(Hypertension. 1998;32:923-928.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Chronic Sodium Balance and Blood Pressure Response to Captopril in Conscious Mice
From the Department of Physiology, Medical College of Wisconsin, Milwaukee, Wis.
Correspondence to Dr David L. Mattson, Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail dmattson{at}mcw.edu
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Abstract—The influence of chronic administration of the converting enzyme inhibitor captopril on blood pressure and sodium balance was evaluated in conscious Swiss Webster mice. Arterial pressure was measured with chronic indwelling catheters, and sodium balance was determined by infusing sodium intravenously in isotonic saline and collecting urine 24 h/d. Experiments to validate sodium balance measurements in mice demonstrated recovery of 100±3% of sodium intake under steady-state conditions (n=20 mice on 70 individual days, sodium intake range 160 to 1000 µmol/d). It was further demonstrated that mean arterial pressure, heart rate, and body weight were unaltered from 115±7 mm Hg, 646±12 bpm, and 34±0.6 g, respectively, as sodium intake was increased stepwise from 150 to 900 µmol NaCl per day. An additional validation group (n=7) demonstrated that daily and cumulative sodium balance can be accurately determined during and after the intravenous administration of an agent known to alter renal sodium handling (furosemide 50 mg · kg-1 · d-1). Experiments were then performed to examine the influence of intravenous captopril infusion (40 mg · kg-1 · d-1, n=7) in mice in which the daily sodium intake was fixed at
200 µmol/d. This dose of
captopril was determined to significantly decrease the pressor response
to a 10-ng bolus of angiotensin I (Ang I) from 24±5 in the
control state to 6±2 mm Hg (n=5). After 5 days of infusion of
the converting enzyme inhibitor, mean arterial
pressure significantly fell from 114±3 to 58±2 mm Hg, body
weight significantly decreased from 36±1 to 33±1 g, and cumulative
sodium balance significantly decreased to -270±55 µmol. These
parameters returned toward control during 5 postcontrol
days. Results of this study demonstrate that accurate sodium balance
measurements can be obtained from individual conscious mice over a
5-fold range of sodium intake. The experiments also indicate that
converting enzyme inhibition has a potent influence to lower blood
pressure in normal mice; the hypotensive response appears to be due in
part to increased urinary sodium excretion.
Key Words: renin-angiotensin system • captopril • blood pressure • sodium
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Introduction |
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Techniques in molecular biology have allowed the development of a number of interesting transgenic and knockout models in which important cardiovascular/renal control systems have been genetically altered.1 One cardiovascular regulatory system that has been the subject of intense investigation using transgenic technology in the mouse has been the renin-angiotensin system (RAS). Manipulation of the genes encoding renin,2 3 angiotensinogen,2 3 4 angiotensin-converting enzyme (ACE),5 6 7 and the AT18 9 and AT2 receptors10 11 has produced profound effects on cardiovascular homeostasis. One of the most potent effects observed with manipulation of the RAS has been the hypotensive effect of deletion of the ACE gene. Arterial blood pressure, measured by both tail-cuff plethysmography5 7 and direct arterial cannulation,6 has been reported to decrease by as much as 50% in ACE knockout mice. This hypotensive effect is extremely potent when compared with the blood pressure response to pharmacological ACE inhibition (ACEI) in normotensive humans,12 13 dogs,14 15 16 and rats.17 It is unclear whether pharmacological ACEI in the mouse will decrease mean arterial pressure (MAP) to levels similar to those observed in mice in which the ACE gene has been genetically deleted. It is also not clear from these experiments what changes (if any) occur in fluid and electrolyte homeostasis to lead to the steady-state level of blood pressure in mice lacking the ACE gene. The present studies were designed to examine the changes in blood pressure and sodium balance in conscious, chronically instrumented mice during pharmacological blockade of ACE with captopril.
To examine the influence of ACEI on blood pressure and sodium balance in conscious mice, it was necessary to deliver saline intravenously with and without captopril, measure sodium intake and output, and quantify arterial blood pressure. We previously reported a method that allows the long-term measurement of arterial pressure and continuous intravenous infusion in conscious mice.18 The goals of the present study were 3-fold. The first aim was to develop a strategy for the measurement of daily and cumulative sodium balance in conscious mice. The second aim was to determine the appropriate dose (continuously delivered intravenously) of the ACE inhibitor captopril on MAP and the pressor response to angiotensin I (Ang I) in mice. The third aim was to determine the influence of chronic intravenous infusion of captopril on blood pressure and sodium balance in conscious mice.
