| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Department of Medicine, Duke University and Durham Veterans Affairs Medical Center, Durham 27710; and 2 Departments of Medicine and 3 Cell and Molecular Physiology, University of North Carolina, Chapel Hill, North Carolina 27599-7545
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
The kidney plays a
central role in long-term regulation of arterial blood pressure and
salt and water homeostasis. This is achieved in part by the local
actions of paracrine and autacoid mediators such as the arachidonic
acid-prostanoid system. The present study tested the role of specific
PGE2 E-prostanoid (EP) receptors in the regulation of renal
hemodynamics and vascular reactivity to PGE2. Specifically,
we determined the extent to which the EP2 and
EP3 receptor subtypes mediate the actions of PGE2 on renal vascular tone. Renal blood flow (RBF) was
measured by ultrasonic flowmetry, whereas vasoactive agents were
injected directly into the renal artery of male mice. Studies were
performed on two independent mouse lines lacking either EP2
or EP3 (
/) receptors and the results were compared with
wild-type controls (+/+). Our results do not support a unique role of
the EP2 receptor in regulating overall renal hemodynamics.
Baseline renal hemodynamics in EP2/ mice [RBF
EP2/: 5.3 ± 0.8 ml · min
1 · 100 g kidney
wt1; renal vascular resistance (RVR) 19.7 ± 3.6 mmHg · ml1 · min · g kidney wt]
did not differ statistically from control mice (RBF +/+: 4.0 ± 0.5 ml · min1 · 100 g kidney
wt1; RVR +/+: 25.4 ± 4.9 mmHg · ml1 · min · 100 g kidney
wt1). This was also the case for the peak RBF increase
after local PGE2 (500 ng) injection into the renal artery
(EP2/: 116 ± 4 vs. +/+: 112 ± 2% baseline
RBF). In contrast, we found that the absence of EP3
receptors in EP3/ mice caused a significant increase (43%) in basal RBF (7.9 ± 0.8 ml · min1 · g kidney wt1,
P < 0.05 vs. +/+) and a significant
decrease (41%) in resting RVR (11.6 ± 1.4 mmHg · ml1 · min · g kidney
wt1, P < 0.05 vs. +/+). Local
administration of 500 ng of PGE2 into the renal artery
caused more pronounced renal vasodilation in EP3/ mice
(128 ± 2% of basal RBF, P < 0.05 vs.
+/+). We conclude that EP3 receptors mediate
vasoconstriction in the kidney of male mice and its actions are
tonically active in the basal state. Furthermore, EP3
receptors are capable of buffering PGE2-mediated renal vasodilation.
knockout mice; renal blood flow; EP receptor; cAMP; renal circulation; vascular smooth muscle cells
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
THE MAINTENANCE of precisely controlled blood flow within the kidney is essential for regulating appropriate salt and water balance. Paracrine and autacoid mediators play an important role in the control of renal vascular resistance (RVR). PGE2 has long been recognized as a key product of the arachidonic acid metabolism pathway by cyclooxygenase. PGE2 is a major arachidonic acid metabolite in the kidney and is known to exert important actions on both renal hemodynamics and tubular transport. It can also be released along with PGI2 from the vascular endothelium and vascular smooth muscle cells (VSMC) (13, 24, 37). Among the cyclooxygenase products thromboxane A2, PGI2, and PGE2, PGE2 is released in greatest abundance from all nephron segments (3). Infusion of PGE2 into the kidney commonly causes renal vasodilation, although there are a few reports (2, 10, 11, 16) of reductions in renal hemodynamics, depending on the species, preparations, and doses. Such variability implicates actions of PGE2 on multiple cell surface receptors in the regulation of renal tubular transport and hemodynamics.
PGE2 elicits its biological effects through interactions with a family of G protein-coupled cell surface receptors. To date, four distinct PGE2 (E-prostanoid, EP1-4) receptors have been cloned; each originates from a distinct gene (19). These EP receptors differ in their amino acid identities, pharmacological characteristics, and signal transduction properties. The existence of unique coupling of EP subtypes to a given signal transduction pathway provides the molecular basis for the diverse and complex physiological actions of PGE2. All of the EP receptor subtypes are found in the kidney (12). More is known about the localization of EP receptors along the nephron than the vasculature. EP1 and EP3 receptors are present in cells of the collecting ducts (cortex and medulla) and connecting segments (18, 33). In situ hybridization and Northern blot studies (4, 12, 33) reveal EP4 receptor mRNA in rat and human glomeruli. A recent study (18) employing immunohistochemistry reveals EP3 and EP4 receptors in human glomeruli. Antibodies localized all four EP receptors to large preglomerular arteries, EP1-3 to the afferent arteriole, EP1 to the efferent arteriole, and all but EP2 on vasa recta of human kidneys (18).
