| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 1996;28:961-966.)
© 1996 American Heart Association, Inc.
Articles |
Losartan Blocks Aldosterone and Renal Vascular Responses to Angiotensin II in Humans
Vanderbilt University Medical Center, Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Nashville, Tenn.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
In vitro and animal studies have demonstrated that the effect of angiotensin II (Ang II) on aldosterone is mediated through the Ang II type 1 receptor. However, it has been difficult to demonstrate an effect of Ang II type 1 receptor blockade on aldosterone levels in human studies. One possible explanation is that subjects have not been studied under salt-controlled conditions. Therefore, we examined the effects of losartan on the aldosterone and renal plasma flow responses to Ang II infusion in six normotensive subjects under low and high salt conditions. Ang II was infused in graded doses (0.3 to 10 ng/kg per minute) in the presence and absence of losartan (a single 50-mg oral dose). Renal plasma flow was assessed by measurement of para-aminohippurate clearance. Blood pressure, plasma aldosterone levels (low salt conditions only), and para-aminohippurate clearance were measured before and after each Ang II dose. Losartan had no effect on baseline systolic pressure but attenuated the systolic pressure response to exogenous Ang II during both low salt (0.7±1.9 versus 6.7±1.4 mm Hg, P=.001) and high salt (2.0±1.9 versus 12.3±2.1 mm Hg, P=.006) conditions. Under low salt conditions, losartan reduced the baseline plasma aldosterone level from 1135±204 to 558±102 pmol/L (P=.015) and blocked the aldosterone response to Ang II (-49±110 versus +436±83 pmol/L, P=.019). During high salt conditions, losartan had no effect on baseline renal plasma flow but attenuated the renal plasma flow response to Ang II (-90.1±15.1 versus -185.1±2.6 mL/min per 1.73 m2, P=.013). These data confirm that losartan lowers both basal and exogenous Ang II–stimulated aldosterone levels under low salt conditions. Losartan does not significantly affect baseline renal plasma flow but does attenuate the renal plasma flow response to exogenous Ang II under high salt conditions.
Key Words: losartan • angiotensin II • receptors, angiotensin • aldosterone • renal circulation
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Losartan and other specific AT1 receptor antagonists have been used to delineate the physiological role of Ang II in vivo. In vitro and animal studies have demonstrated that the effects of exogenous Ang II on blood pressure and aldosterone secretion are mediated through the AT1 receptor. For example, losartan administration antagonizes salt depletion–stimulated increases in aldosterone-synthase mRNA and plasma aldosterone in hypertensive rats.1 Losartan also attenuates the effect of exogenous Ang II on blood pressure and aldosterone in rats, dogs, and nonhuman primates.2 3 4 5 6 In humans, losartan has been shown to block the pressor response to both exogenous Ang I and Ang II; however, it has been difficult to demonstrate a consistent effect of AT1 receptor blockade on aldosterone levels in normotensive human volunteers.7 8 9 10 11 12 13 14 15 16 17 18 19 20 This finding has been attributed to the confounding factor of circadian variation in aldosterone secretion.7 13 16 Other possible confounding factors include a limited duration of adrenal AT1 receptor blockade and inadequate adrenal levels of losartan.14
An important possible reason why previous studies have demonstrated little effect of losartan on aldosterone levels is that subjects have not been studied under salt-controlled conditions.12 Ang II is hypothesized to be the primary regulator of aldosterone secretion in response to changes in volume or salt status.21 22 Salt depletion stimulates Ang II–mediated aldosterone secretion.23 24 In addition, the renin status of the subject may influence the effect of losartan on aldosterone levels. Normal- or high-renin subjects may be more sensitive to the effects of AT1 blockade than low-renin subjects.8 16 17
