(Hypertension. 2001;37:485.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Endothelin Type A Receptor Blockade Attenuates the Hypertension in Response to Chronic Reductions in Uterine Perfusion Pressure
From the Departments of Physiology and Obstetrics and Gynecology, Center for Excellence in Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson.
Correspondence to Joey P. Granger, PhD, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216-4505. E-mail jgranger{at}physiology.umsmed.edu
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Abstract |
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A chronic reduction in uterine perfusion pressure in pregnant rats is associated with a significant elevation in mean arterial pressure (MAP) and reduction in kidney function. The purpose of this study was to examine the role of endothelin in mediating the hypertension in response to chronic reductions in uterine perfusion pressure in conscious, chronically instrumented, pregnant rats. MAP in pregnant rats with chronic reductions in uterine perfusion pressure (123.0±1.8 mm Hg) was significantly higher than that in control pregnant rats (101.3±4.0 mm Hg). Renal expression of preproendothelin mRNA as determined by ribonuclease protection assay was also significantly elevated in the medulla (>45%, P<0.05) and in the cortex (>22%, P<0.05) of the pregnant rats with chronic reductions in uterine perfusion pressure compared with control pregnant rats. Chronic administration of the selective endothelin type A receptor antagonist (ABT-627, 5 mg/kg per day for 10 days) markedly attenuated the increase in MAP observed in the pregnant rats with chronic reductions in uterine perfusion pressure (103.3±5.6 mm Hg, plus endothelin antagonist; P<0.05). However, endothelin type A receptor blockade had no significant effect on blood pressure in the normal pregnant animals (96.0±2.7 mm Hg, plus endothelin antagonist). These findings suggest that endothelin plays a major role in mediating the hypertension produced by chronic reductions in uterine perfusion pressure in pregnant rats.
Key Words: preeclampsia • hypertension, pregnancy • endothelial growth factors • endothelin • receptors, endothelin
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Introduction |
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Hypertensive disorders of pregnancy, such as preeclampsia, occur in 6% to 8% of all pregnancies.1 2 Despite being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are unknown.1 2 3 The hypertension associated with preeclampsia develops during pregnancy and abates after delivery, implicating the placenta as a central culprit in this disease.1 3 The initiating event in preeclampsia has been postulated to involve reduced placental perfusion, which leads to widespread dysfunction of the maternal vascular endothelium by mechanisms that are unknown and may involve a delicate balance of vasodilators and vasoconstrictors, of which endothelin may play an important role.1 2 3
Endothelin, an endothelium-derived peptide, is a potent vasoconstrictor.4 Because endothelial damage is a known stimulus for endothelin synthesis,5 increases in the production of endothelin may participate in preeclampsia. Evidence indicates that endothelin may play an important role in mediating the physiological changes that occur during preeclampsia.6 A number of studies have found increased plasma concentrations of endothelin in women with preeclampsia compared with normotensive pregnant women.7 8 9 Elevation of the circulating levels of endothelin in pregnant sheep resulted in a significant increase in mean arterial pressure (MAP), renal vascular resistance, and proteinuria,10 all features observed in women with preeclampsia.1 2 An endothelin type A (ETA)-selective receptor antagonist significantly attenuated the hypertension induced by a chronic infusion of the NO synthase inhibitor NG-nitro-L-arginine methyl ester in pregnant rats, thus supporting a role for endothelin in mediating the hypertension in this animal model of pregnancy-induced hypertension.11 Whether increased synthesis of endothelin occurs within the kidney during preeclampsia remains unknown, inasmuch as some studies have found a decrease in urinary excretion of endothelin, a measure of local renal synthesis, in preeclamptic women compared with normotensive pregnant women.12 13
We recently reported that chronic reduced uterine perfusion pressure (RUPP) in pregnant rats resulted in significant elevations in MAP and reductions in kidney function.14 Because the kidneys play a major role in the long-term regulation of arterial pressure, the first aim of the present study was to determine whether increases in renal preproendothelin mRNA expression were associated with the hypertension produced by chronic RUPP in pregnant rats. Subsequently, the next aim was to test the hypothesis that blockade of the ETA receptor would prevent the hypertension produced by chronic RUPP in pregnant rats. Therefore, the overall goal of the present study was to assess the role that endothelin plays in mediating the hypertension produced by chronic RUPP in pregnant rats.