The functional roles and patterns of EP receptor control of peripheral vascular resistance in different organs in general and tone of resistance arterioles in the kidney are unknown. It is difficult to predict which specific receptor mediates PGE2 actions on the renal vasculature in experimental animals. One approach to resolve these issues is to use EP subtype-specific ligands in functional studies. Unfortunately, the weak binding profiles and less-than-ideal selectivity of these compounds limits interpretation of experiments based solely on pharmacological agonist/antagonists action. These imprecise properties complicate their utility in whole animal physiology and render results less than conclusive. To circumvent these limitations, we took a different approach and studied mice in which specific EP receptors were deleted by gene targeting.
The purpose of the present study was to gain insight into the roles of
EP2 and EP3 receptors in the control of renal
hemodynamics in the mouse. Steady-state and dynamic responses of renal
blood flow (RBF) were recorded with the use of an ultrasonic flow probe in EP2- or EP3-deficient (EP2/
and EP3/, respectively) mice. We tested the
hypotheses that the inability of selected EP receptors to function
would affect the renal microcirculation during basal conditions and/or
in response to administered PGE2.
| |
MATERIALS AND METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Generation of EP2/ and EP3/ mice.
EP2/ and EP3/ animals were generated as
previously described (9, 35) and maintained on a 129 background. Genotypes were determined by Southern blot analysis. We
maintained 129 mice in the University of North Carolina, Chapel Hill
animal facility as controls. Only 4- to 5-mo-old male mice were
studied. All animal experiments were performed according to approved
institutional guidelines.
RBF measurements. Surgical procedures were performed as described previously (28, 29). In brief, a polyethylene (PE-10) catheter was inserted into the right jugular vein for the administration of 4.7 g/dl BSA in saline to maintain constant plasma oncotic pressure during surgery (10 µl/min) and then reduced to 2 µl/min for the duration of an experiment. A second catheter was placed in the left carotid artery to monitor systemic arterial blood pressure with a transducer (Gulton-Statham P23 dB).
Blood flow in the left kidney was measured continuously by using a noncannulating ultrasonic flowmeter system (Transonic Systems; Ithaca, NY) interfaced with a 5-mm V-shaped probe around the left renal artery. This system has been previously validated in mice by our laboratory (29, 30). A PE-10 catheter, pulled to a smaller diameter with the tip bent at 90°, was inserted into the abdominal aorta, and its tip was placed ~0.5 mm into the left renal artery. Saline was infused continuously into the renal artery (2 µl/min), except during bolus injections of vasoactive agents. Placement of the catheter tip at the origin of the renal artery did not affect RBF. There was a 30-min stabilization period after the 60- to 90-min surgical procedures, followed by an observation period of 2-3 h. PGE2 (Cayman Chemical; Ann Arbor, MI) was resuspended in 100% ethanol at a final concentration of 50 mg/ml. We then used this solution to prepare the various dilutions using saline. The highest concentration of ethanol was 0.1% vol/vol (500 ng/10 µl bolus). Thirty seconds before the injection of bolus (10 µl), the saline infusion rate into the renal artery was increased to 50 µl/min. At 2-min postinjection, the saline infusion was returned to 2 µl/min.Data analysis. RBF measurements and arterial blood pressure readings were recorded by using NotebookPro software (Labtech; Andover, MA) and then transferred into a spreadsheet and analyzed with the use of statistical software (GraphPad; San Diego, CA). All of the data presented are means ± SE. Statistical analyses were performed with the use of Student's t-test and linear regression by least-squares analysis (GraphPad). P < 0.05 was considered statistically significant.
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
EP3/ mice
altered baseline renal hemodynamics.