In this study, we aimed to determine the effect of losartan on aldosterone levels in normal- to high-renin normotensive subjects under conditions in which endogenous Ang II levels are increased, namely, salt depletion. Furthermore, we measured the effect of losartan on the aldosterone response to stimulation by exogenous Ang II infusion. Finally, both the aldosterone response to Ang II under salt-depleted conditions and the renovascular response to exogenous Ang II under salt-replete conditions have been used to characterize a group of individuals with normal- to high-renin essential hypertension, called non-modulators.25 26 Non-modulators are resistant to the effects of exogenous Ang II27 28 29 ; it is not known whether this resistance reflects increased endogenous Ang II with AT1 receptor downregulation or an intrinsic abnormality of the AT1 receptor. Depending on the mechanism, differences in the potency of AT1 receptor blockade may prove useful in distinguishing non-modulators from individuals with modulating hypertension. For this reason, in the present study, we set out to define not only the effect of losartan on the aldosterone response to Ang II under salt-depleted conditions but also the effect of losartan on the renovascular response to Ang II under salt-replete conditions in normal human control subjects.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
Six healthy normal- to high-renin normotensive men were studied in a crossover design study (Fig 1
) in the outpatient and inpatient divisions of the Vanderbilt University Hospital Clinical Research Center. Subjects underwent an initial history, physical examination, electrocardiogram, and laboratory screen. All had no history or evidence of cardiovascular, endocrine, or renal disease. All were within 20% of ideal body weight. Subjects were defined as normal- or high-renin normotensive if they had an upright plasma renin activity of at least 2.4 ng/mL per hour when in balance on a diet of 10 mmol sodium per day (day 5, see Fig 1 and Table) as defined by previously established criteria.27 30 Subjects with a positive family history of hypertension were excluded. All subjects gave written, informed consent; the study protocol was approved by the Institutional Review Board of Vanderbilt University.
|
Protocol
Fig 1
outlines the study protocol. Subjects first ingested a xanthine-free diet with 10 mmol sodium, 100 mmol potassium, and 2500 mL fluid per day for 9 days. Subjects collected their urine each day for measurement of sodium, potassium, and creatinine. On the morning of the 5th day, blood for upright plasma renin activity was obtained after 30 minutes of upright posture. Significant increases in plasma renin activity occur within 20 minutes of assumption of upright posture in normal- to high-renin individuals.30 No potential subjects were excluded by a low-renin state. The subjects were admitted to the Clinical Research Center on the evening of the 5th day. Urine collections and the diet were continued.
Each salt-depleted subject's aldosterone and RPF responses to acute Ang II infusion were measured on the morning of the 8th study day. Subjects were kept supine and fasting from after midnight of the night before. At 7 AM, an intravenous catheter was placed in each arm. One catheter was used for drug infusion and the other for venous sampling. Blood pressure and pulse were measured every 2 minutes throughout the study with an automated blood pressure cuff (Dinamap, Critikon). At 7:30 AM, blood was drawn for baseline PAH and aldosterone levels. At 8 AM, the subject was given an 8 mg/kg loading dose of PAH followed by a constant infusion at 12 mg/min. At 9 AM, the subject was given a continuous infusion of Ang II at successive doses for 45 minutes each. The first three subjects were given doses of 0.3, 1, and 3 ng/kg per minute during both the low salt and high salt diets; to maximize the effect of Ang II, the last three subjects were given doses of 1, 3, and 10 ng/kg per minute. Blood samples for PAH were drawn at 8:45, 8:50, and 8:55 AM and then after each successive dose of Ang II. Blood for aldosterone was drawn before and after each successive dose of Ang II during the low salt phase of the study. The subject remained supine for the duration of the Ang II infusion.
The effect of losartan on the aldosterone and RPF responses to Ang II during low salt conditions was studied on the 9th study day. Subjects were kept supine and fasting from the night before. At 6 AM, the subject was given a 50-mg oral dose of losartan. The acute Ang II infusion was then repeated as outlined above. Thus, 3 hours elapsed between the oral administration of losartan and the start of the Ang II infusion. This is approximately the time required to achieve peak levels of E-3174, the primary pharmacologically active metabolite of losartan.10
Immediately after completion of the Ang II infusion on day 9, subjects were switched to a xanthine-free diet of 200 mmol sodium, 100 mmol potassium, and 2500 mL fluid per day for 6 days. Daily urine collections were continued. On the 13th study day, the RPF response to intravenous Ang II infusion was measured. Loading doses and maintenance infusions of PAH were given as before. On day 14, measurement of the RPF response to acute Ang II infusion was repeated in the presence of losartan.