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Methods |
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All studies were performed in timed pregnant Sprague-Dawley rats purchased from Harlan Sprague Dawley Inc (Indianapolis, Ind). Animals were housed 1 to a cage in a temperature-controlled room (23°C) with a 12/12-hour light/dark cycle. All experimental procedures executed in the present study were in accordance with National Institutes of Health guidelines for use and care of animals, and the Animal Care and Use Committee at the University of Mississippi Medical Center approved all protocols.
RUPP in Pregnant Rats
A chronic reduction in uteroplacental perfusion in
rats was achieved by a method previously reported by our
laboratory.14 In brief, all
rats undergoing surgical procedures were anesthetized with 2%
isoflurane.15 Pregnant rats
entering the RUPP group underwent the following clipping procedure at
day 14 of gestation. After a midline incision, the lower abdominal
aorta was isolated, and a silver clip (0.203-mm internal diameter) was
placed around the aorta above the iliac bifurcation. Because
compensation of blood flow to the placenta occurs in pregnant rats
through an adaptive increase in ovarian blood flow, we also
clipped branches of both the right and left ovarian arteries
that supply the uterus with the use of a silver clip (0.100-mm internal
diameter). When the clipping procedure resulted in total reabsorption
of the fetuses, rats were excluded from data
analyses.
Measurement of Renal
Hemodynamics and Arterial Pressure in
Conscious Rats
During isoflurane anesthesia, as
described above, rats at day 16 of pregnancy were surgically
instrumented with catheters (PE-50 tubing) in the femoral vein and
carotid artery for blood sampling and blood pressure monitoring. A
midline lower abdominal incision was made, and the bladder was
cannulated with flare-tipped PE-90 tubing for urine collection. All
catheters were tunneled to the back of the neck and exteriorized. On
day 19 of pregnancy, the rats were placed in modified restraining cages
for renal function measurements. The femoral vein catheter was
connected to an infusion pump that delivered isotonic saline containing
sodium iothalamate (Glofil [125I], 0.05
mCi · kg-1·
min-1, Cypros)
and para-aminohippurate (PAH, 24 mg/mL, Sigma Chemical Co) at a fixed
rate of 3 mL/h. Arterial pressure was monitored in
conscious rats with a pressure transducer connected to a Grass model 7B
chart recorder (Grass Instrument Co) for continuous
recording. After a 60-minute stabilization period, two
20-minute urine collections were obtained, followed by collection of
blood samples. Urine volume was determined gravimetrically. Sodium and
potassium concentrations in plasma and urine were measured by flame
photometry (IL-943, Instrumentation Laboratory). Glomerular
filtration rate (GFR) and effective renal plasma flow (ERPF) were
calculated from the radioactivity of 125I
and concentration of PAH, respectively, in plasma and urine. PAH
concentration was determined
colorimetrically.
Isolation of Total Cellular RNA
The kidneys were removed and sliced into cortical and
medullary sections, quick-frozen in liquid nitrogen, and stored at
-80°C. After each kidney was ground with use of a liquid
nitrogen–chilled mortar and pestle, total cellular RNA was isolated by
use of the acid guanidinium thiocyanate–phenol–chloroform procedure
of Chomczynski and Sacchi16
(ToTALLY RNA kit, Ambion). Total RNA concentration and purity were
determined spectrophotometrically by using absorbance (A) ratios
A260 and A260/280,
respectively. Total RNA integrity was checked by using 1% agarose gel
electrophoresis with a 0.4 mol/L Tris-acetate and 0.001 mol/L EDTA
buffer.
Ribonuclease Protection Assay
The cDNA for rat preproendothelin, a gift from Dr
Ernesto L. Schiffrin17 (The
University of Montreal, Montreal, Canada), was linearized with
XhoI (New England Biolabs). An
antisense internal control template for ß-actin was obtained from
Ambion. Antisense RNA probes were synthesized and labeled with
[
-32P]UTP (Dupont NEN) by use of a
MAXIscript IN VITRO
Transcription kit (Ambion) according to the manufacturer’s
instructions. Full-length probes were purified and eluted from
denaturing 5% acrylamide gels. Ribonuclease protection
assays (RPAs) were performed with an Ambion RPA III kit as described by
the manufacturer. Protected fragments were separated on denaturing 5%
acrylamide gels that were dried, exposed to a Molecular
Imaging screen (Bio-Rad), and quantified with use of the Molecular
Analyst Imager System (Bio-Rad). An equivalent amount of total RNA (20
µg) was used from each rat kidney. In each individual RPA, the RNA
concentration was varied to confirm that the probe was in excess and
that the response was linear. Where indicated, the error bars
represent the SEM from at least 3 separate determinations per
kidney. Quantification represents a ratio of transcript levels
of preproendothelin to actin.
