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Originally Published 9 June 2014
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Prostaglandin I2 and Prostaglandin E2 Modulate Human Intrarenal Artery Contractility Through Prostaglandin E2-EP4, Prostacyclin-IP, and Thromboxane A2-TP Receptors

Morten P. Eskildsen, Pernille B.L. Hansen, Jane Stubbe, Anja Toft, Steen Walter, Niels Marcussen, Lars M. Rasmussen, Paul M. Vanhoutte, and Boye L. JensenAuthor Info & Affiliations
Hypertension
Volume 64, Number 3
https://doi.org/10.1161/HYPERTENSIONAHA.113.03051
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Abstract

Cyclooxygenase inhibitors decrease renal blood flow in settings with decreased effective circulating volume. The present study examined the hypothesis that prostaglandins, prostaglandin E2 (PGE2) and prostacyclin (PGI2), induce relaxation of human intrarenal arteries through PGE2-EP and PGI2-IP receptors. Intrarenal arteries were microdissected from human nephrectomy samples (n=53, median diameter ≈362 μm, 88% viable, 76% relaxed in response to acetylcholine). Rings were suspended in myographs to record force development. In vessels with K+-induced tension (EC70: –log [mol/L]=1.36±0.03), PGE2 and PGI2 induced concentration-dependent relaxation (–log EC50: PGE2=7.1±0.3 and PGI2=7.7). The response to PGE2 displayed endothelium dependence and desensitization. Relaxation by PGE2 was mimicked by an EP4 receptor agonist (CAY10598, EC50=6.7±0.2). The relaxation after PGI2 was abolished by an IP receptor antagonist (BR5064, 10–8 mol/L). Pretreatment of quiescent arteries with PGE2 for 5 minutes (10–6 mol/L) led to a significant right shift of the concentration–response to norepinephrine (EC50 from 6.6±0.1–5.9±0.1). In intrarenal arteries with K+-induced tone, PGE2 and PGI2 at 10–5 mol/L elicited increased tension. This was abolished by thromboxane receptor (TP) antagonist (S18886, 10–6 mol/L). A TP agonist (U46619, n=6) evoked tension (EC50=8.1±0.2) that was inhibited by S18886. Polymerase chain reaction and immunoblotting showed EP4, IP, and TP receptors in intrarenal arteries. In conclusion, PGE2 and PGI2 may protect renal perfusion by activating cognate IP and EP4 receptors associated with smooth muscle cells and endothelium in human intrarenal arteries and contribute to increased renal vascular resistance at high pathological concentrations mediated by noncognate TP receptor.

Introduction

In settings with decreased effective circulating volume and in patients with chronically reduced kidney function, renal perfusion and glomerular filtration rate are sensitive to inhibition of prostaglandin synthesis by cyclooxygenase inhibitors.1 The detrimental effect is attributed predominantly to compromised renal perfusion.1 An increase in endogenous angiotensin II and norepinephrine in response to extracellular volume contraction is associated with increased urinary excretion of prostaglandin E2 (PGE2), and infusion of angiotensin II and norepinephrine to humans leads to increased excretion of both PGE2 and prostacyclin (PGI2).2,3 In experimental animals, the cyclooxygenase inhibitor ibuprofen potentiates angiotensin II–mediated renal preglomerular vasoconstriction.4 This response is reversed by infusion of low concentrations of PGE2 and restored paradoxically by higher doses of this prostanoid.4,5 PGE2 and prostacyclin elicit dilatation of renal pre- and postglomerular resistance vessels.6–9 In rodents, the renal vasodilator response to prostaglandin E2 is predominantly attributable to activation of EP4 receptors with a minor contribution from EP2 receptors.4,10,11 EP4 receptors are found in rat and human preglomerular blood vessels and glomeruli.4,11–14 Data on vascular expression of EP2 are less consistent.11–13 Prostacyclin receptor (IP) has been detected in human preglomerular blood vessels and vasa recta.15 Functional data on the role of prostanoid receptors and their reactivity to PGE2 and prostacyclin in human preglomerular vasculature are not available. The present study was designed to test the hypothesis that PGE2 and prostacyclin relax human renal preglomerular arteries through activation of prostanoid receptors (EP2/EP4/IP), which when activated lead to increased production of cAMP by adenylyl cyclase.