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Methods |
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Experiments were performed on adult Swiss Webster mice obtained from Taconic Farms (Germantown, NY). The mice were housed in the Animal Resource Center at the Medical College of Wisconsin with normal food and tap water provided ad libitum. All animal procedures were approved by the Medical College of Wisconsin Animal Care Committee, and the mice were closely monitored to ensure that none experienced undue stress or discomfort.
Mice were surgically prepared for chronic studies as we have previously described.18 The animals were preanesthetized with methoxyflurane and administered sodium pentobarbital (50 mg/kg IP) to induce anesthesia. Supplemental anesthetic was administered as needed. Using aseptic techniques, we placed catheters in the femoral artery for the measurement of arterial pressure and in the femoral vein for infusion. The arterial catheters were filled with 500 U of heparin in saline, sealed, and opened only when they were used for recording. Arterial pressure data were collected using computerized data acquisition software as previously described.18 19 The venous catheters were continuously infused with saline or saline with drug at the rates indicated in the individual protocols.
Protocol 1: Sodium Balance and MAP in Conscious Mice Maintained on
Different Daily Sodium Intake
Mice were surgically prepared as described above and housed in
stainless steel metabolic cages (14 cm wide, 20 cm long,
and 10 cm high) with silicone-coated collection funnels. After the
recovery period, the animals were maintained ad libitum on tap water
and sodium-free liquid rodent chow (Dyets) by use of feeders fabricated
in our laboratory. All sodium intake was delivered by
intravenous infusion of sterile isotonic saline. The range
of sodium intake was chosen based on preliminary experiments in which
mice maintained on normal chow (1.0% NaCl) had an average daily sodium
intake of 530 µmol/d; this level of sodium intake was used as
a reference to normal intake, with the lower and upper levels of sodium
intake spaced around that value. Mice were initially infused with
saline at 1 mL/d to provide 150 µmol of sodium per day. After
3 days on this regimen, the intravenous infusion was
increased to 3 mL/d (450 µmol/d) for an additional 3-day
period. Finally, the infusion was increased to 6 mL/d (900
µmol/d) for the final 3 days of this protocol. This technique is an
adaptation of a method we have used to perform sodium balance studies
in rats.19
The MAP and heart rate (HR) of the mice were measured on each day of the experiment during a 2- to 3-hour recording period. After the recording period, the daily urine volume was measured and the urine collection funnel on each individual cage was washed with distilled water. This wash volume was added to the urine, the total volume of the urine and wash was determined, and the sodium concentration of the solution was determined by flame photometry.
Protocol 2: Daily and Cumulative Sodium Balance in Conscious
Mice After Furosemide Administration
Experiments in protocol 1 were performed to document the ability
to measure sodium balance over a 6-fold range of sodium intake.
Experiments in this protocol were designed to demonstrate the ability
to quantify changes in daily and cumulative sodium balance during and
after the administration of an agent known to alter renal sodium
handling (furosemide). Mice were prepared as described above and
infused intravenously with isotonic saline at 3 mL/d
(450 µmol/d NaCl). After 3 control days, furosemide was added to
the intravenous infusate to deliver 50 mg ·
kg-1 · d-1 for 24
hours. The infusion was then returned to saline for the final 2
postcontrol days. MAP was measured from 5 of the mice during a 2- to
3-hour period each day, and daily measurements of body weight were
obtained from all mice on each day of the protocol.
Protocol 3: Dose-Response Effect of Captopril on MAP and Pressor
Response to Ang I in Conscious Mice
Mice were instrumented as described above with chronic
indwelling femoral arterial and venous catheters. After a
5- to 7-day recovery from surgery, the blood pressure of the mice was
measured during a 2- to 3-hour daily recording period. During
the control period, the mice were infused intravenously
with saline (3.0 mL/d) and maintained ad libitum on normal chow (1.0%
NaCl) and tap water. After 2 stable control days of blood pressure
measurement, the intravenous infusate was switched to
captopril in saline to deliver 20 mg/kg per day for the first 24 hours,
40 mg · kg-1 ·
d-1 for the next 24 hours, and 80 mg ·
kg-1 · d-1 for the
final 24 hours. Blood pressure was measured after a 24-hour infusion of
each dose of captopril.
