Hypertension
Laboratory Studies
Effect of Captopril and Hydralazine on Arterial
Pressure-Urinary Output Relationships in
Spontaneously Hypertensive Rats
ROBERT L. KLINE AND PAUL F. MERCER
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
SUMMARY Angiotensin I converting enzyme inhibitors are typically classified as peripheral vasodilators. We studied the effect of captopril and a known vasodilator, hydralazine, on arterial pressure-urinary output relationships in adult spontaneously hypertensive rats to determine whether
these drugs produced similar changes in this relationship. Tail-cuff pressure and 24-hour urine output
and sodium excretion were measured under steady state conditions during ingestion of tap water or
saline (1% NaCI) ad libitum. Sodium intake increased seven to nine times when rats drank saline, but
in the absence of drug treatment, tail-cuff pressure was not altered significantly (water, 213 ± 3 vs
saline, 220 ± 5 mm Hg). Daily administration of captopril (100 mg/kg p.o.) or hydralazine (15 mg/kg
p.o.) for 2 weeks lowered tail-cuff pressure significantly (175 ± 3 and 166 ± 3 mm Hg, respectively;
p<0.01) while rats drank tap water. Continued administration of hydralazine plus 2 weeks of
drinking saline did not alter tail-cuff pressure (162 ± 4 mm Hg), but with the addition of saline during
captopril treatment, tail-cuff pressure was elevated significantly (210 ± 5 mm Hg; p<0.01). Thus,
hydralazine produced a parallel shift of the arterial pressure-urinary output relationship along the
pressure axis. In contrast, captopril produced a marked change in the slope of this relationship,
making arterial pressure extremely salt-sensitive. The results suggest that the two drugs have different
effects on the mechanisms that contribute to the long-term control of arterial pressure. The changes
associated with captopril treatment are consistent with the removal of the normal renal effects of the
renin-angiotensin system, rather than with a nonspecific peripheral vasodilation.
(Hypertension 10: 590-594, 1987)
KEY WORDS • renal function curve • sodium excretion • sodium sensitivity
antihypertensive drugs • captopril • spontaneously hypertensive rats
the kidneys to excrete sodium and water is a primary
determinant of the long-term steady state level of arterial pressure.2-3 The importance of pressure-diuresis
and pressure-natriuresis to the long-term control of
arterial pressure has recently been reviewed.4 This relationship between arterial pressure and excretion of
sodium and water by the kidneys, called the renal
function curve (RFC), has also been described for several models of experimental hypertension.5"7 Clearly,
many factors, including antihypertensive drugs, are
capable of changing the position and slope of the RFC
and thus are capable of changing the steady state level
of arterial pressure. To date, this concept has not been
used to characterize the effects of antihypertensive
drugs in basic or clinical research (i.e., to determine
how commonly used antihypertensive drugs alter the
RFC). Such information may help in understanding the
mechanism of action of these agents.
We have used this approach in a simple experimental paradigm to characterize the effect of a vasodilator,
hydralazine, and a converting enzyme inhibitor, capto-
A LTHOUGH numerous types of drugs are effec/ \
tive in treating primary hypertension, the
A. \ - physiological changes leading to the decrease
in arterial pressure during administration of these
drugs are not well documented. One of the major obstacles to understanding the mechanism of action of
antihypertensive agents is the failure to adequately describe the pathophysiology of hypertension. Using a
systems analysis approach, Guyton et al.1 have provided a useful conceptual framework for understanding the long-term control of the circulation in normal
and abnormal conditions, including hypertension. According to the predictions of their model, the ability of
From the Department of Physiology, Health Sciences Center,
University of Western Ontario, London, Ontario, Canada.
Supported by the Heart and Stroke Foundation of Ontario.
Address for reprints: Dr. R. L. Kline, Department of Physiology,
University of Western Ontario, London, Ontario, Canada N6A
5C1.
Received March 27, 1987; accepted July 15, 1987.
590
RENAL FUNCTION CURVES IN SHRJKline and Mercer
pril, on the renal function curve of adult spontaneously
hypertensive rats (SHR). The results indicate that these
two drugs produce different effects on the RFC, suggesting that a direct, generalized reduction of vascular
resistance is not the primary mechanism of action of
captopril.