Experimental Design
The animals were divided into 4 groups: normal
pregnant (NP group), normal pregnant plus ETA
receptor antagonist (NP+ETA group),
pregnant with chronic RUPP (RUPP group), and pregnant with chronic RUPP
plus ETA antagonist
(RUPP+ETA group). An
ETA-selective receptor antagonist
(ABT-627, Abbott Laboratories) was administered in the drinking water
at a dose of 5 mg/kg per day, and treatment was initiated at day 10 of
pregnancy. At day 14, all rats were instrumented with bladder
catheters, and animals destined to enter the RUPP group were clipped as
described above. On day 16, the rats were instrumented with
arterial and venous catheters as described above for the
measurement of renal function and arterial pressure, which
were performed on day 19. A total of 8 NP, 8 RUPP, 8
NP+ETA, and 9 RUPP+ETA
rats were used for analysis of renal preproendothelin mRNA
expression. A total of 14 NP, 12 RUPP, 17
NP+ETA, and 16 RUPP+ETA
rats were used for renal and systemic hemodynamic
analyses. In all groups, animal and pup weights were
recorded on day 19 of pregnancy.
Statistical Analysis
All data are expressed as mean±SEM. Comparisons of
control pregnant rats with RUPP rats, both treated and untreated, were
analyzed by use of factorial ANOVA, followed by the Scheffé
test. A value of P<0.05 was
considered statistically
significant.
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Results |
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MAP in Pregnant Rats With Chronic RUPP
Chronic RUPP in pregnant rats resulted in significant increases in arterial pressure relative to that in NP rats. MAP averaged 101±4 mm Hg in NP rats (Figure 1a). Arterial pressure in the pregnant rats with chronic RUPP averaged 123±2 mm Hg, which was 22 mm Hg above the level in NP rats (P<0.05, RUPP versus NP; Figure 1a). Pretreatment with ABT-627 (+ETA) markedly attenuated the increase in arterial pressure in the RUPP rats. Arterial pressure in RUPP rats pretreated with the ETA receptor antagonist averaged 103±6 mm Hg and was not significantly different from that in NP rats (P<0.05, RUPP versus RUPP+ETA groups). Pretreatment with the ETA receptor antagonist in NP animals did not significantly alter MAP (96±3 mm Hg, NP+ETA group; Figure 1b).
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P<0.05 vs RUPP rats) and NP rats (b). All data are expressed as mean±SEM.Chronic RUPP resulted in a decreased body weight at day 19 of gestation in the RUPP rats relative to NP rats (295.1±5.5 versus 351.3±9.1 g, respectively; P<0.05). Pretreatment with the ETA receptor antagonist did not attenuate the decrease in body weight observed in the RUPP rats (301.6±9.2 g, RUPP+ETA group; P<0.05 relative to NP control group), nor did it alter body weight in NP rats (349.0±6.8 g, NP+ETA group). Pup weight was also decreased in RUPP rats relative to NP rats (3.2±0.2 versus 3.9±0.2 g, respectively; P<0.05). Pretreatment with the ETA antagonist resulted in a slight increase in pup weight in the RUPP rats (3.5±0.2 g, RUPP+ETA group; no longer significant relative to NP group) but did not significantly alter pup weight in the control rats (3.8±0.3 g, NP+ETA group). In addition, at day 19 of pregnancy, the RUPP rats were also associated with a decrease in litter size (5.7±0.9 versus 15.3±0.63 pups, RUPP versus NP groups; P<0.05). Pretreatment with the ETA receptor antagonist did not attenuate the decrease in litter size observed in the RUPP rats (7.3±1.3 pups, RUPP+ETA group; P<0.05 relative to NP rats), nor did it significantly change the litter size in normal pregnancy (12.6±0.9 pups, NP+ETA group).