A similar protocol was performed to evaluate the pressor response to an
intravenous bolus of Ang I. Preliminary studies
demonstrated a dose-dependent effect of Ang I to increase MAP in doses
from 1 to 10 ng in a 0.1-mL saline bolus. The bolus volume itself had a
minimal influence on blood pressure (<3 mm Hg). It was
determined that the 10-ng Ang I bolus reproducibly increased MAP by
20 mm Hg. The increase in MAP after administration of a 10-ng
bolus of Ang I was, therefore, evaluated on an initial control day and
after 24 hours of infusion of captopril at rates of 20, 40, and 80
mg · kg-1 ·
d-1 on successive days in the same animal. An
additional protocol was performed in a separate group in which the MAP
response to an Ang I bolus was measured during a control day and after
5 days of intravenous captopril (40 mg ·
kg-1 · d-1). The
Ang I bolus was administered twice each day, and the average of the 2
measurements was taken as the value for that day.
Protocol 4: Influence of Chronic Intravenous Captopril
on MAP and Sodium Balance in Conscious Mice
Mice were instrumented and housed in individual
metabolic cages as described above. The animals were given
sodium-free liquid chow and tap water ad libitum. All sodium
was delivered intravenously in saline (1 mL/d). After 2
stable control days, captopril was added to the intravenous
infusate to deliver 40 mg · kg-1 ·
d-1. After 5 days of captopril, the drug
infusion was stopped and saline was infused for an additional 5
postcontrol days. Daily measurements of MAP, HR, sodium excretion, and
body weight were obtained throughout this protocol.
Statistical Methods
Data are expressed as mean±SE. The within-group changes were
evaluated using 1-way ANOVA for repeated measures with a Tukey post hoc
test. Between-group comparisons were made with 2-way ANOVA. A
probability level of P<0.05 was considered significant.
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Results |
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Protocol 1: Sodium Balance and MAP in Conscious Mice Maintained on Different Daily Sodium Intakes
The MAP, daily sodium intake and output, and daily sodium balance values from the initial group of mice are illustrated in Figure 1
. As shown in the middle panel, sodium
intake was maintained at 165 to 180 µmol/d for 3 days, increased
to 460 to 490 µmol/d for 3 additional days, and finally
increased to 830 to 950 µmol/d for a final 3-day period in
conscious Swiss Webster mice (n=7). Neutral sodium balance, indicated
by no difference between sodium intake and output, was achieved in the
mice during each of the 3 days in which they were maintained on the
lower level of sodium intake. On the first day after the transition
from low to normal sodium intake, 125±44 µmol of sodium was
retained (P<0.05). By the second and third day at this
level, sodium intake and output were again equal. The same general
pattern was observed after the transition from the normal to high level
of sodium intake. Sodium was retained (99±23 µmol of sodium,
P<0.05) on the initial day at the upper level of sodium
intake, but the mice came into a steady state by the second day at this
level of sodium intake. Despite the significant sodium retention on the
initial day after the increase to both normal and high sodium intake,
the calculated cumulative sodium balance was not significantly altered
throughout the protocol. Cumulative balance averaged -53±67
µmol of sodium on the third day on low sodium intake, a value not
significantly different from the average of 146±145 µmol
observed on the third day of high sodium intake. MAP, HR, and body
weight were also unaltered throughout the protocol, averaging
115±8 mm Hg, 646±12 bpm, and 33.9±0.6 g, respectively, on the
final day of low sodium intake and 118±8 mm Hg, 683±15 bpm, and
34.2±0.7 g on the final day of the high sodium intake.
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The daily sodium balance data from the final 2 days (steady-state
conditions) at each level of sodium intake in this protocol and the
control data from protocols 2, 3, and 4 (described below) were pooled
to evaluate the ability to accurately collect sodium output in mice
during steady-state conditions with intakes ranging from 160 to
1012 µmol/d (n=20 mice on 75 individual days, Figure 2). The mean recovery (measured sodium
output divided by intake) averaged 100±3% for all days. A linear
regression on these data had a correlation coefficient of 0.93, a slope
of 0.96, and a y intercept of 31 µmol.