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
Materials and Methods
Fifteen male SHR (Charles River Breeding Laboratories, Montreal, Quebec, Canada) were maintained
on a diet of tap water and Purina rat chow (St. Louis,
MO, USA) ad libitum in individual metabolism cages
until 16 weeks of age, when rat chow pellets were
replaced with pulverized rat chow so that food intake
could be measured. Rats were handled repeatedly during this time and were fully accustomed to the restraining cage and equipment used to measure tail-cuff pressure (IITC, Woodland Hills, CA, USA). All rats were
subsequently cycled through a schedule of treatments
(each 2 weeks in duration; Table 1) beginning at 17
weeks of age, in which steady state measurements
were obtained during normal salt intake (rat chow plus
tap water ad libitum) or high salt intake (rat chow plus
1% NaCl drinking fluid ad libitum). Tap water was not
available to the rats during the high salt regimen.
Food intake, fluid intake, and urinary output were
measured over a 24-hour period twice each week. Urinary sodium concentration was measured using a
flame photometer (Model FLM3; Radiometer, Copenhagen, Denmark) and used to calculate sodium excretion. Tail-cuff pressure was measured twice a week
using a protocol described previously.8 Arterial pressure was not measured on days that were used to monitor intakes and outputs. Hydralazine (15 mg/kg p.o.)
and captopril (100 mg/kg p.o.) were given each moming in tap water (0.5 ml/100 g body weight) using a
standard pediatric feeding tube (5 F; 45 cm long).
These doses have been shown to lower arterial pressure
significantly when given chronically to SHR. 9 ' 10 On
days when tail-cuff pressure was measured, the drugs
were given after the measurement was made.
Results obtained during the second week of each
cycle were averaged to give values for that week. Data
were expressed as means ± SE. There was little difference between values for Week 1 and Week 2 in any
given condition, indicating rapid adjustment to new
steady state conditions. Data within the tap water and
1% NaCl conditions were analyzed using an analysis
of variance (ANOVA) with repeated measures (drug
treatments) followed by Newman-Keuls tests for differences between individual means." For the arterial
pressure data, an ANOVA for repeated measures (drug
treatments) under different conditions (tap water vs 1 %
NaCl) was done, followed by paired t tests of appropriate comparisons. To construct estimated RFCs, data
for average urine output and urinary sodium excretion
were plotted against average tail-cuff pressure during
tap water and 1% NaCl conditions. The slope of the
estimated RFC for each animal was calculated assuming a linear relationship between the two data points.
This was a reasonable assumption for the range of
591
sodium intake used in this study, based on a previous
detailed study of RFCs in the SHR.5 The reciprocal of
the slope was used to express the sensitivity of arterial
pressure to dietary sodium. A value was calculated for
each animal, averaged, and tested for statistical significance among groups using ANOVA and NewmanKeuls tests. Analyses yielding p values below 0.05
were considered to indicate statistically significant differences among treatments or between conditions.
Results
Complete results for both tap water and 1 % NaCl
conditions for each treatment were obtained in 10 rats.
Table 2 summarizes the input-output data while rats
were drinking tap water. After 2 weeks of either no
drug treatment, captopril treatment, or hydralazine
treatment there were no significant differences in food
or water intake among the groups, although urine output was significantly elevated during captopril treatment when compared with control or hydralazine treatment values, and sodium excretion during hydralazine
treatment was increased significantly compared with
control values. Tail-cuff pressure was decreased significantly during captopril treatment or hydralazine
treatment.
TABLE 1. Experimental Protocol Used to Cycle SHR Through
Normal and High Salt Intake Conditions and Drug Treatments
Drinking
fluid
Cycle
Treatment
1
2
3
4
5
6
normal salt diet Tap water Control (no drug)
normal salt diet Tap water Captopnl (100 mg/kg p.o.)
high salt diet
1% NaCl
Captopril
high salt diet
1% NaCl
Control
high salt diet
1% NaCl
Hydralazine (15 mg/kg p.o.)
normal salt diet Tap water Hydralazine
Each cycle lasted 2 weeks; rats had ad libitum access to normal
rat chow at all times.