To assess the contribution of individual EP receptors to resting levels
of renal hemodynamics, baseline RBF was compared among age-matched
controls (+/+), EP2/, and EP3/ male
mice. There were no significant differences in animal body
weight, kidney weight, or mean arterial blood pressure among genotypes
(Table 1). RBF and RVR were similar in
control mice and EP2/ mice. An important finding was
that the absence of functional EP3 receptors (EP3/ mice) had a significant effect on renal
hemodynamics. Baseline RBF was increased 43% in EP3/
compared with wild-type mice (Fig. 1).
Because arterial pressure was similar in both groups, RVR was reduced
in the EP3/ mice by almost 50% (Fig. 1). These data
suggest that EP3 receptors mediate tonic renal
vasoconstriction in these animals under resting conditions. In marked
contrast, EP2 receptors appear to have little, if any,
discernable effect on basal renal hemodynamics.
|
|
EP3/ mice
display increased renal responsiveness to PGE2.
RBF studies were conducted to evaluate RVR and assess the functional
response to PGE2 injected directly into the renal artery of
mice lacking EP2 or EP3 receptors. In these
studies, renal vascular reactivity in response to receptor activation
was assessed utilizing a combination of continuous measurement of RBF
and drug delivery directly into the renal artery of the experimental
kidney (29, 30). This approach allows for the study of
local hormonal effects on the renal circulation without systemic
effects of the agonists on arterial pressure. By design, mean arterial
blood pressure was unaffected by intrarenal injection of
PGE2 in all experiments.
|
/ and wild-type mice
[116 ± 4% (n = 3) and 112 ± 2% of
baseline RBF (n = 6), respectively]. It is possible
that a difference exists between EP2/ and +/+ mice
that could not be detected due to the sample size of our
experiments. In contrast, deletion of the EP3/
receptor had a profound effect on the renal response to PGE2. The maximum RBF response was appreciably greater
(128 ± 2% of baseline RBF; n = 5) in the absence
of a functional EP3 receptor than in either of the other
two groups (P < 0.05 vs. +/+ or
EP2/). In addition, the integrated area under the
response curve was significantly greater in the EP3/
mice than wild-type or EP2/ animals. Thus the
difference in the integrated RBF response was virtually identical to
that observed for peak changes in RBF. These results suggest that
EP3 but not EP2 receptors contribute to the
PGE2-mediated vascular responsiveness in the murine kidney.
|
Dose-dependent responsiveness to PGE2 in
EP3/ animals.
To further explore the differences in renal reactivity to
PGE2 in EP3/ mice, we examined RBF
responses to a range of PGE2 doses (25-500 ng). All
tested doses elicited renal vasodilation in all groups. As shown in
Fig. 4, wild-type mice exhibited a maximal increase in RBF (111 ± 2% of control RBF) with 25 ng of PGE2. No additional RBF increase was recorded between 25 and 500 ng PGE2 in +/+ mice. Higher doses of
PGE2 (
1,000 ng) compromised the systemic hemodynamic
stability of the animals, preventing us from utilizing these results.
|
/ mice displayed a more readily
discernable dose-dependent increase in RBF responsiveness to
PGE2. The effects of 25 ng PGE2 were slightly
greater in EP3/ mice (117 ± 3% basal RBF) than
in wild-type controls. The exaggerated response in EP3/ mice became more pronounced as the dose of PGE2 was
increased, with 500 ng of PGE2 producing a greater increase
in RBF (128 ± 2 vs. 112.3 ± 2.1% control RBF in control
mice) (Fig. 4).
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Our studies focused on the role of EP2 and EP3 receptors in the control of whole kidney hemodynamics. We focused on these specific subtypes because they have been shown to be present in the kidney and EP2- and EP3-deficient mice are available on the same 129 genetic backgrounds. The contribution of genetic background is an important consideration with any gene targeting experiment (21). Therefore, intergroup comparisons can be made in these studies without background genes contributing to data variability.
Although general actions of PGE2 are well characterized, very little is known about which EP receptor subtypes mediate the biological effects of this prostanoid. With regard to EP receptor actions on the cardiovascular system, we have demonstrated previously (1) in mice that activation of EP2 receptors is responsible for a systemic depressor response to intravenous injection of PGE2. In contrast, PGE2-mediated activation of EP3 receptors causes an increase in mean systemic arterial pressure. The present study extends these findings by characterizing the extent to which EP2 and EP3 receptors contribute to the regulation of the microcirculation in the kidney.