Analytic Methods
Urinary electrolytes were measured by flame photometry. All blood samples were collected on ice, spun, and frozen until the time of assay. Plasma renin activity was measured by radioimmunoassay for Ang I.31 Aldosterone was measured with a radioimmunoassay kit from Diagnostic Products Corp.32 RPF was measured by determination of PAH clearance from plasma.22 33 When corrected for body surface area, PAH clearance reflects about 90% of RPF for the plasma concentrations of PAH achieved during this study. Plasma PAH levels were measured by spectrophotometric autoanalyzer techniques. PAH clearance was determined as previously described.34 The coefficient of variation for PAH clearance in our laboratory is 3.91±3.53% (SD). RVR was calculated as the ratio of mean arterial pressure to RPF.35
Statistical Analysis
Results are presented as mean±SE. Statistical analysis was performed with the SPSS Advanced Statistics program (SPSS Inc). The angiotensin dose-response curves in the presence and absence of losartan were compared by two-way ANOVA with repeated measures in which the within-subject variables were Ang II dose, the presence or absence of losartan, and salt condition. Comparisons between treatment arms at specific Ang II doses were made with a two-tailed, paired Student's t test. Probability values reported are from the t tests unless indicated otherwise. The criterion for significance was a value of P<.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The upright plasma renin activity of the subjects in the salt-depleted state was 7.61±1.88 ng Ang I/mL per hour. Baseline characteristics of the subjects on each study day before initiation of Ang II infusion are shown in the Table
. Losartan had no effect on baseline systolic pressure, diastolic pressure, or RPF in either the salt-depleted or salt-replete state. Although the relatively small sample size of this study may have limited our ability to detect a significant effect of losartan on baseline RPF under salt-depleted conditions, our findings were similar to those of two previous larger studies.9 36 Under salt-depleted conditions, losartan significantly lowered baseline aldosterone level from 1135±204 to 558±102 pmol/L (P=.015). In the absence of losartan, exogenous Ang II significantly increased blood pressure (Fig 2). The blood pressure response to exogenous Ang II was significantly greater in the salt-replete state than in the salt-depleted state (ANOVA, P=.002). Losartan administration dramatically attenuated the pressor response to Ang II in both the salt-depleted and salt-replete states (Fig 2, ANOVA, P<.001). There was no difference between the effect of losartan on the pressor response to Ang II in the salt-depleted and salt-replete states; for example, the systolic pressure response to acute Ang II infusion at 3 ng/kg per minute in the presence of losartan during salt depletion was 1.8±15% of the response in the absence of losartan compared with 6.7±24% during salt repletion (P=.811).
|
|
) and salt repletion (
) in the presence (dotted lines) and absence (solid lines) of losartan. +P<.05, ++P<.005 vs baseline; *P<.03, **P<.003 vs the presence of losartan.
The aldosterone response to Ang II infusion was measured in the salt-depleted state. After an initial decrease in aldosterone, Ang II caused a significant rise in aldosterone compared with baseline. The increment change in aldosterone was similar to that reported for salt-depleted normotensive subjects in other studies.23 27 The addition of losartan dramatically attenuated the aldosterone response to exogenous Ang II (Fig 3, ANOVA, P<.001).
|
Dietary sodium modifies the aldosterone and renovascular responses to Ang II in opposite directions. Thus, whereas salt depletion accentuates the aldosterone response to Ang II, the renovascular response to Ang II is greater in the salt-replete state. As illustrated in Fig 4, RPF, as measured by PAH clearance, decreased significantly in response to exogenous Ang II (ANOVA, P<.001), and this decrease was greater in the salt-replete than in the salt-depleted state (ANOVA, P<.05). The magnitude of the decrease in RPF was similar to that reported in previous studies of normotensive subjects.23 27 28 RVR (Fig 5) increased significantly in response to exogenous Ang II (ANOVA, P<.001). This response was also greater during salt repletion (ANOVA, P=.05). Losartan significantly attenuated but did not abolish the RPF and RVR responses to Ang II (ANOVA, P<.02). The magnitude of this losartan effect was similar under both salt conditions.