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Protocol 2: Daily and Cumulative Sodium Balance in Conscious
Mice After Furosemide Administration
Daily and cumulative sodium balance results from this
experiment are presented in Figure 3. Daily sodium balance averaged
1±24 µmol, cumulative sodium balance averaged -21±28
µmol, and body weight averaged 42.2±0.9 g on the third control day
(n=7). After 24 hours of furosemide infusion, daily sodium balance
significantly decreased to -360±31 µmol (P<0.01),
cumulative sodium balance significantly decreased to -381±40
µmol (P<0.01), and body weight significantly decreased to
39.0±1.9 g (P<0.01). MAP measured from 5 mice averaged
117±4 mm Hg on the third control day and decreased to
100±1 mm Hg after furosemide (P<0.05). After 1 day
of saline infusion after furosemide administration (postcontrol day 1),
sodium balance averaged 332±33 µmol and cumulative balance was
not significantly different from control. By the second postcontrol
day, daily sodium balance also returned to levels no different from
control (-56±84 µmol/d), and MAP averaged 111±2
mm Hg.
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P<0.01 from
value on control day 3.
Protocol 3: Dose-Response Effect of Captopril on MAP and Pressor
Response to Ang I in Conscious Mice
Chronic intravenous captopril infusion led to a
progressive decrease in MAP from a control value of 117±5 mm Hg
to 94±4, 82±5, and 77±7 mm Hg as the daily infusion rate was
increased from 20 to 40 and finally to 80 mg ·
kg-1 · d-1,
respectively, on 3 successive days (n=8, P<0.01). HR was
not significantly altered from the control value of 623±27 bpm
throughout the protocol. The blood pressure response to a 10-ng bolus
of Ang I averaged 22±2 mm Hg during the control period and
decreased to 13±2, 11±2, and 6±1 mm Hg over this same dose
range (n=6, P<0.01). In a final group of mice (n=5), it was
determined that the pressor response to a 10-ng intravenous
Ang I bolus was significantly reduced from 24±5 to 6±2 mm Hg
after 5 successive days of captopril infusion at 40 mg ·
kg-1 · d-1
(P<0.05).
Protocol 4: Influence of Chronic Intravenous Captopril
on MAP and Sodium Balance in Conscious Mice
The long-term influence of intravenous captopril
infusion on MAP and daily sodium balance in mice maintained on a sodium
intake of 200 µmol/d is illustrated in Figure 4 (n=6). Daily sodium balance, cumulative
sodium balance, MAP, and body weight averaged -7±20 µmol,
-16±35 µmol, 114±5 mm Hg, and 36.2±1.7 g,
respectively, on the second control day. MAP significantly decreased
from 114±5 mm Hg on the second control day to 95±6 mm Hg
after 1 day and to 58±3 mm Hg on the fifth day of captopril
infusion (P<0.01). The decrease in arterial
pressure was accompanied by increased sodium excretion that led to a
significantly negative sodium balance (-117±21 µmol/d,
P<0.05) on the third day of captopril infusion. As the
experiment progressed, cumulative sodium balance became more negative
and body weight significantly (P<0.01) decreased, averaging
-270±56 µmol and 33.1±1.5 g on the fifth day of captopril
infusion. Interestingly, when the captopril infusion was stopped, the
daily sodium balance tended to become positive as MAP returned toward
control values. It was observed, however, that both MAP and cumulative
sodium balance were significantly (P<0.01) lower than the
control values, averaging 83±5 mm Hg and -177±97 µmol
of sodium after 5 postcontrol days.
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Discussion |
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The present studies describe an experimental method in which accurate daily sodium balance can be obtained from conscious mice over a 5-fold range of sodium intake (200 to 1000 µmol/d). As demonstrated by the furosemide study, this technique can also be used to accurately quantify changes in cumulative sodium balance. This method was then used to examine the influence of ACEI in conscious mice. Continuous intravenous infusion of captopril (40 mg · kg-1 · d-1) decreased blood pressure response to an Ang I bolus by 75% and led to marked hypotension. The decrease in MAP was associated with a significant decrease in cumulative sodium balance, indicating that at least part of the hypotensive effect of ACEI in mice is because of increased sodium excretion and contraction of extracellular fluid volume.