TABLE 2. Effect ofChronic (2 wk) Administration of Captopril or
Hydralazine in 10 Adult SHR Fed Normal Salt Diet (Drinking Tap
Water Ad Libitum)
Captopril
Hydralazine
Control
(100 mg/kg)
(15 mg/kg)
Variable
Food intake
(g/24 hr)
23.2 + 0.7
22.7±0.5
21.0±0.6
Water intake
(ml/24 hr)
44.5+1.5
47.7 ±1.5
43.3 ±2.3
Urine volume
(ml/24 hr)
13.7 ± 1.6
18.5±4.1*
15.5±1.6*t
Sodium excretion
(mmol/24 hr)
1.48±0.14 1.59±0.07*
I.76±0.13*-t
Tail-cuff pressure
213 + 3
175±3*
166±3*4
(mm Hg)
Values are means ± SE of average values measured twice during
the second week of each cycle (see Table 1).
*p < 0.05, compared with control values (by Newman-Keuls test
after repeated-measures ANOVA).
tp<0.05, compared with captopril values (by Newman-Keuls
test after repeated-measures ANOVA).
HYPERTENSION
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
When rats were permitted free access to 1% NaCl
drinking fluid, sodium intake was increased approximately seven to nine times. During captopril treatment
the rats drank significantly less of the 1% NaCl solution than during the control or hydralazine conditions.
Food intake was increased slightly while rats were
receiving captopril, but urine volume and sodium excretion were significantly less during captopril treatment than during either control or hydralazine conditions (Table 3). Urine volume and sodium excretion
were also significantly less during hydralazine treatment when compared with the control values. Tail-cuff
pressure during captopril treatment was slightly but
significantly lower when compared with the control
value, while tail-cuff pressure during hydralazine
treatment was significantly lower when compared with
either the control or captopril treatment values. By
comparing the tap water and 1% NaCl conditions, it
can be seen that increasing the intake of NaCl did not
significantly alter tail-cuff pressure in the control condition or during hydralazine treatment, but it did significantly (/?<0.01) increase tail-cuff pressure during
captopril treatment.
Estimated RFCs for each treatment are summarized
in Figures 1 and 2. When the relationship of either
urine volume or sodium excretion was plotted against
tail-cuff pressure, compared with control values, hydralazine treatment produced a parallel shift of the
RFC along the pressure axis, while captopril treatment
produced a marked change in the slope of the RFC.
When the reciprocal of the slope of the RFC was used
as an index of the sensitivity of arterial pressure to
steady state changes in sodium load, arterial pressure
was found to be insensitive to dietary sodium during
control or hydralazine conditions, while during captopril treatment, arterial pressure was altered significantly by increasing sodium intake (Figure 3).
TABLE 3. Effect of Chronic (2 wk) Administration of Captopril or
Hydralazine in 10 Adult SHR Fed High Salt Diet (Drinking 1%
NaCl Ad Libitum)
Captopril
Hydralazine
(100 mg/kg)
Variable
Control
(15 mg/kg)
Food intake
24.5 ±0.8*
(g/24 hr)
21.0±0.4
22.0±0.6*t
Fluid intake
74.1 ±4.8*
90.1 ±6.8* t
(ml/24 hr)
93.0±7.8
Urine volume
42.0±4.8*
6O.8±6.5
50.4±5.8*t
(ml/24 hr)
Sodium
excretion
(mmol/
18.75±1.66 10.81 ±0.94* 14.68±1.32*t
24 hr)
Tail-cuff
pressure
210 + 4*
220 ±5
162±4*t
(mm Hg)
Values are means ± SE of average values measured twice during
the second week of each cycle (see Table 1).
*p<0.05, compared with control values (by Newman-Keuls test
after repeated-measures ANOVA).
t p < 0 . 0 5 , compared with captopril values (by Newman-Keuls
test after repeated-measures ANOVA).
VOL
10,
No
6,
DECEMBER
1987
75
60
45
i
o
UJ
z
30
c
=>
15
150
175
200
TAIL CUFF PRESSURE ImmHgl
225
FIGURE I. Arterial pressure-urine output relationships in 10
adult SHR during control conditions, captopril treatment, and
hydralazine treatment.
20
16
i 12
10*
592
tUJ
yu 8
a
Q
O
V)
4
0
150
175
200
225
TAIL CUFF PRESSURE ( mmHg )
FIGURE 2. Arterial pressure-sodium output relationships in
10 adult SHR during control conditions, captopril treatment,
and hydralazine treatment.