Renal vascular reactivity in vivo was investigated by using a recently
refined approach in which injection of PGE2 into the renal
artery was combined with continuous measurement of RBF with a
miniaturized ultrasound flow transducer. Our results indicate that the
EP3 receptor contributes importantly to the baseline renal
hemodynamics by enhancing vasomotor tone. EP3/ mice
exhibit a 43% increase in baseline RBF and a 41% decrease in RVR
independent of changes in systemic arterial blood pressure. On the
other hand, the EP2 receptor does not appear to be a major
contributor to resting renal vasomotor tone as basal RBF was
independent of EP2 receptor deletion. The absence of
detectable differences in our experiments between EP2/
and +/+ mice is strongly suggestive that the EP2
receptors are not present in the majority of renal cortical resistance
vessels of male mice, or if present, receptor-mediated vasodilation is
undetectable in our experimental conditions.
The same general pattern of contribution was observed in renal vascular
reactivity to exogenous PGE2. Injection of PGE2
into the renal artery of wild-type mice produced net renal vasodilation as RBF rose 10-15% above baseline levels. This degree of renal vasodilation was also observed in EP2/ or
EP3/ mice in response to relatively low doses of
PGE2 (25 ng) injected into the renal artery. Higher doses
of PGE2 elicited more pronounced vasodilation in
EP3/ mice. These results suggest that EP3
receptors mediate renal vasoconstriction such that activation of
EP3 receptors in wild-type mice buffers or counteracts some
of the vasodilation triggered by other EP receptors. In marked
contrast, our data on EP2/ mice suggest the
EP2 receptors contribute little to basal RBF and the
vasodilatory effect of PGE2. Thus the EP2
receptor appears to play a minor role, if any, in modulating renal
vasomotor tone, at least at the whole kidney level in male mice.
The vasoconstrictor action of EP3 receptors in the renal
vasculature is consistent with what is known about signal transduction pathways in other cell types. On the bais of information largely obtained on receptors transfected into nonvascular host cells, the
EP2, EP3, and EP4 receptors are
thought to regulate intracellular cAMP concentration
([cAMP]i) levels. In general, agonist-dependent activation of the EP2 and EP4 subtypes,
G
s-coupled receptors, stimulates [cAMP]i.
Such changes in cAMP are predicted to cause relaxation of VSMC and
vasodilation. In renal epithelial cells, EP3 receptors are
primarily coupled to the inhibitory G protein, Gi, as
demonstrated by inhibition of [cAMP]i production in rabbit collecting duct cells and the bovine renal medulla (32, 36). Thus EP3 receptors may antagonize the
stimulatory effect of Gs-coupled EP receptors.
Agonist-dependent activation of EP1 and EP3
receptors produces an increase in cytosolic calcium concentration in
most nonvascular cell types tested to date. Therefore, EP1-
and EP3-dependent stimulation of intracellular second
messengers are predicted to induce VSMC contraction and increase
vascular resistance. In VSMC of the rat tail artery, PGE2
is reported (26) to modulate both intracellular cAMP and
calcium-dependent pathways leading to the regulation of
voltage-dependent rectifier K+ channels and modulation of
vascular tone. However, the identity of specific EP subtypes involved
in these processes is unknown.
In the absence of a detectable phenotypic effect of EP2
receptor mutation on whole kidney hemodynamics, the remaining
G
s-coupled EP4 receptors might be expected
to mediate vasodilation by virtue of their ability to stimulate
[cAMP]i production. Therefore, it is reasonable
to conclude that EP4 receptors are the predominant EP
receptor subtype most likely to mediate PGE2-dependent
vasodilation in control wild-type animals. The net vasodilatory action
of renal PGE2 and its ability to buffer vasoconstrictor
agents more effectively in control than in genetic hypertension has
been previously established in animal models (6, 7). In
this setting, the vasodilatory effects of PGE2 were reduced
in 6-wk-old spontaneously hypertensive rats (SHR) compared with
aged-matched Wistar-Kyoto (WKY) controls (6). There is
evidence of a defective EP receptor Gs-coupled (stimulation
of cAMP production) signaling pathway in the renal vasculature of SHR.
In vitro studies reveal that PGE2 stimulation produces
weaker-than-normal increases in [cAMP]i in isolated
preglomerular arterioles of young SHR versus WKY mice. In vivo RBF
studies (8) support this view.