|
|
Both the adrenal response to Ang II in the salt-depleted state and the renovascular response to Ang II in the salt-replete state have been used to characterize non-modulators. Both the aldosterone and renovascular responses to Ang II are highly reproducible within subjects.25 Moreover, the increment in aldosterone in subjects ingesting a diet of 10 mmol sodium has been reported to correlate significantly with the decrement in PAH clearance in the same subjects ingesting a diet of 200 mmol sodium.25 Fig 6 illustrates the correlation between the change in PAH clearance in the salt-replete state and the change in aldosterone in the salt-depleted state. In the absence of losartan, there was a highly significant correlation between the aldosterone and renovascular responses to exogenous Ang II (P<.005). The addition of losartan abolished this relationship. These data may reflect the fact that although not significant, losartan tended to have a greater effect on the aldosterone response to Ang II than on the renovascular response. For example, at the highest doses of Ang II (3 and 10 ng/kg per minute), losartan blocked the aldosterone response to -11% of baseline, whereas losartan decreased the renovascular response to 40% of baseline (P=.089 for the effect of losartan on the aldosterone response in the salt-depleted state versus the effect of losartan on the renovascular response in the salt-replete state).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This study is the first to examine the effect of acute administration of the specific AT1 receptor antagonist losartan on aldosterone under salt-depleted conditions and in response to exogenous Ang II. Losartan significantly decreased baseline plasma aldosterone levels and completely blocked the effect of Ang II on aldosterone.
Despite the fact that in vitro and animal studies indicate that the AT1 receptor mediates the steroidogenic effect of Ang II,1 3 4 5 6 it has been difficult to demonstrate a significant effect of AT1 receptor blockade on aldosterone secretion in previous studies of normotensive humans.7 8 9 10 11 12 13 14 15 16 17 18 19 20 This apparent lack of effect of losartan on aldosterone levels has been attributed to a confounding diurnal variation in aldosterone levels.7 13 14 16 In prior studies, aldosterone levels decreased significantly after acute losartan administration but decreased to a similar magnitude under control conditions.7 9 14 Such a diurnal fall in aldosterone levels was suggested in the present study by the finding that on the control day, plasma aldosterone levels appeared to decrease at the lowest Ang II dose before increasing in response to higher doses. Interestingly, this initial fall was not seen in the presence of losartan.
One striking difference between the present study and prior studies in normotensive subjects that failed to show an effect of losartan on aldosterone is the fact that in the present study, subjects were studied while in balance on a diet of 10 mmol sodium per day. Although factors regulating aldosterone synthesis include Ang II, corticotropin, and potassium,37 Ang II is the primary stimulant of aldosterone secretion in response to changes in salt or volume status.21 22 Conditions of salt depletion increase the adrenal sensitivity to exogenous Ang II.23 24 Among the prior studies, only Burnier et al9 and Tsunoda et al16 controlled for sodium intake, studying subjects ingesting diets of 50 mmol and 10 g (435 mmol) sodium per day, respectively. In the present study, because the aldosterone response to losartan was measured only during salt depletion, we cannot exclude the possibility that losartan also lowers aldosterone during high salt intake.
Although the majority of investigators have found no aldosterone response to acute administration of losartan,7 9 10 11 14 16 18 four groups have reported a significant decrease in plasma aldosterone after chronic losartan administration,8 12 17 19 although two of the four studies were not controlled. One of the four groups also reported an acute effect of 100 mg losartan, but not 25 mg, on plasma aldosterone.12 Interestingly, in addition to studying chronic doses of losartan, all four of these investigations studied hypertensive individuals. Hypertensive subjects may be more sensitive to the aldosterone-lowering effects of losartan than normotensive subjects. Normal- or high-renin hypertensive subjects have previously been shown to have an enhanced aldosterone response to exogenous Ang II compared with normotensive subjects.38 An increased sensitivity to losartan has been demonstrated in spontaneously hypertensive rats compared with normotensive Wistar-Kyoto rats.4 Hypertensive individuals may also have greater adrenal AT1 receptor sensitivity to AT1 blockade. Comparison of the aldosterone response to losartan between hypertensive and normotensive subjects in salt-depleted and salt-replete conditions may help elucidate this possible difference. Gottleib et al15 reported a significant decrease in plasma aldosterone after acute administration of losartan in individuals with congestive heart failure. These subjects may have increased sensitivity to AT1 receptor blockade resulting from the activation of the renin-angiotensin axis observed in heart failure.39
The present study is the first to examine the effect of losartan on the aldosterone response to continuous infusion of exogenous Ang II. The aldosterone response to Ang II has been used to characterize patients with essential hypertension, with a normal response defined as an increase in aldosterone of at least 15 ng/dL in response to a continuous infusion of 3 ng/kg per minute Ang II during salt depletion.25 All six subjects studied exhibited a normal response to Ang II. Christen et al14 and Munafo et al13 have measured the effect of losartan on the pressor response to boluses of Ang I and Ang II, respectively. Although plasma aldosterone levels were measured sequentially after losartan in these studies, the aldosterone response to Ang I or Ang II boluses was not specifically ascertained.