RENAL FUNCTION CURVES IN SUR/Kline and Mercer
2
2
8
3
'o
E 2
- 1 l-
CONTROL
CAPTOPRIL
HYDRALAZINE
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
FIGURE 3. Index of sensitivity of arterial pressure to changes
in dietary sodium in 10 adult SHR treated with captopril or
hydralazine. The value for each condition was calculated using
the reciprocal of the slope of the arterial pressure-sodium excretion relationship for each rat. Value for captopril was significantly (p<0.0l) different from that for the control or hydralazine conditions.
Discussion
We have used relatively simple experimental techniques to demonstrate that hydralazine and captopril
produce characteristically different effects on the RFC
of adult SHR. The estimated RFCs produced in the
present study by using measurements of tail-cuff pressure and 24-hour urine collections agree well with published RFCs obtained with carefully controlled loading
conditions and direct measurements of mean arterial
pressure. For example, Norman et al.5 showed that the
RFC in adult SHR was nearly vertical over the range of
sodium intakes used in the present study, and other
investigators have shown the relative insensitivity of
arterial pressure in adult SHR to changes in dietary
sodium.12'13 In addition, captopril is known to decrease
the slope of the RFC in normotensive dogs,14 and the
effect of captopril in increasing the sensitivity of arterial pressure to dietary sodium has been reported in SHR
during the development of hypertension.15 Finally, the
parallel shift of the RFC produced by hydralazine in
this study agrees with the effect of this drug on the RFC
of rats with established deoxycorticosterone acetatesalt hypertension.16 Thus, our results provide reasonable estimates of the RFC in untreated SHR and in
SHR treated with antihypertensive drugs. If we assume
that renal function is an important determinant of the
steady state level of arterial pressure,1"3 these results
provide useful clues to the mechanism of action of
these agents used to treat hypertension.
Both hydralazine9 and captopril10 are effective antihypertensive drugs when given chronically in the
SHR. Presumably, hydralazine acts primarily as a nonspecific peripheral vasodilator. 1718 The parallel shift
of the RFC in hydralazine-treated SHR is consistent
593
with predicted effects of a vasodilator (including renal
vasodilation) in conditions where the hypertension is
characterized by a vertical RFC." The primary physiological change leading to a sustained decrease in arterial pressure during chronic administration of converting
enzyme inhibitors is less well understood, although
peripheral vasodilation is frequently cited as the
mechanism of action of these drugs. 20 ' 21 The results of
Koike et al., 22 showing decreased regional vascular
resistance in SHR treated chronically with captopril,
seem to support this conclusion. In recent years, the
effectiveness of captopril in decreasing peripheral vascular resistance and arterial pressure has been interpreted as evidence for an involvement of an abnormal
vascular wall renin-angiotensin system in the maintenance of hypertension in SHR.23 Support for this
hypothesis comes from studies showing differences in
the renin-angiotensin system found in vascular tissue
of SHR compared with that seen in normotensive
rats 2423 and the correlation between the hypotensive
effects of converting enzyme inhibitors and inhibition
of the enzyme in various tissues, including blood vessels, during chronic treatment in SHR.26 Thus, inhibition of an abnormal vascular wall renin-angiotensin
system has been suggested to lead to peripheral vasodilation and to explain the antihypertensive activity of
captopril in renin-independent models of hypertension.23 If this were the case, then one might predict that
hydralazine, a known vasodilator, and captopril would
produce similar effects on the RFC. That this was not
the case suggests that captopril and hydralazine have
different effects on the mechanisms that contribute to
the long-term control of arterial pressure.
Norman et al.5 have shown that the RFC of adult
SHR is similar in shape to that seen in normotensive
rats, but shifted along the pressure axis. Our results,
showing a decreased slope of the RFC during captopril
treatment in the SHR, support the conclusion that the
renal effects of angiotensin II are important in maintaining the steep relationship between arterial pressure
and sodium excretion, thus making arterial pressure
relatively insensitive to changes in sodium intake.14
Based on these findings, we suggest that the major
antihypertensive effect of captopril administered
chronically in the adult SHR is due to removal of the
renal effects of angiotensin II. This view supports the
suggestion that the intrarenal renin-angiotensin system
is an important site of action of converting enzyme
inhibitors for producing chronic reductions in arterial
pressure in SHR,26 although removal of the effect of
circulating angiotensin II may also be involved. Captopril may decrease peripheral vascular resistance by
inhibiting the vascular wall renin-angiotensin system
in addition to altering renal function, but the changes
in regional vascular resistance may also be secondary
to local functional or structural adjustments associated
with the hemodynamics of altered renal function.