Materials and Methods

Patient Tissue Collection

Patients were included at Department of Urology and Department of Thoracic and Cardiovascular Surgery at Odense University Hospital, Odense, Denmark. The collection of kidney tissue for artery dissection and left internal thoracic artery (ITA) were approved by the Regional Ethics Committee (kidney: S-VF-20010035; ITA: S-20100044) and was performed only after informed, written consent of the donors. Patient characteristics are shown in Table S1 in the online-only Data Supplement. The dissection procedure was as described previously,16 and further details are found in the online-only Data Supplement.

Protocols, Solution, and Experimental Series

The intrarenal artery rings (median diameter: 362 μm [177; 486]; thickness ≈2–3 mm, n=46 nephrectomy patients) were suspended for measurement of force generation in a Multi Wire Myograph System, 610M version 2.2 (Danish Myo Technology), filled with Krebs–Henseleit solution aerated with 5% CO2 in air. Details of microdissection, solutions, agonists, protocols, and experimental series are given in the online-only Data Supplement. To prevent interference from endogenously formed prostanoids, all experiments were performed in the presence of indomethacin (10–5 mol/L), a concentration that did not significantly affect the concentration–response curve to KCl (Figure S1A). K+ at EC70 (4×10−2 mol/L; Figure S1A) was used to induce stable tension. The response to K+ at EC70 did not wane for 2 hours and did not display oscillations (Figure S1B). The preparations included were accepted as viable based on a development of force >2 mN in response to KCl. Acetylcholine (10–5 mol/L), added during stable tension, caused relaxation in excess of 10% (of the response to KCl) in 76% of rings (Figure S1C), indicating the presence (or not) of functional endothelium. Responses to agonists, in the absence and presence of pharmacological antagonists, were obtained either in contracted (4×10−2 mol/L KCl) or in quiescent preparations.

Data Analysis and Statistics

Increases in isometric force were expressed relative to either the maximal force (100%) to the respective substance or to KCl (4×10−2 mol/L)-induced tone. Relaxation was expressed as percentage of the preexisting tone. Data are shown as mean±SEM; n represents the number of experiments with rings from different patients. For comparison of single and group mean values, 1-way and 2-way ANOVA followed by Bonferroni multiple comparison tests were performed, respectively, using GraphPad Prism software (GraphPad Prism 5.0). P values <0.05 were considered to indicate statistically significant differences.