The aldosterone response to exogenous Ang II during salt-depleted conditions and the RPF response to Ang II under salt-replete conditions have been used to define a subset of individuals with normal- or high-renin hypertension.25 27 These non-modulators exhibit decreased sensitivity to exogenous Ang II, and this decreased sensitivity may reflect an abnormality, either intrinsic or related to desensitization, in the AT1 receptor. Since comparison of the effects of AT1 blockade with losartan may prove useful in distinguishing normotensive individuals and modulators from non-modulators, we measured the effect of losartan on the RPF response to Ang II infusion. Similar to the findings of Burnier et al,9 36 we found no significant difference in baseline RPF after AT1 receptor blockade in normotensive subjects. Also as reported previously, the renal vasoconstrictor response to exogenous Ang II was greater during salt repletion than during salt depletion.23 Losartan significantly attenuated the renal constrictor response to Ang II, and the shifts in the Ang II–RPF and Ang II–RVR dose-response curves were similar under low and high salt conditions. In contrast to the aldosterone response to Ang II during salt depletion, losartan did not completely block the renal vasoconstrictor response to Ang II during salt repletion. Although one possible mechanism for this differential effect of AT1 receptor blockade on the aldosterone and renal vasoconstrictor responses to exogenous Ang II could be differences in plasma concentrations of losartan and its active metabolite under low and high salt conditions, the lack of an effect of salt balance on the effect of AT1 receptor blockade of the pressor response to Ang II does not support this possibility. Differences in the renal and adrenal predominance of AT1 receptor subtypes may also underlie the differences in AT1 receptor blockade. In rats, the AT1A receptor is the predominant subtype expressed in the kidney. In contrast, the AT1B subtype is predominant in the rat adrenal gland.40 41 There may be differences in the degree of receptor blockade achieved with losartan between subtypes, although human data are thus far lacking. Further studies are needed to characterize the relative potency of AT1 receptor antagonists for blocking the adrenal and renal vascular responses to Ang II.
In summary, this study demonstrates an unequivocal effect of acute losartan administration on Ang II–stimulated aldosterone secretion under salt-depleted conditions. Losartan attenuates the renal vasoconstrictor response to Ang II. In future studies, the potency of losartan in blocking the adrenal and renal hemodynamic responses to exogenous Ang II may be used to further characterize subgroups of individuals with essential hypertension.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This work was supported by grants from Merck Research Laboratories, the National Institutes of Health (GM-07569-19 and 5MO1-RR0095-533), and the American Heart Association, Tennessee Affiliate (TN 94613). Dr Brown is a Clinical Associate Physician, Vanderbilt General Clinical Research Center.
|
Footnotes |
|---|
Reprint requests to Nancy J Brown, MD, Vanderbilt University, 560 MRB-1, 23rd Ave S at Pierce Ave, Nashville, TN 37232-6602. E-mail nancy.brown@mcmail.vanderbilt.edu.
Received March 19, 1996; first decision April 15, 1996; accepted July 19, 1996.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Volpe M, Rubattu S, Gigante B, Ganten D, Porcellini A, Russo R, Romano M, Enea I, Lee MA, Trimarco B. Regulation of aldosterone biosynthesis by adrenal renin is mediated through AT1 receptors in renin transgenic rats. Circ Res. 1995;77:73-79.
2.
Wong PC, Price WA, Chiu AT, Duncia JV, Carini DJ, Wexler RR, Johnson AL, Timmermans PB. Hypotensive action of DuP753, an angiotensin II antagonist, in spontaneously hypertensive rats: nonpeptide angiotensin II receptor antagonists: X. Hypertension. 1990;15:459-468.
3.