Vasodilation in the kidney may play a part in the specific action of captopril, 1421 but the overall effect on
the RFC is quite dissimilar to that produced by a peripheral vasodilator such as hydralazine.
594
HYPERTENSION
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
Moreover, the hypotensive effect of captopril may
not be specific for hypertensive conditions, but may
simply reveal the effect of chronic inhibition of the
renal effects of angiotensin II, which are normally
involved in the long-term control of arterial pressure. 14 - 27 ' 28 According to this reasoning, the fact that
captopril lowers arterial pressure in the SHR does not
necessarily mean that there are abnormalities in either
the circulating or local tissue renin-angiotensin systems but rather that, even when the renin-angiotensin
system is functioning normally, elimination of its important renal effects will lead to a decrease in arterial
pressure at normal or low levels of sodium intake. This
conclusion is supported by the observation that captopril lowers arterial pressure in normotensive animals14-29 and by the studies of MacGregor et al., 30
using normotensive and hypertensive subjects.
In summary, we have described a simple technique
for estimating RFCs in SHR and have shown the differential modification of this relationship by two commonly used antihypertensive drugs. The results are
consistent with the conclusion that the antihypertensive effect of captopril given chronically in the SHR is
due primarily to inhibition of the normal renal effects
of angiotensin II with subsequent changes in renal
function, rather than to a generalized vasodilation produced by inhibition of the vascular wall renin-angiotensin system.
Acknowledgments
The authors acknowledge the gift of captopril from S. J. Lucania,
of the Squibb Institute for Medical Research, Princeton, NJ, USA,
and the excellent technical assistance of Mrs. Ka-Yuk Chow.
References
1. Guyton AC, Coleman TG, Cowley AW Jr, Manning RD Jr,
Norman RA Jr, Ferguson JD. A systems analysis approach to
understanding long-range arterial blood pressure control and
hypertension. Circ Res 1974;35:159-176
2. Guyton AC. Arterial pressure and hypertension. Philadelphia:
Saunders, 1980:100-125 (Circulatory physiology; vol 3)
3. Guyton AC, Hall JE, Lohmeier TE, Jackson TE, Kastner PR.
Blood pressure regulation: basic concepts. Fed Proc 1981;
40:2252-2256
4. Hall JE, Guyton AC, Coleman TG, Mizelle HL, Woods LL.
Regulation of arterial pressure: role of pressure natriuresis and
diuresis. Fed Proc 1986;45:2897-2903
5. 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
6. Cowley AW Jr, Lohmeier TE. Changes in renal vascular sensitivity and arterial pressure associated with sodium intake during long-term intrarenal norepinephrine infusion in dogs. Hypertension 1979; 1:549-558
7. DeClue JW, Guyton AC, Cowley AW Jr, Coleman TG, Norman RA, McCaa RE. Subpressor angiotensin infusion, renal
sodium handling and salt-induced hypertension. Circ Res
1978;43:503-512
8. Kline RL, Kelton PM, Mercer PF. Effect of renal denervation
on the development of hypertension in spontaneously hypertensive rats. Can J Physiol Pharmacol 1978;56:818-822
9. Jespersen LT, Nyborg NCB, Pedersen OL, Mikkelsen EO,
Mulvany MJ. Cardiac mass and peripheral vascular structure in
hydraiazine-treated spontaneously hypertensive rats. Hypertension 1985;7:734-741
10. Rubin B, Antonaccio MJ, Horovitz ZP. The antihypertensive
effects of captopril in hypertensive animal models. In: Horo-
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
VOL 10, No 6, DECEMBER
1987
vitz ZP, ed. Angiotensin converting enzyme inhibitors. Baltimore; Munich: Urban and Schwarzenberg, 1981:27-53
Winer BJ. Statistical principles in experimental design. New
York: McGraw-Hill, 1971:518-532
Ely DL, Norlander M, Friberg P, Folkow B. The effects of
varying sodium diets on hemodynamics and fluid balance in
the spontaneously hypertensive rat. Acta Physiol Scand
1986; 126:199-207
Peuler JD, Beyer KH Jr. Sodium balance and blood pressure
during high sodium ingestion in spontaneously hypertensive
and Wistar Kyoto normotensive rats. Pharmacology 1985;
30:83-85
Hall JE, Guyton AC, Smith MJ Jr, Coleman TG. Blood pressure and renal function during chronic changes in sodium intake: role of angiotensin. Am J Physiol 1980;239:F271-F280
Coleman TG, Samar RE. Sodium-angiotensin interaction in
the Okamoto spontaneously hypertensive rat (SHR) [Abstract].