Results

Prostaglandin E2

The cumulative addition of increasing concentrations (10–9–10–5 mol/L) of PGE2 induced concentration-dependent relaxations of intrarenal arteries with an Emax of 10–6 mol/L (Figure 1A and 1B). At 10–5 mol/L, PGE2 caused a significant increase in tension (Figure 1A and 1B). Addition of a single concentration (10–6 mol/L) of PGE2 to K+-stimulated intrarenal arteries yielded a significantly larger relaxation than that obtained with the same concentration as part of a cumulative concentration–response (Figure S2A). There was a significantly larger relaxation in response to 10–6 mol/L PGE2 in arteries with functional endothelium (Figure S2B). In K+-stimulated left ITA, PGE2 (10–9–10–5 mol/L) caused concentration-dependent increases in tension (Figure S2D).
Figure 1. A, Original trace showing force generation in a single human intrarenal artery ring in response to 40 mmol/L K+ and increasing concentrations of prostaglandin E2 (PGE2). An abrupt change in reactivity from relaxation to tension development was seen >10–6 mol/L PGE2. B, Cumulative concentration–response curves to PGE2 in KCl-precontracted intrarenal arteries. x axis shows PGE2, log (PGE2 mol/L); y axis: relative tension expressed as % of 40 mmol/L KCl (n=13). **P<0.01 and ***P<0.001 PGE2 vs time control (2-way ANOVA, Bonferroni post hoc test). ¤¤¤P<0.001, 10–6 mol/L vs 10–5 mol/L (unpaired t test).
Norepinephrine caused concentration (10–9–10–5 mol/L)-dependent increases in tension (EC50=6.6±0.1 mol/L; Figure 2A). Pretreatment with 10–6 mol/L PGE2 for 5 minutes before the exposure to norepinephrine caused a significant rightward shift of the concentration–response curve (EC50: 5.9±0.1 mol/L) without affecting the maximal response to the catecholamine (Figure 2A). The selective EP4 agonist CAY1059817 (10–9–10–5 mol/L) induced concentration-dependent relaxations of K+-stimulated arteries that was not significantly different from the response to PGE2 in concentrations ≤10–6 mol/L (Figure 1 versus Figure 2). CAY10598 did not induce tension at higher concentrations but rather decreased tension further (Figure 2B and 2C).
Figure 2. A, Cumulative concentration–response to norepinephrine (NE) in intrarenal artery rings, from the same patients, with and without 5-minute preincubation with prostaglandin E2 (PGE2) at 10–6 mol/L. x axis: NE, log (NE mol/L); y axis: relative tension expressed as % of 10–5 mol/L NE (n=6). *P<0.05 and ***P<0.001, NE vs NE+PGE2 (2-way ANOVA, Bonferroni post hoc test). B, Original trace showing force development in a single intrarenal artery ring in response to 40 mmol/L K+ and increasing concentrations of the specific PGE2-EP4 agonist CAY10598. C, The EP4 agonist CAY10598 led to a concentration-dependent relaxation in K+-stimulated arteries. x axis: CAY10598, log (CAY10598 mol/L); y axis: relative tension expressed as % of 40 mmol/L KCl (n=6). **P<0.01 and ***P<0.001, CAY10598 vs time control (2-way ANOVA, Bonferroni post hoc test).

Prostacyclin

Addition of prostacyclin (10–8–10–5 mol/L) to KCl-stimulated intrarenal arteries yielded concentration-dependent relaxations ≤10–6 mol/L (EC50: −log 7.7 mol/L; Figure 3A). Stratification of the arteries according to endothelial function did not yield significant correlation between the responsiveness to prostacyclin and that to acetylcholine (data not shown). At concentrations of prostacyclin >10–6 mol/L, the relaxation reversed to a significant increase in tension (Figure 3A and 3B). The IP1 receptor antagonist BR5064 (10–8 mol/L)18 abolished prostacyclin-induced relaxations while increased tension at 10–5 mol/L was not affected by the blocker (Figure 3C). With ITA, prostacyclin elicited a similar relaxation but with a markedly stronger increase in tension at high concentrations (4× above the KCl-induced tone; Figure S4C).
Figure 3. A, Original trace showing force generation in a single intrarenal artery ring in response to 40 mmol/L K+ and subsequent addition of increasing concentrations of prostacyclin. Brief mechanical artefacts result from the complete exchange of the bath solution at each prostacyclin concentration. An abrupt change in reactivity from relaxation to tension development was seen at and >10–6 mol/L of prostacyclin. B, Cumulative concentration–response to prostacyclin in KCl-stimulated human intrarenal arteries. x axis: prostacyclin concentration, log (PGI2 mol/L); y axis: relative tension expressed as % of 40 mmol/L KCl (n=9). **P<0.01 and ***P<0.001, prostacyclin (PGI2) vs time control (2-way ANOVA, Bonferroni post hoc test). ¤¤P<0.01, 10–6 mol/L vs 10–5 mol/L (Student t test for unpaired observations). C, Cumulative concentration–response to prostacyclin in KCl-prestimulated intrarenal arteries in the presence of an IP receptor antagonist (BR5064, 10–8 mol/L). x axis: PGI2, log (PGI2 mol/L); y axis: relative tension expressed as % of 40 mmol/L KCl (n=5). ***P<0.001, PGI2 vs time control (2-way ANOVA, Bonferroni post hoc test).