Recently, we (1) described the impact of EP2
and EP3 receptor mutations on the effects of
PGE2 in the systemic circulation. Both of these receptors
contributed significantly to the PGE2-dependent actions on
the regulation of arterial blood pressure. Intravenous injection of
PGE2 injected elicited a 25-mmHg reduction in mean arterial
pressure in wild-type control animals. In EP2/ mice, the same dose of PGE2 caused a smaller 10-mmHg depressor
response, suggesting that EP2 receptors are vasodilatory
and contribute to a decrease in total peripheral resistance, possibly
through proposed activation of Gs proteins and increases in
[cAMP]i. There was an accentuated vasodepressor response
in male EP3/ consistent with a constrictor action of
EP3 receptors in the peripheral vasculature, perhaps
mediated through activation of Gi and subsequent reductions in [cAMP]i and/or stimulation of intracellular calcium.
It is not known which vascular beds contribute to the systemic pressor effects of PGE2. Our current study provides new information
about the importance of EP3 receptors in mediating renal
vasoconstriction and the apparent absence of EP2 actions on
the renal vasculature of male mice. Two recent reports (25,
34) described the role of EP receptors in transducing
PGE2 effects in the rat renal preglomerular microcirculation. These investigators provided convincing evidence supporting the role of EP1 and/or EP3 and
EP4 receptors in kidney hemodynamics. These observations
are consistent with our present report.
This is especially relevant in view of documented differences in the actions of PGE2 among species. The physiological response to PGE analogues is quite different between isolated preparations of rabbit and piglet saphenous veins (15), suggesting that individual EP receptors contribute differently to the PGE2-dependent vasomotor activity of these preparations. This situation is not unique to saphenous vein preparations. Differences in PGE2 potencies were also reported between human and rabbit preparations of basilar arteries (22). In human artery preparations, PGE2 and its analogue 16,16-dimethyl PGE2 (EP3>EP4>EP2) cause contractions. In contrast, in the rabbit artery, both compounds cause relaxation. Therefore, caution must be exercised in extrapolating results from one species to the next (e.g., mouse to human) as relative levels of EP receptors or efficacy in receptor-evoked signal transduction may differ appreciably.
Our whole kidney RBF results pertain to total vascular resistance in vivo. It would be of interest to extend our studies to discern which specific vascular segments in the renal microcirculation are responsible for the observed changes in total resistance. In this regard, identification of EP receptor location and function in the afferent and efferent arterioles is worthy of further investigation as are relative contributions in superficial and juxtamedullary nephron populations.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are potent inhibitors of the cyclooxygenase enzymes, and their anti-inflammatory effects occur through inhibition of the production of prostanoids such as PGE2 (31). PGE2 can act as a major determinant of renal vascular tone by acting as a vasodilator and counteracting the effects of vasoconstrictor agents. Administration of NSAIDs can cause marked renal vasoconstriction (8) and reversible acute renal failure (5, 23) in elderly patients and patients with congestive heart failure or volume depletion. Recently, cyclooxygenase-2-specific inhibitors have also been shown (27) to cause significant transient renal vasoconstriction. The undesired side effects of subtype and nonsubtype-specific NSAIDs may be due in part to the reduction of PGE2 from the circulation (38). In this situation, the actions of vasoconstrictors become unrestrained and dominant, resulting in a deleterious attenuation of renal perfusion. This is especially relevant in view of the counteracting vasodilatory effect of PGE2 with respect to vasoconstrictors such as ANG II, endothelin, norepinephrine, and vasopressin (17, 20). Alternatively, there is evidence (19) suggesting that EP3 isoforms may be able to exert effects independent of agonist. It is interesting to speculate on the implications and the therapeutic potential of using specific EP receptor agonists and/or antagonists in disease states and during NSAID therapy.