Renal Preproendothelin mRNA Expression in
Pregnant Rats With Chronic RUPP
RPA was used to quantify the renal levels of
preproendothelin mRNA in pregnant rats with chronic RUPP.
Figure 2a shows a representative RPA blot in
which a significant increase in preproendothelin mRNA expression in the
medulla of RUPP hypertensive rats was evident. Quantification of renal
preproendothelin transcript levels in RUPP rats relative to NP rats for
both medulla and cortex is shown in
Figure 2b. Preproendothelin mRNA levels were significantly
elevated in the medulla of RUPP rats compared with NP rats by 
45%
(44.1±6.3 versus 24.0±2.6 densitometric units, respectively;
P<0.05). Preproendothelin mRNA
levels were also significantly elevated by 22% in the cortex of RUPP
rats compared with NP rats (37.7±2.4 versus 29.4±2.8 densitometric
units, respectively;
P<0.05).
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Effects of an
ETA-Selective Receptor Antagonist on
Renal Hemodynamics in Pregnant Rats With Chronic
RUPP
Although nonsignificant, both GFR and ERPF
decreased by 13% in the RUPP rats compared with NP rats (GFR, 1.9±0.2
versus 2.3±0.3 mL/min for RUPP versus NP, respectively; ERPF, 5.5±0.3
versus 6.3±0.8 mL/min for RUPP versus NP, respectively)
(Figure 3). Although ERPF was increased by 11% in the RUPP
rats pretreated with the ETA
antagonist (6.2±0.9 mL/min,
RUPP+ETA group;
Figure 3b), ETA
antagonist pretreatment did not attenuate the GFR response
to chronic RUPP (1.8±0.2 mL/min, RUPP+ETA
group;
Figure 3a).
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Discussion |
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One of the leading theories concerning the etiology of pregnancy-induced hypertension suggests a pathway starting with inadequate trophoblast invasion of maternal spiral arteries, which leads to decreased placental perfusion.18 This, in turn, leads to placental ischemia, which results in placental release of factors, subsequent maternal endothelial dysfunction, and then systemic vasoconstriction.19 20 Chronic RUPP in pregnant animals has been used by numerous investigators to study the potential mechanisms of human preeclampsia as it initiates the disorder at a early step in the cascade described above.21 22 23 We recently reported that chronic RUPP in pregnant rats resulted in significant elevations in MAP, proteinuria, intrauterine growth restriction, and reductions in kidney function.14 In the present study, we confirmed that chronic RUPP in pregnant rats resulted in elevations in MAP, intrauterine growth restriction, and reductions in kidney function. We have extended our previous findings in the present study by showing that the endothelin system plays an important role in mediating the hypertension produced by chronic RUPP in pregnant rats.
Evidence from human studies indicates that endothelin may
play an important role in mediating the
pathophysiological changes that occur during
preeclampsia. Some, but not all, studies have found increased plasma
concentrations of endothelin in women with preeclampsia compared with
normal pregnant
women.7 8 9
Whether increased synthesis of endothelin occurs within the kidney
during preeclampsia remains unknown, inasmuch as some studies have
found a decrease or no significant change in urinary excretion of
endothelin in preeclamptic women compared with normotensive pregnant
women.24 25 Because
the kidneys play a major role in the long-term regulation of
arterial pressure and because abnormalities in the renal
pressure–natriuresis relationship have been observed in all forms of
hypertension examined to date, we examined whether increases in renal
preproendothelin mRNA expression were associated with the hypertension
produced in response to chronic RUPP in pregnant rats. We observed a
significant increase in preproendothelin mRNA expression in the cortex
and medulla of RUPP hypertensive rats. Preproendothelin mRNA levels
were significantly elevated in the medulla of RUPP rats compared with
NP rats by 45%. Preproendothelin mRNA levels were also
significantly elevated by 22% in the cortex of RUPP rats compared with
NP rats. Therefore, hypertension produced in response to chronic RUPP
in pregnant rats is associated with a significant increase in renal
expression of preproendothelin mRNA.