TP Receptors

To determine whether or not TP receptors are involved in PGE2 and prostacyclin-induced force generation (Figures 1A and 3A), the selective TP receptor antagonist S18886 (terutroban,19,20 10–6 mol/L for 5 minutes) was added to the bath solution. S18886 did not affect relaxations but abolished PGE2-induced (Figure 4A) and prostacyclin-induced (Figure 4B) force development (original traces in Figure S3). The TP receptor agonist U46619 caused concentration-dependent increases in tension in intrarenal arteries with EC50 values of (−log mol/L) 7.7±0.2 (Figure S4A). The increased tension of U46619 was antagonized by S18886 at concentrations from 10–6 mol/L (Figure S4B). In ITA, the increase in tension (in response to the highest concentration of prostacyclin) was abolished by the TP receptor antagonist (Figure S4C).
Figure 4. Concentration–response curves for prostaglandin E2 (PGE2; A) and prostacyclin (PGI2; B) as log (mol/L) in K+-stimulated human intrarenal arteries in the absence or presence of TP receptor antagonist (S18886, 10–6 mol/L). y axis: relative tension expressed as % of tension after 40 mmol/L KCl; n=4 with S18886 in both series. ***P<0.001, PGE2 vs PGE2+S18886 10–6 mol/L (2-way ANOVA, Bonferroni post hoc test).

EP, IP, and TP Receptor Expression

By Western immunoblotting of homogenates from intrarenal artery rings from same segments as used for myography, proteins with a migratory pattern at the predicted molecular size of receptors EP4 (52 kDa), IP (deglycosylated protein at 40 kDa), and TP (55 kDa) were observed (Figure 5). Immunostaining of kidney sections showed IP receptor labeling in media smooth muscle of intrarenal arteries (Figure 5). Intrarenal arteries expressed EP4, IP, and TP receptors and PGI2 and thromboxane A2 synthases (Figure S5 and S6).
Figure 5. Western immunoblotting of dissected intrarenal artery homogenate from same segments as used for myography; EP4 and IP were detected at the expected sizes (lanes 3, 5, and 7). As a positive control, human internal thoracic artery (ITA) homogenate was loaded in lanes 1: 30 μg and lane 2:15 μg. Serial dilution of homogenate from intrarenal (IR) arteries from 1 patient is shown in lanes 3 (30 μL) and 4 (15 μL), and dilution of homogenate from different pools of isolated intrarenal arteries obtained from 4 patients is run in lanes 5 to 8 (30 and 15 μL). TP was detected in kidney cortex (C), ITA, and intrarenal artery homogenate from various patients (IR1–3). β-Actin is used as a loading control. IP immunoreactive labeling was associated with the media layer of vascular smooth muscle cells in kidney (left). In the absence of primary antibody, no signal was observed (right, n=3).