Wong PC, Price WA, Chiu AT, Carini DJ, Duncia JV, Johnson AL, Wexler RR, Timmermans PB. Nonpeptide angiotensin II receptor antagonists: studies with EXP9270 and DuP753. Hypertension. 1990;15:823-834.
4.
Tofovic SP, Pong AS, Jackson EK. Effects of angiotensin subtype 1 and subtype 2 receptor antagonists in normotensive versus hypertensive rats. Hypertension. 1991;18:774-782.
5. MacFayden RJ, Tree M, Lever AF, Reid JL. Haemodynamic and hormonal responses to losartan (DuP753/MK954) infusion during cardiac catheterization in conscious salt-deplete dogs. Clin Sci. 1993;85:157-163.[Medline] [Order article via Infotrieve]
6.
DeGraaf GL, Pals DT, Couch SJ, Lawson JA. Hormonal and cardiovascular effects of losartan (DuP753), an angiotensin receptor antagonist, in non-human primates. J Pharmacol Exp Ther. 1992;264:6-10.
7. Christen Y, Waeber B, Nussberger J, Lee RJ, Timmermans PB, Brunner HR. Dose-response relationships following oral administration of DuP753 to normal humans. Am J Hypertens. 1991;4:350S-354S.[Medline] [Order article via Infotrieve]
8. Grossman E, Pelig E, Carroll J, Shamiss A, Rosenthal T. Hemodynamic and humoral effects of the angiotensin II antagonist losartan in essential hypertension. Am J Hypertens. 1994;7:1041-1044.[Medline] [Order article via Infotrieve]
9.
Burnier M, Rutchmann B, Nussberger J, Versaggi J, Shahinfar S, Waeber B, Brunner HR. Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects. Hypertension. 1993;22:339-347.
10. Ohtawa M, Takayama K, Saitoh K, Yoshinaga T, Nakashima M. Pharmacokinetics and biochemical efficacy after single and multiple oral administration of losartan, an orally active nonpeptide angiotensin II receptor antagonist, in humans. Br J Clin Pharmacol. 1993;35:290-297.[Medline] [Order article via Infotrieve]
11.
Goldberg MR, Tanaka W, Barchowsky A, Bradstreet TE, McCrea J, Lo M, McWilliams EJ, Bjornsson TD. Effects of losartan on blood pressure, plasma renin activity, and angiotensin II in volunteers. Hypertension. 1993;21:704-713.
12.
Goldberg MR, Bradstreet TE, McWilliams EJ, Tanaka WK, Lipert S, Bjornsson TD, Waldman SA, Osborne B, Pivadori L, Lewis G, Blum R, Herman T, Abraham PA, Halstenson CN, Lo M, Lu H, Spector R. Biochemical effects of losartan, a non-peptide angiotensin II receptor antagonist, on the renin-angiotensin-aldosterone system in hypertensive patients. Hypertension. 1995;25:37-46.
13. Munafo A, Christen Y, Nussberger J, Shum L, Borland M, Lee RJ, Waeber B, Biollaz J, Brunner HR. Drug concentration response relationships in normal volunteers after oral administration of losartan, an angiotensin II receptor antagonist. Clin Pharmacol Ther. 1992;51:513-521.[Medline] [Order article via Infotrieve]
14.
Christen Y, Waeber B, Nussberger J, Porchet M, Borland RM, Lee RJ, Maggon K, Shum L, Timmermans PB, Brunner HR. Oral administration of DuP753, a specific angiotensin II receptor antagonist, to normal male volunteers. Circulation. 1991;83:1333-1342.
15. Gottleib SS, Dickstein K, Fleck E, Kostis J, Levine TB, LeJemtel T, DeKlock M. Hemodynamic and neurohumoral effects of the angiotensin II antagonist losartan in patients with congestive heart failure. Circulation. 1993;88(part 1):1602-1609.
16. Tsunoda K, Abe K, Hagino T, Omata K, Misawa S, Imai Y, Yoshinaga K. Hypotensive effect of losartan, a nonpeptide angiotensin II receptor antagonist, in essential hypertension. Am J Hypertens. 1993;6:28-32.[Medline] [Order article via Infotrieve]
17. Bauer IH, Reams GP, Wu Z, Lau-Sieckman A. Effects of losartan on the renin-angiotensin-aldosterone axis in essential hypertension. J Hum Hypertens. 1995;9:237-243.[Medline] [Order article via Infotrieve]
18. Ogihara T, Arakawa K, Iimura O, Abe K, Saruta T, Ishii M, Hiwada K, Fujishima M, Fukiyama K. Open clinical studies on a new angiotensin II receptor antagonist, TCV 116. J Hypertens. 1994;12:S35-S38.