To test the hypothesis that blockade of the endothelin receptor would prevent the hypertension observed in the pregnant rats with chronic RUPP, we pretreated rats with a selective ETA receptor antagonist. We found that pretreatment with the ETA receptor antagonist markedly attenuated the increase in arterial pressure in the RUPP rats. Arterial pressure in RUPP rats pretreated with the ETA receptor antagonist was not significantly different from that in NP rats. This effect of the receptor antagonist appears to be specific to the RUPP rats, inasmuch as pretreatment with the ETA receptor antagonist in NP animals did not significantly alter MAP. Whether endothelin type B activation plays a role in mediating the decrease in arterial pressure observed on ETA receptor blockade in the RUPP rats is unknown because this aspect has not yet been examined by our laboratory. The increase in MAP observed in the RUPP rats was associated with slight, but nonsignificant, decreases in both GFR and ERPF compared with the reaction in NP rats. Although pretreatment with the ETA receptor antagonist tended to improve renal function in the RUPP rats, statistical significance was not reached because of variability in the response.
Animal studies indicate that disruptions in endothelin-1 expression or blockade of endothelin-1 activation through the endothelin receptor results in abnormal fetal development and growth, thus indicating that use of endothelin receptor blockade as a mode of antihypertensive treatment during early pregnancy is contraindicated.26 27 However, specific animal studies regarding the teratogenicity of ETA-selective antagonists are lacking. As preeclampsia develops closer to term, risks of adverse effects indicated for early stages of development may not be applicable, and studies are needed to determine both developmental and long-term fetal risk regarding the use of ETA-selective antagonists in the treatment of preeclampsia.
Although reductions in blood flow to the uteroplacental unit
are known to result in cardiovascular and renal
abnormalities consistent with the
pathophysiological features of human
pregnancy-induced hypertension, the mechanisms linking placental
ischemia with the abnormalities in endothelial
function and enhanced synthesis of endothelin are unclear. Several
lines of evidence support the hypothesis that the ischemic
placenta contributes to endothelial cell
activation/dysfunction of the maternal circulation by enhancing the
synthesis of cytokines, such as tumor necrosis factor- and
interleukin-1.28 Tumor
necrosis factor- and interleukin-1 are inflammatory
cytokines that have been shown to induce structural as well as
functional alterations in endothelial
cells.20 These inflammatory
cytokines also enhance the in vitro formation of a number of
endothelial cell substances, such as
endothelin.29 Also supporting
a potential role of cytokines in preeclampsia are findings that
plasma levels of tumor necrosis factor- are significantly elevated
in women with preeclampsia by
2-fold.30 31
Whether chronic and modest increases in plasma cytokines in
response to chronic RUPP can stimulate endothelin synthesis is unknown
and requires further investigation.
In summary, we found that chronic RUPP in the pregnant rat was associated with significant increases in arterial pressure and renal expression of preproendothelin mRNA in both the medulla and the cortex. Chronic administration of the selective ETA receptor antagonist ABT-627 markedly attenuated the increase in MAP observed in the pregnant rats with chronic RUPP. However, ETA receptor blockade had no significant effect on blood pressure in the NP rats. These results suggest that endothelin may play a major role in mediating the hypertension produced by chronic RUPP.
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Acknowledgments |
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This work was supported by National Institutes of Health (NIH) grants HL-38499and HL-51971. Dr Alexander was supported by NIH National Research Service Award HL-10137-01. The authors would like to thank Dr Terry J. Opgenorth for the endothelin type A selective receptor antagonist, ABT-627 (Abbott Laboratories).
Received October 25, 2000; first decision December 11, 2000; accepted December 18, 2000.