The goal of the present experiments was to examine the renal and cardiovascular effects of pharmacological blockade of ACE in conscious mice. Despite the ability to chronically monitor pressure and infuse compounds intravenously into conscious mice,18 the accurate measurement of sodium balance was found to be extremely difficult. Our original strategy to determine balance in mice was to measure the amount of food consumed and to collect the urinary output. We have previously noted in rats, however, that accurate balance measurements are extremely difficult to perform when sodium intake is in solid chow.19 This is apparently because of difficulty in quantifying the amount of food consumed and because of fecal loss of sodium, problems that are even more exaggerated in mice. To avoid these problems, the mice were fed a sodium-free liquid diet ad libitum and all sodium intake was delivered intravenously. This method permitted the collection of an average of 100±3% of sodium intake over a 5-fold range, allowing accurate collection of urinary sodium output and precise control of sodium intake.
The results of protocol 2 are further evidence of the utility of this method to accurately measure sodium balance. In this experiment, cumulative sodium balance returned to a level not significantly different from control after the mice underwent a 6-day protocol that included 3 control days, a 24-hour intravenous infusion of furosemide (which led to a loss of >300 µmol of sodium for that day), and 2 postcontrol days. Despite daily sodium balance measurements that were significantly positive or negative on 2 of the 6 experimental days, the final cumulative balance point was not significantly different from control in this study. This experiment demonstrated that this approach can be used to account for most of the sodium that has been lost or gained in an individual protocol. Together, these validation data indicate that daily and cumulative sodium balance can be accurately measured in mice by use of this procedure.
In addition to the validation of the balance-measurement technique, several interesting observations arose from protocols 1 and 2. First, MAP, cumulative sodium balance, and body weight were not altered after the 9-day protocol in which sodium intake was successively increased from 150 to 900 µmol/d. The lack of sodium sensitivity of blood pressure in the normal mouse is similar to that observed in normotensive rats20 and dogs.14 A second interesting observation from these validation experiments was the relatively rapid adjustment of the renal/cardiovascular system to changes in dietary sodium intake or altered urinary sodium output. When sodium intake was incrementally increased from either low to normal or normal to high in protocol 1, or when intake was maintained constant and furosemide was administered in protocol 2, an alteration in daily sodium balance was observed on the initial day. Neutral sodium balance, however, was achieved in each case by the second day after the alteration in balance. The integrated renal, cardiovascular, neuronal, and hormonal regulation of fluid and electrolyte homeostasis appears to function very efficiently within a 1- to 2-day period after an alteration in sodium balance in the mouse.
The final experiments in this study evaluated the influence of a 5-day infusion of captopril (40 mg · kg-1 · d-1) on MAP and sodium balance in conscious mice maintained on a low (200 µmol/d) sodium intake. ACEI had an extremely potent influence on MAP, decreasing pressure from 114 to 58 mm Hg after only 5 days of infusion. This surprisingly potent effect on arterial pressure was accompanied by a cumulative loss of 270 µmol of sodium and a decrease in body weight that exceeded 3 g, indicating that a portion of the hypotensive response to ACEI was because of contraction of the extracellular volume. It was also observed, however, that blood pressure rapidly fell after only 1 day of captopril infusion before any changes were observed in sodium balance. It is therefore likely that part of the decrease in MAP in the conscious mouse was because of a decrease in total peripheral resistance.
The changes in arterial pressure after captopril observed
in the present study compare favorably with the results previously
obtained in mice in which the ACE gene was deleted. Systolic
arterial pressure was reduced by 30 to 40 mm Hg when
measured by tail-cuff plethysmography,5 7 and MAP
was reduced by approximately 50 mm Hg as measured by direct
arterial
catheterization6 in conscious
mice lacking ACE. Furthermore, the MAP response to a 100-ng/kg IV bolus
of Ang I was decreased from 29 mm Hg in wild-type mice to
5 mm Hg in mice with the ACE gene
absent.6 Both the hypotensive response (MAP
decreased by 56 mm Hg) and the decreased pressor response to a
10-ng Ang I bolus (24 versus 6 mm Hg) after 5 days of
intravenous captopril infusion in the present
experiments qualitatively agree with the data generated in ACE gene
deletion mice. Interestingly, the effect of ACEI in mice was relatively
potent compared with that observed in other species. Though
normotensive humans,12 13
dogs,14 15 16 and rats17
maintained on a low sodium intake or depleted of sodium exhibit a
hypotensive response after ACEI, the magnitude of the hypotensive
response was not as large as that observed in the present study. In
studies in sodium-deprived dogs14 15 and
rats,17 a decrease in MAP to approximately
70 mm Hg occurred after chronic ACEI. The mechanism of the
hypotensive response in the mouse presumably involves blockade of the
formation of Ang II from Ang I. However, it is possible that other
mechanisms may also participate in this hypotensive response in the
mouse. The decrease in blood pressure observed in mice in which the ACE
gene has been genetically deleted5 7 and with the
pharmacological blockade of ACE in this study is much greater than the
decrease in blood pressure observed in mice with
angiotensinogen gene deleted4 or the
decrease in blood pressure observed in mice deficient in the
AT1 receptor.8 9 It is
conceivable that kinins or other humoral and/or paracrine factors could
participate in the potent blood pressure–lowering effect observed in
mice in which ACE activity has been genetically or pharmacologically
reduced. Experiments to explore this possibility remain to be
performed.