19. Smith MC, Barrows S, Meibohm A, Shahinfar S, Simpson RL, Wegel K, Dunn MJ. The effects of angiotensin II receptor blockade with losartan on systemic blood pressure and renal and extrarenal prostaglandin synthesis in women with essential hypertension. Am J Hypertens. 1995;8:1177-1183.[Medline] [Order article via Infotrieve]
20.
van den Meiracker AH, Admiraal PJ, Janssen JA, Kroodsma J, de Ronde WA, Boomsa F, Sissman J, Blankestijn PJ, Mulder PG, Man in't Veld AJ, Schalekamp MA. Hemodynamic and biochemical effects of the AT1 receptor antagonist irbesartan in hypertension. Hypertension. 1995;25:22-29.
21. Aguilera G, Menard RH, Catt KJ. Regulatory actions of angiotensin II on receptors and steroidogenic enzymes in adrenal glomerulosa cells. Endocrinology. 1980;107:1277-1284.
22.
Swartz SL, Williams GH, Hollenberg NK, Dluhy RG, Moore TJ. Primacy of the renin-angiotensin system in mediating the aldosterone response to sodium restriction. J Clin Endocrinol Metab. 1980;50:1071-1074.
23. Hollenberg NK, Chenitz WR, Adams DF, Williams GH. Reciprocal influence of salt intake on adrenal glomerulosa and renal vascular responses to angiotensin II in normal man. J Clin Invest. 1974;54:34-42.
24.
Oelkers W, Brown JJ, Fraser R, Lever AF, Morton JJ, Robertson JI. Sensitization of the adrenal cortex to angiotensin II in sodium-deplete man. Circ Res. 1974;34:69-77.
25.
Williams GH, Dluhy RG, Lifton RP, Moore TJ, Gleason R, Williams R, Hunt SC, Hopkins PN, Hollenberg NK. Non-modulation as an essential intermediate phenotype in essential hypertension. Hypertension. 1992;20:788-796.
26. Williams GH, Hollenberg NK. Functional derangements in the regulation of aldosterone secretion in hypertension. Hypertension. 1991;18(suppl III):III-143-III-149.
27. Shoback DM, Williams GH, Moore TJ, Dluhy RG, Podolsky S, Hollenberg NK. Defect in the sodium-modulated tissue responsiveness to angiotensin II in essential hypertension. J Clin Invest. 1983;72:2115-2124.
28.
Shoback DM, Williams GH, Hollenberg NK, Davies RO, Moore TJ, Dluhy RG. Endogenous angiotensin II as a determinant of sodium-modulated changes in tissue responsiveness to angiotensin II in normal man. J Clin Endocrinol Metab. 1983;57:764-770.
29.
Taylor T, Moore TJ, Hollenberg NK, Williams GH. Converting-enzyme inhibition corrects the altered adrenal response to angiotensin II in essential hypertension. Hypertension. 1984;6:92-99.
30. Tuck ML, Dluhy RG, Williams GR. Sequential responses of the renin-angiotensin-aldosterone axis to acute postural change: effect of dietary sodium. J Lab Clin Med. 1975;86:754-763.[Medline] [Order article via Infotrieve]
31. Workman RJ, Sussman CR, Burkett DW, Liddle GW. Circulating levels of angiotensin I measured by radioimmunoassay in hypertensive subjects. J Lab Clin Med. 1979;93:847-856.[Medline] [Order article via Infotrieve]
32. Kubasik NP, Warren K, Sine HE. Evaluation of a new commercial radioimmunoassay kit for aldosterone using an iodinated tracer. Clin Biochem. 1979;10:59-61.