In summary, we have measured RBF with the use of an ultrasonic
flowmeter system in anesthetized mice. Compared with wild-type control
animals, resting RBF is elevated in EP3 receptor-deficient mice but is normal in mice with EP2 receptors rendered
nonfunctional by gene mutation. Deletion of putative vasodilatory
EP2 receptors had no discernable effect on renal
vasodilation elicited by intrarenal PGE2. In contrast, more
pronounced vasodilation was clearly observed in EP3/
mice. Our results suggest a very weak or nonexistent role for
EP2 receptors in either baseline or
PGE2-dependent vascular responsiveness. The ablation of
gene expression by homologous recombination is a powerful tool for the
study of gene function. However, it is important to appreciate that the
phenotype of any "knockout" study may not only reflect on the
absence of the targeted gene, but also on the potential compensation of
other genes that may be upregulated in these genetically modified
animals. For example, a significant upregulation of PGE2
biosynthesis is noted in fibroblasts isolated from PGH2
synthase (PGHS1 / or PGHS2 /) animals
compared with their wild-type controls (14). In mice, our
data suggest that EP3 receptors are present on renal resistance vessels and mediate vasoconstriction that plays a role in
damping the strength of vasodilation triggered by PGE2. On the basis of our current knowledge of signal transduction, it is
reasonable to postulate that the major vasodilatory action of
PGE2 is mediated by another EP receptor, such as the
EP4 receptor that couples to a Gs protein
and stimulates [cAMP]i. The vasoconstrictor EP3
receptor may play an important role in the control of renal hemodynamics.
| |
ACKNOWLEDGEMENTS |
|---|
This work was supported by National Institutes of Health Grants HL-02334 (to W. J. Arendshorst), HL-58554 (to B. H. Koller), P01-DK-38103 and DK-38108 and the Research Service of the Department of Veterans Affairs (to T. M. Coffman). L. P. Audoly is a recipient of an American Heart Association fellowship.
| |
FOOTNOTES |
|---|
Present address of L. P. Audoly: Inflammation, Pfizer Global Research and Development, Eastern Point Rd., Groton, CT 06340.
Address for reprint requests and other correspondence: W. J. Arendshorst, Dept. Cell and Molecular Physiology, CB# 7545, School of Medicine, Rm. 152, Medical Sciences Research Bldg., The Univ. of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7545 (E-mail: arends{at}med.unc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 5 May 2000; accepted in final form 28 August 2000.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Audoly, LP,
Tilley SL,
Goulet J,
Key M,
Nguyen MT,
Stock J,
McNeish J,
Koller BH,
and
Coffman TM.
Identification of specific EP receptors responsible for the hemodynamic effects of PGE2.
Am J Physiol Heart Circ Physiol
277:
H924-H930,
1999
2.
Baer, PG,
and
McGiff JC.
Comparisons of effects of prostaglandins E2 and I2 on rat renal vascular resistance.
Eur J Pharmacol
54:
359-363,
1976.
3.
Bonvalet, JP,
Pradelles P,
and
Farman N.
Segmental synthesis and actions of prostaglandins along the nephron.
Am J Physiol Renal Fluid Electrolyte Physiol
253:
F377-F387,
1987
4.
Breyer, MD,
Davis L,
Jacobson HR,
and
Breyer RM.
Differential localization of prostaglandin E receptor subtypes in human kidney.
Am J Physiol Renal Fluid Electrolyte Physiol
39:
F912-F918,
1996.
5.
Brezin, JH,
Morider Katz S,
Schwartz AB,
and
Chinitz JL.
Reversible renal failure and nephrotic syndrome associated with nonsteroidal anti-inflammatory drugs.
N Engl J Med
301:
1271-1276,
1979[Web of Science][Medline].
6.
Chatziantoniou, C,
and
Arendshorst WJ.
Renal vascular reactivity to vasodilator prostaglandins in genetically hypertensive rats.
Am J Physiol Renal Physiol
31:
F124-F130,
1992.
7.
Chatziantoniou, C,
and
Arendshorst WJ.
Impaired ability of prostaglandins to buffer renal vasoconstriction in genetically hypertensive rats.
Am J Physiol Renal Physiol
32:
F573-F580,
1992.
8.
Finn, WF,
and
Arendshorst WJ.
Effect of prostaglandin synthetase inhibitors on renal blood flow in rats.
Am J Physiol
231:
1541-1545,
1976.
9.
Fleming, EF,
Athirakul K,
Oliverio MI,
Key M,
Goulet J,
Koller BH,
and
Coffman TM.
Urinary concentrating function in mice lacking EP3 receptors for prostaglandin E2.
Am J Physiol Renal Physiol
275:
F955-F961,
1998
10.
Haylor, J,
and
Towers J.
Renal vasodilator activity of prostaglandin E2 in the rat anesthetized with pentobarbitone.