Fed Proc 1981;40:435
Sugai T, Nakagawa Y, Takeda K, Imai S. Arterial pressureurinary output relationship in DOCA-saline hypertensive rats.
Am J Physiol 1983;245:R633-R636
van Zwieten PA. Vasodilator drugs with direct action on
smooth muscle. In: van Zwieten PA, ed. Pharmacology of
antihypertensive drugs. Amsterdam: Elsevier Sciences Publishers BV, 1984:307-330 (Handbook of hypertension; vol 3)
Struyker-Boudier HAJ, Van Essen H, Smits JFM. Hemodynamic effects of the arteriolar vasodilators hydralazine, dihydralazine and endralazine in the conscious spontaneously hypertensive rat. Eur J Pharmacol 1983;95:151-159
Guyton AC. Arterial pressure and hypertension. Philadelphia:
Saunders, 1980:500-501 (Circulatory physiology; vol 3)
Scriabine A, Johnson CE. Vasodilators in hypertension. In:
Ong HH, Lewis JC, eds. Hypertension: physiological basis and
treatment. New York: Academic Press, 1984:193-231
Sweet CS, Blaine EH. Angiotensin-converting enzyme inhibitors. In: van Zwieten PA, ed. Pharmacology and antihypertensive drugs. Amsterdam: Elsevier Science Publishers BV,
1984:343-363 (Handbook of hypertension; vol 3)
Koike H, Ito K, Miyamoto M, Nishino H. Effects of long-term
blockade of angiotensin converting enzyme with captopril (SQ
14,225) on hemodynamics and circulating blood volume in
SHR. Hypertension 1980;2:299-303
Dzau VJ. Significance of the vascular renin-angiotensin pathway. Hypertension 1986;8:553-559
Antonaccio MJ, Kerwin L. Pre- and postjunctional inhibition
of vascular sympathetic function by captopril in SHR: implication of vascular angiotensin II in hypertension and antihypertensive actions of captopril. Hypertension 1981;3(suppl I):
I-54-I-62
Asaad MM, Antonaccio MJ. Vascular wall renin in spontaneously hypertensive rats: potential relevance to hypertension
maintenance and antihypertensive effect of captopril. Hypertension 1982;4:487-493
Unger T, Ganten D, Lang RE, Scholkens BA. Is tissue converting enzyme inhibition a determinant of the antihypertensive efficacy of converting enzyme inhibitors? Studies with two
different compounds, Hoe498 and MK421, in spontaneously
hypertensive rats. J Cardiovasc Pharmacol 1984;6:872-880
Hall JE. Control of sodium excretion by angiotensin II: intrarenal mechanisms and blood pressure regulation. Am J Physiol
1986;250:R960-R972
Hall JE, Mizelle HL, Woods LL. The renin-angiotensin system
and long-term regulation of arterial pressure. J Hypertens
1986;4:387-397
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(suppl I):45-53
MacGregor GA, Markander 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. Baltimore; Munich: Urban and
Schwarzenberg, 1981:329-349
Effect of captopril and hydralazine on arterial pressure-urinary output relationships in
spontaneously hypertensive rats.
R L Kline and P F Mercer
Hypertension. 1987;10:590-594
doi: 10.1161/01.HYP.10.6.590
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1987 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://hyper.ahajournals.org/content/10/6/590
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in
Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located, click
Request Permissions in the middle column of the Web page under Services. Further information about this
process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Hypertension is online at:
http://hyper.ahajournals.org//subscriptions/