In summary, the present experiments demonstrate a technique that allows the quantitative measurement of daily and cumulative sodium balance in conscious mice. This technique was used to demonstrate the changes in sodium balance that occur during chronic ACEI in conscious mice. The influence of sodium intake on the hypotensive response to ACEI in mice, the relative role of Ang II, kinins, or other humoral mediators in this response, and the mechanisms (renal, vascular, or mixed) of this hypotensive response remain to be examined. The pharmacological approach to study ACE in mice in this study complements the previously reported results obtained using genetic deletion to further lend to our understanding of the importance of ACE in blood pressure control. While the genetic manipulation approach permits a much more selective manipulation of ACE without the dose-sensitive effects and possible undesirable side effects of pharmacological agents, the approach used in the present study permits the examination of a single animal before and after inhibition of the targeted system and allows the examination of transient changes in hemodynamic and/or fluid and electrolyte balance that may ultimately contribute to the long-term changes in blood pressure.
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Acknowledgments |
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This work was partially supported by grants HL-29587 and DK-50739 from the National Institutes of Health, Bethesda, MD. The authors thank Timothy Bachman for technical assistance with some of these protocols.
Received April 3, 1998; first decision April 30, 1998; accepted July 1, 1998.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Chien KR. Genes and physiology: molecular physiology in genetically engineered animals. J Clin Invest. 1996;98:S19–S26.
2. Merrill DC, Thompson MW, Carney CL, Schlager G, Robillard JE, Sigmund CD. Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes. J Clin Invest. 1996;97:1047–1055.[Medline] [Order article via Infotrieve]
3.
Thompson MW, Merrill DC, Yang G, Robillard JE, Sigmund
CD. Transgenic animals in the study of blood pressure regulation and
hypertension. Am J Physiol. 1995;269:E793–E803.
4.
Kim HS, Krege JH, Kluckman KD, Hagaman JR, Hodgin JB,
Best CF, Jennette JC, Coffman TM, Maeda N, Smithies O. Genetic control
of blood pressure and the angiotensinogen locus. Proc
Natl Acad Sci U S A. 1995;92:2735–2739.
5. Krege JH, John SWM, Langenbach LL, Hodgin JB, Hagaman JR, Bachman ES, Jennette JC, O'Brien DA, Smithies O. Male-female differences in fertility and blood pressure in ACE-deficient mice. Nature. 1995;375:146–148.[Medline] [Order article via Infotrieve]
6.
Tian B, Meng OC, Chen Y-F, Krege JH, Smithies O,
Oparil S. Blood pressures and cardiovascular
homeostasis in mice having reduced or absent
angiotensin-converting enzyme gene function.
Hypertension. 1997;30:128–133.
7. Esther CR Jr, Howard TE, Marino E, Goddard JM, Capecchi MR, Bernstein KE. Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male fertility. Lab Invest. 1996;74:953–965.[Medline] [Order article via Infotrieve]
8.
Ito M, Oliverio ML, Mannon PJ, Best CF, Maeda N,
Smithies O, Coffman TM. Regulation of blood pressure by the type 1A
angiotensin II receptor gene. Proc Natl Acad Sci
U S A. 1995;92:3521–3525.
9.
Sugaya T, Nishimatsu S-I, Tanimoto K, Takimoto E,
Yamagishi T, Imamura K, Goto S, Imaizumi K, Hisada Y, Otsuka A, Uchida
H, Sugiura M, Fukuta K, Fukamizu A, Murakami K. Angiotensin
II type 1A receptor-deficient mice with hypotension and hyperreninemia.
J Biol Chem. 1995;270:18719–18722.