Br J Pharmacol
76:
131-137,
1982[Web of Science][Medline].
11.
Jackson, EK,
Heidemann HT,
Branch RA,
and
Gerkens GF.
Low dose of intrarenal infusions of PGE2, PGI2, and 6-keto-PGE1 vaodilate the in vivo rat kidney.
Circ Res
51:
67-72,
1982
12.
Jensen, BL,
Mann B,
Skott O,
and
Kurtz A.
Differential regulation of renal prostaglandin receptor mRNAs by dietary salt intake in the rat.
Kidney Int
56:
528-537,
1999[Web of Science][Medline].
13.
Kirchenbaum, MA,
and
Chaudhari A.
Calcium dependent synthesis of vasodilator renal microvascular prostanoids.
Am J Nephrol
6:
46-53,
1986.
14.
Kirtikara, K,
Morham SG,
Raghow R,
Laulederkind SJF,
Kanekura T,
Goorha S,
and
Ballou LR.
Compensatory prostaglandin E2 biosynthesis in cyclooxygenase 1 or 2 null cells.
J Exp Med
187:
517-523,
1998
15.
Lydford, SJ,
McKechnie KCW,
and
Dougall IG.
Pharmacological studies on prostanoid receptors in the rabbit isolated saphenous veins: a comparison with the rabbit isolated ear artery.
Br J Pharmacol
117:
13-20,
1996[Web of Science][Medline].
16.
Malik, KU,
and
McGiff JC.
Modulation by prostaglandins of adernergic transmission in the isolated perfused rabbit and rat kidney.
Circ Res
36:
599-609,
1975
17.
McGiff, JC,
Malik KU,
and
Terragno NA.
Prostaglandins as determinants of vascular reactivity.
Fed Proc
35:
2382-2387,
1976[Web of Science][Medline].
18.
Morath, R,
Klein T,
Seyberth HW,
and
Nusing RM.
Immunolocalization of the four prostaglandin E2 receptor proteins EP1, EP2, EP3, and EP4 in human kidney.
J Am Soc Nephrol
10:
1851-1860,
1999
19.
Narumiya, S,
Sugimoto Y,
and
Ushikubi F.
Prostanoid receptors: structures, properties, and functions.
Physiol Rev
79:
1193-1226,
1999
20.
Nasjletti, A,
and
Arthur C.
Corcoran Memorial Lecture. The role of eicosanoids in angiotensin-dependent hypertension.
Hypertension
31:
194-200,
1998
21.
Nguyen, M,
Camenisch T,
Snouwaert JN,
Hicks E,
Coffman TM,
Anderson P,
Malouf NN,
and
Koller B.
The prostaglandin receptor EP4 triggers remodelling of the cardiovascular system at birth.
Nature
390:
78-81,
1997[Medline].
22.
Parsons, A,
and
Whalley ET.
Effects of prostanoids on human and rabbit basilar arteries precontracted in vitro.
Cephalalgia
9:
165-171,
1989[Web of Science][Medline].
23.
Perneger, TV,
Whelton PK,
and
Klag MJ.
Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs.
N Engl J Med
331:
1675-9,
1994
24.
Purdy, KE,
and
Arendshorst WJ.
Calcium dependent synthesis of vasodilator renal microvascular prostanoids.
Am J Nephrol
277:
F850-F858,
1999.
25.
Purdy, KE,
and
Arendshorst WJ.
EP1 and EP4 receptors mediate prostaglandin E2 actions in the microcirculation of the rat kidney.
Am J Physiol Renal Physiol
279:
F755-F764,
2000
26.
Ren, J,
Karpinski E,
and
Benishin CG.
The actions of prostaglandin E2 on potassium currents in rat tail artery vascular smooth muscle cells: regulation by protein kinase A and protein kinase C.
J Pharmacol Exp Ther
277:
394-402,
1996
27.
Rossat, J,
Maillartd M,
Nussberger J,
Brunner HR,
and
Burnier M.
Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects.
Clin Pharmacol Ther
66:
76-84,
1999[Web of Science][Medline].
28.
Ruan, X,
Chatziantoniou C,
and
Arendshorst WJ.
Impaired PGE2 or PGI2-Gs protein interaction and stimulation of cAMP formation in isolated renal resistance vessels of young genetically hypertensive rats.
