimation of that contribution? According to one construct, the blockade of kininase, and consequent bradykinin accumulation followed by prostaglandin and nitric oxide generation, should have led to a more substantial renal vasodilator response than that induced by the renin inhibitors39 40 41 42 or by the Ang II antagonist in this study. The alternative possibility was an unanticipated, nonspecific vasodilator response to the renin inhibitors. An identical vasodilator response to several renin inhibitors and now to an Ang II antagonist makes that explanation extremely unlikely. A far more probable explanation involves the limited ability of ACE inhibitors to interrupt Ang II formation in the kidney.43 At the top of the ACE inhibitor dose-response relationship, substantial authentic Ang II is still present. The blockade induced by ACE inhibitors is incomplete. In the cascade it is the renin-angiotensinogen interaction and not the ACE step that is rate limiting.44 45 Moreover, there are non–ACE-dependent pathways for Ang II formation. Whatever the explanation, the Ang II antagonist eprosartan acts at the final step in the cascade. The consequence is more effective and more complete blockade. A benefit for diabetic nephropathy, and possibly other forms of nephropathy, is well documented with ACE inhibition.36 37 46 47 48 If an Ang II antagonist indeed provides more complete blockade, it might provide greater therapeutic efficacy as well.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by National Institutes of Health grants T32 HL-07609, NCRR GCRC M01RR026376, P01AC00059916, and 1 P50ML53000-01. Dr Naomi Fisher was supported by a Clinical Associate Physician Award and Dr Deborah Price by a Minority Clinical Associate Physician Award, both from the National Institutes of Health. It is a pleasure to acknowledge the nursing support of Charlene Malarick, RN, the technical research support of Diane Passan, MT, and the administrative support of Diana Page-Capone in the preparation and submission of this manuscript.
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Footnotes |
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Reprint requests to Deborah A. Price, MD, Brigham and Women's Hospital, 221 Longwood Ave, Boston, MA 02115.
Received August 28, 1996; first decision October 15, 1996; accepted January 10, 1997.
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