10. Hein L, Barsh GS, Pratt RE, Dzau VJ, Kobilka BK. Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor gene in mice. Nature. 1995;377:744–747.[Medline] [Order article via Infotrieve]
11. Ichiki T, Labosky PA, Shiota C, Okuyama S, Imagawa Y, Fogo A, Niimura F, Ichikawa I, Hogan BL, Inagami T. Effects on blood pressure and exploratory behaviour of mice lacking the angiotensin type-2 receptor. Nature. 1995;377:748–750.[Medline] [Order article via Infotrieve]
12. MacGregor GA, Markandu ND, Roulston JE. Does the renin-angiotensin system maintain blood pressure in both hypertensive and normotensive subjects? A comparison of propranolol, saralasin, and captopril. Clin Sci. 1979;57:145s–148s.
13. MacGregor GA, Markandu ND, Roulston JE, Jones JC, Morton JJ. The renin-angiotensin-aldosterone system: a normal mechanism for maintaining blood pressure in normotensive and hypertensive subjects. In: Horovitz ZP, ed. Angiotensin Converting Enzyme Inhibitors: Mechanisms of Action and Clinical Implications. Baltimore-Munich: Urban & Schwartzenberg; 1981.
14. Hall JE, Guyton AC, Smith MJ Jr, Coleman TC. Blood pressure and renal function during chronic changes in sodium intake: role of angiotensin. Am J Physiol. 1980;239:F271–F280.
15.
Hall JE, Guyton AC, Smith MJ Jr, Coleman TC. Chronic
blockade of angiotensin II formation during sodium
deprivation. Am J Physiol. 1979;237:F424–F432.
16. McCaa RE, Hall JE, McCaa CS. The effects of angiotensin I-converting enzyme inhibitors on arterial blood pressure and urinary sodium excretion. Circ Res. 1978;43:I-33–I-39.
17. Bengis RG, Coleman TG, Young DB, McCaa RE. Long-term blockade of angiotensin formation in various normotensive and hypertensive rat models using converting enzyme inhibitor (SQ 14,225). Circ Res. 1978;43:I-45–I-53.
18. Mattson DL. Long-term measurement of arterial blood pressure in conscious mice. Am J Physiol. 1998;274:R564–R570.
19.
Mattson DL, Lu S-H, Nakanishi K, Papanek PE, Cowley AW
Jr. Effect of chronic renal medullary nitric oxide inhibition on blood
pressure. Am J Physiol. 1994;266:H1918–H1926.
20. Norman RA Jr, Enobakhare JA, DeClue JW, Douglas BH, Guyton AC. Arterial pressure-urinary output relationship in hypertensive rats. Am J Physiol. 1978;234:R98–R103.
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B. C. Cholewa and D. L. Mattson Role of the renin-angiotensin system during alterations of sodium intake in conscious mice Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2001; 281(3): R987 - R993. [Abstract] [Full Text] [PDF]
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 A. Russell and S. Watts Vascular Reactivity of Isolated Thoracic Aorta of the C57BL/6J Mouse J. Pharmacol. Exp. Ther., August 1, 2000; 294(2): 598 - 604. [Abstract] [Full Text]
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 S. Rao and A. S. Verkman Analysis of organ physiology in transgenic mice Am J Physiol Cell Physiol, July 1, 2000; 279(1): C1 - C18. [Abstract] [Full Text] [PDF]
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 J. Tornel, M. I. Madrid, M. Garcia-Salom, K. J. Wirth, and F. J. Fenoy Role of Kinins in the Control of Renal Papillary Blood Flow, Pressure Natriuresis, and Arterial Pressure Circ. Res., March 17, 2000; 86(5): 589 - 595. [Abstract] [Full Text] [PDF]
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S. H. Carlson and J. M. Wyss Long-Term Telemetric Recording of Arterial Pressure and Heart Rate in Mice Fed Basal and High NaCl Diets Hypertension, February 1, 2000; e5(2): . [Abstract] [Full Text] [PDF]
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B. J. A. Janssen, P. J. A. Leenders, and J. F. M. Smits Short-term and long-term blood pressure and heart rate variability in the mouse Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2000; 278(1): R215 - R225. [Abstract] [Full Text] [PDF]
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 P. L. Sinn, X. Zhang, and C. D. Sigmund JG cell expression and partial regulation of a human renin genomic transgene driven by a minimal renin promoter Am J Physiol Renal Physiol, October 1, 1999; 277(4): F634 - F642. [Abstract] [Full Text] [PDF]
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