33. Schnurr E, Lahme W, Kuppers H. Measurement of renal clearance of inulin and PAH in the steady state without urine collection. Clin Nephrol. 1980;13:26-29.[Medline] [Order article via Infotrieve]
34. Brun C. A rapid method for the determination of para-aminohippuric acid in kidney function test. J Lab Clin Med. 1951;37:955-958.[Medline] [Order article via Infotrieve]
35. van Paassen P, de Zeeuw D, de Jong PE. Renal and systemic effects of the renin inhibitor remikiren in patients with essential hypertension. J Cardiovasc Pharmacol. 1995;26:39-45.[Medline] [Order article via Infotrieve]
36. Burnier M, Hagman M, Nussberger J, Biollaz J, Armagnac C, Brouard R, Waeber B, Brunner HR. Short-term and sustained renal effects of angiotensin II receptor blockade in healthy subjects. Hypertension. 1995;25(part 1):22-29.
37. Sealey JE, Laragh JH. The renin-angiotensin-aldosterone system for normal regulation of blood pressure and sodium and potassium homeostasis. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management. New York, NY: Raven Press Publishers; 1990:1287-1317.
38.
Kisch ES, Dluhy RG, Williams GH. Enhanced aldosterone response to angiotensin II in human hypertension. Circ Res. 1976;38:502-505.
39. Braunwald E. Pathophysiology of heart failure. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia, Pa: WB Saunders Co; 1992:393-418.
40. Du Y, Yao A, Guo D, Inagami T, Wang DH. Differential regulation of angiotensin II receptor subtypes in rat kidney by low dietary sodium. Hypertension. 1995;25(part 2):872-877.
41.
Healy HP, Ye M, Troyanoskaya M. Localization of angiotensin II type 1 receptor subtype mRNA in rat kidney. Am J Physiol. 1995;268:F220-F226.
This article has been cited by other articles:
 |
|
 |
|
  J. P Collister and D. B Nahey Changing dietary sodium alters the chronic cardiovascular effects of losartan in rats Journal of Renin-Angiotensin-Aldosterone System, March 1, 2008; 9(1): 10 - 16. [Abstract] [PDF]
|
|
|
|
 |
|
 S.-L. Zhang, C. To, X. Chen, J. G. Filep, S.-S. Tang, J. R. Ingelfinger, and J. S. D. Chan Essential Role(s) of the Intrarenal Renin-Angiotensin System in Transforming Growth Factor-{beta}1 Gene Expression and Induction of Hypertrophy of Rat Kidney Proximal Tubular Cells in High Glucose J. Am. Soc. Nephrol., February 1, 2002; 13(2): 302 - 312. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Myerson, H. E. Montgomery, M. Whittingham, M. Jubb, M. J. World, S. E. Humphries, and D. J. Pennell Left Ventricular Hypertrophy With Exercise and ACE Gene Insertion/Deletion Polymorphism : A Randomized Controlled Trial With Losartan Circulation, January 16, 2001; 103(2): 226 - 230. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-L. Zhang, S.-S. Tang, X. Chen, J. G. Filep, J. R. Ingelfinger, and J. S. D. Chan High Levels of Glucose Stimulate Angiotensinogen Gene Expression Via the P38 Mitogen-Activated Protein Kinase Pathway in Rat Kidney Proximal Tubular Cells Endocrinology, December 1, 2000; 141(12): 4637 - 4646. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Y. Osei, D. A. Price, L. M. B. Laffel, M. C. Lansang, and N. K. Hollenberg Effect of Angiotensin II Antagonist Eprosartan on Hyperglycemia-Induced Activation of Intrarenal Renin-Angiotensin System in Healthy Humans Hypertension, July 1, 2000; 36(1): 122 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-H. Wu, Xing Chen, S.-L. Zhang, Li Pang, C. To, T.-T. Wang, T. C Hohman, J. G Filep, and J. S. Chan Molecular mechanism(s) of insulin action on the expression of the angiotensinogen gene in kidney proximal tubular cells Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 166 - 174. [Abstract] [PDF]
|
|
|
|
|
|
N. J. Brown, M. Agirbasli, and D. E. Vaughan Comparative Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Antagonism on Plasma Fibrinolytic Balance in Humans Hypertension, August 1, 1999; 34(2): 285 - 290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Montanari, E. Tateo, E. Fasoli, D. Giberti, P. Perinotto, A. Novarini, and P. Dall'Aglio Angiotensin II Blockade Does Not Prevent Renal Effects of L-NAME in Sodium-Repleted Humans Hypertension, September 1, 1997; 30(3): 557 - 562. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||