Hypertension
34:
1134-1140,
1999
29.
Ruan, X,
Oliverio MI,
Coffman TM,
and
Arendshorst WJ.
Renal vascular reactivity in mice: Ang II-induced vasoconstriction in AT1a receptor null mice.
J Am Soc Nephrol
10:
2620-2630,
1999
30.
Ruan, X,
Purdy KW,
Oliverio MI,
Coffman TM,
and
Arendshorst WJ.
Effects of candesartan on angiotensin II-induced renal vasoconstriction in rats and mice.
J Am Soc Nephrol
10:
S202-S207,
1999.
31.
Samuelsson, B.
An elucidation of the arachidonic acid cascade. Discovery of prostaglandins, thromboxane and leukotrienes.
Drugs
33:
2-9,
1987.
32.
Sonnenburg, WK,
Zhu J,
and
Smith W.
A prostaglandin E receptor coupled to a pertussis toxin-sensitive guanine nucleotide regulatory protein in rabbit cortical collecting duct cells.
J Biol Chem
265:
8479-8483,
1990
33.
Sugimoto, Y,
Namba T,
Shigemoto R,
Negishi M,
Ichikawa A,
and
Narumiya S.
Distinct cellular localization of mRNAs for three subtypes of prostaglandin E receptor in kidney.
Am J Physiol Renal Physiol
35:
F823-F828,
1994.
34.
Tang, L,
Loutzenhiser K,
and
Loutzenhiser R.
Biphasic actions of prostaglandin E2 on the renal afferent arteriole: Role of EP3 and EP4 receptors.
Circ Res
86:
663-670,
2000
35.
Tilley, SL,
Audoly LP,
Hicks EH,
Kim HS,
Flannery PJ,
Coffman TM,
and
Koller BH.
Reproductive failure and reduced blood pressure in mice lacking the EP2 prostaglandin E2 receptor.
J Clin Invest
103:
1539-1545,
1999[Web of Science][Medline].
36.
Watanabe, T,
Umegaki K,
and
Smith W.
Association of a solubilized prostaglandin E2 receptor from renal medulla with a pertussis toxin-reactive guanine nucleotide regulatory rotein.
J Biol Chem
621:
13430-13437,
1986.
37.
Wekslet, BB,
Marcus AJ,
and
Jaffe EA.
Synthesis of prostaglandin I2 (prostacyclin) by cultured human and bovine endothelial cells.
Proc Natl Acad Sci USA
74:
3922-3926,
1977
38.
Zambraski, EJ.
The effects of nonsteroidal anti-inflammatory drugs on renal function: experimental studies in animals.
Semin Nephrol
15:
205-213,
1995[Web of Science][Medline].
This article has been cited by other articles:
|
|
 |
|
  H. Francois, C. Facemire, A. Kumar, L. Audoly, B. Koller, and T. Coffman Role of Microsomal Prostaglandin E Synthase 1 in the Kidney J. Am. Soc. Nephrol., May 1, 2007; 18(5): 1466 - 1475. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Opay, C. R. Mouton, J. J. Mullins, and K. D. Mitchell Cyclooxygenase-2 inhibition normalizes arterial blood pressure in CYP1A1-REN2 transgenic rats with inducible ANG II-dependent malignant hypertension Am J Physiol Renal Physiol, September 1, 2006; 291(3): F612 - F618. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Schweda, J. Klar, S. Narumiya, R. M. Nusing, and A. Kurtz Stimulation of renin release by prostaglandin E2 is mediated by EP2 and EP4 receptors in mouse kidneys Am J Physiol Renal Physiol, September 1, 2004; 287(3): F427 - F433. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Suganami, K. Mori, I. Tanaka, M. Mukoyama, A. Sugawara, H. Makino, S. Muro, K. Yahata, S. Ohuchida, T. Maruyama, et al. Role of Prostaglandin E Receptor EP1 Subtype in the Development of Renal Injury in Genetically Hypertensive Rats Hypertension, December 1, 2003; 42(6): 1183 - 1190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Imig, M. D. Breyer, and R. M. Breyer Contribution of prostaglandin EP2 receptors to renal microvascular reactivity in mice Am J Physiol Renal Physiol, September 1, 2002; 283(3): F415 - F422. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
, +/+ mice (n = 5); 
, EP3