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J. P. Granger Response to Modeling Preeclampsia: The True Model for the Uniquely Human Disease Preeclampsia Is the Human Female Not the Pregnant Rat Hypertension, April 1, 2007; 49(4): e22 - e22. [Full Text] [PDF]
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G. Gadonski, B. B. D. LaMarca, E. Sullivan, W. Bennett, D. Chandler, and J. P. Granger Hypertension Produced by Reductions in Uterine Perfusion in the Pregnant Rat: Role of Interleukin 6 Hypertension, October 1, 2006; 48(4): 711 - 716. [Abstract] [Full Text] [PDF]
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 C. M. Anderson, F. Lopez, H.-Y. Zhang, Y. Shirasawa, K. Pavlish, and J. N. Benoit Mesenteric Vascular Responsiveness in a Rat Model of Pregnancy-Induced Hypertension Experimental Biology and Medicine, September 1, 2006; 231(8): 1398 - 1402. [Abstract] [Full Text] [PDF]
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 C. M. Anderson, F. Lopez, A. Zimmer, and J. N. Benoit Placental Insufficiency Leads to Developmental Hypertension and Mesenteric Artery Dysfunction in Two Generations of Sprague-Dawley Rat Offspring Biol Reprod, March 1, 2006; 74(3): 538 - 544. [Abstract] [Full Text] [PDF]
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L. Roberts, B. B. D. LaMarca, L. Fournier, J. Bain, K. Cockrell, and J. P. Granger Enhanced Endothelin Synthesis by Endothelial Cells Exposed to Sera From Pregnant Rats With Decreased Uterine Perfusion Hypertension, March 1, 2006; 47(3): 615 - 618. [Abstract] [Full Text] [PDF]
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B. B. D. LaMarca, K. Cockrell, E. Sullivan, W. Bennett, and J. P. Granger Role of Endothelin in Mediating Tumor Necrosis Factor-Induced Hypertension in Pregnant Rats Hypertension, July 1, 2005; 46(1): 82 - 86. [Abstract] [Full Text] [PDF]
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C. M. Anderson, F. Lopez, H.-Y. Zhang, K. Pavlish, and J. N. Benoit Reduced Uteroplacental Perfusion Alters Uterine Arcuate Artery Function in the Pregnant Sprague-Dawley Rat Biol Reprod, March 1, 2005; 72(3): 762 - 766. [Abstract] [Full Text] [PDF]
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 J. P. Granger Inflammatory cytokines, vascular function, and hypertension Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2004; 286(6): R989 - R990. [Full Text] [PDF]
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M. T. Llinas, B. T. Alexander, M. F. Capparelli, M. A. Carroll, and J. P. Granger Cytochrome P-450 Inhibition Attenuates Hypertension Induced by Reductions in Uterine Perfusion Pressure in Pregnant Rats Hypertension, March 1, 2004; 43(3): 623 - 628. [Abstract] [Full Text] [PDF]
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A. A. da Silva, J. J. Kuo, L. S. Tallam, and J. E. Hall Role of Endothelin-1 in Blood Pressure Regulation in a Rat Model of Visceral Obesity and Hypertension Hypertension, February 1, 2004; 43(2): 383 - 387. [Abstract] [Full Text] [PDF]
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M. H. Sedeek, M. T. Llinas, H. Drummond, L. Fortepiani, S. R. Abram, B. T. Alexander, J. F. Reckelhoff, and J. P. Granger Role of Reactive Oxygen Species in Endothelin-Induced Hypertension Hypertension, October 1, 2003; 42(4): 806 - 810. [Abstract] [Full Text] [PDF]
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J. P. Granger Endothelin Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R298 - R301. [Full Text] [PDF]
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B. T. Alexander Placental Insufficiency Leads to Development of Hypertension in Growth-Restricted Offspring Hypertension, March 1, 2003; 41(3): 457 - 462. [Abstract] [Full Text] [PDF]
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R. A. Khalil and J. P. Granger Vascular mechanisms of increased arterial pressure in preeclampsia: lessons from animal models Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2002; 283(1): R29 - R45. [Abstract] [Full Text] [PDF]
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J. B. Giardina, K. L. Cockrell, J. P. Granger, and R. A. Khalil Low-Salt Diet Enhances Vascular Reactivity and Ca2+ Entry in Pregnant Rats With Normal and Reduced Uterine Perfusion Pressure Hypertension, February 1, 2002; 39(2): 368 - 374. [Abstract] [Full Text] [PDF]
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B. T. Alexander, K. Cockrell, F. D. Cline, and J. P. Granger Inducible Nitric Oxide Synthase Inhibition Attenuates Renal Hemodynamics During Pregnancy Hypertension, February 1, 2002; 39(2): 586 - 590. [Abstract] [Full Text] [PDF]
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 B. T. Alexander, W. A. Bennett, R. A. Khalil, and J. P. Granger Preeclampsia: Linking Placental Ischemia with Cardiovascular-Renal Dysfunction Physiology, December 1, 2001; 16(6): 282 - 286. [Abstract] [Full Text] [PDF]
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J. P. Granger, B. T. Alexander, M. T. Llinas, W. A. Bennett, and R. A. Khalil Pathophysiology of Hypertension During Preeclampsia Linking Placental Ischemia With Endothelial Dysfunction Hypertension, September 1, 2001; 38(3): 718 - 722. [Abstract] [Full Text] [PDF]
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