Discussion

The present study shows that PGE2 and prostacyclin exert dual effects on human intrarenal arteries with relaxation in the nanomolar range, mediated by EP4 and IP receptors, whereas in high micromolar concentrations, tension development was observed resulting from thromboxane TP receptor activation. PGE2 led to a significant right shift in the concentration–response to norepinephrine. Thus, PGE2 and PGI2 may account for the support of renal blood flow and glomerular filtration rate that is uncovered by inhibitors of cyclooxygenase in patients with challenged kidney function.1 The tested artery rings had median diameter of ≈360 μm, which is exactly between human arcuate arteries (4–500 μm) and cortical radial arteries (150–200 μm).21 There was little variation in concentration–response to K+, norepinephrine, prostanoids, and receptor antagonists. This suggests effective washout of drugs in the isolation procedure and a stable expression pattern of voltage-gated calcium channels, prostanoid receptors, and adrenoceptors in intrarenal arteries across age, sex, and morbidities. Acetylcholine-mediated relaxation was observed in 75% of vessels. Because endothelium-derived hyperpolarization is responsible for acetylcholine-induced responses in NO-blocked, human renal interlobar arteries22 and K+-depolarization attenuates the response to acetylcholine compared with agonists,23 the present data may have underestimated the functional state of the endothelium and the relaxing effect of PGI2 and prostacyclin because membrane potential is clamped in response to elevated K+.
The relaxation induced by prostacyclin was blocked by an IP receptor antagonist; the response was independent of the functional state of the endothelium, and IP mRNA and protein were detected in intrarenal arteries. This indicates that prostacyclin mediates an IP receptor–dependent relaxation through a direct action on the vascular smooth muscle. Previous studies with systemic infusion of prostacyclin24 and iloprost25 to healthy humans showed a significant increase in renal plasma flow, despite a decrease in arterial blood pressure. This is in agreement with the present findings of a direct relaxant action by prostacyclin on human renal resistance vessels. PGE2 in nanomolar concentration relaxed intrarenal arteries. In renal vascular myocytes, PGE2 attenuates transmembrane calcium influx26 and suppresses intracellular calcium mobilization.11,27 The PGE2-induced relaxation was likely mediated by the EP4 receptor: the response was mimicked by an EP4 agonist; it exhibited desensitization28,29 and depended partially on functional state of the endothelium as is the case in the murine aorta.13 In accordance with previous immunohistochemical data, EP4 mRNA and protein were present in intrarenal arteries.13 The relaxing response to PGE2 was not observed in ITA. This could be because of impaired endothelial function or to higher EP1/3 receptor expression. The rightward shift by PGE2 of the concentration–effect curve for norepinephrine in intrarenal arteries confirms observations on renal blood flow in animal studies, for example.30 In vitro studies with isolated human renal arteries showed that norepinephrine-induced contractions depend on extracellular calcium with an ECmax at 10–5 mol/L.26 In smaller human intrarenal arteries, this response was mimicked by an α1-adrenoceptor agonist.21,31 α1-Adrenoceptors are expressed in the human renal artery.22 The present findings are consistent with the concept that PGE2 protects renal perfusion in vivo in settings of extracellulær volume contraction. Several animal studies show a concentration-dependent constriction of renal vessels in response to PGE2 in higher concentration.4,5 Therefore, the present study also sought to address the question whether this biphasic effect is because of expression of several classes of EP receptors as, for example, in the rat4 or to noncognate activation of thromboxane TP receptors, as observed in other vascular beds.13,32 High concentrations of PGI2 may also activate TP receptors.33 The TP antagonist terutroban (S18886) antagonized the increase in tension in response to PGE2 and PGI2 in high, micromolar concentration. Endogenous TxA2 production was less likely because the constant presence of indomethacin and activation of cognate constrictor receptors for PGE2 (EP1, EP3) were not likely because the effective concentration was far above the dissociation constant. TP receptors were demonstrated in intrarenal arteries.22 Activation of TP by PGE2 and prostacyclin has been observed in mouse and rat aorta.13,32 Prostaglandin F2α, prostaglandin H2, and isoprostanes may act as agonists at the TP receptor.32,34 In ITA, PGE2-induced tension began at lower concentrations (Figure S3) and was only partially blocked by the TP antagonist (not shown), which indicates involvement of EP1/EP3 receptors. Force development in response to micromolar concentrations of PGI2 was abolished by S18883, similarly to what was observed in the intrarenal artery. It is concluded that PGE2 and prostacyclin relax intrarenal arteries through direct effects on EP4 and IP receptors and that prostacyclin and PGE2 are low-affinity agonists at the TP receptor across human vascular beds.

Perspectives

The relaxant effect of PGE2 and prostacyclin may preserve human renal perfusion during common conditions with a challenged effective circulating volume. In situations with high local concentrations of several prostaglandins and isoprostanes, for example, endotoxemia,35 there could be a converging activation of the TP receptor to elicit ischemic renal failure. A cooperative action of angiotensin II-AT1 and TP receptors to lower renal perfusion has been observed in experimental models.8,36 The TP receptor seems as an attractive target to counter ischemic renal failure.

Acknowledgments

Kenneth Andersen, Susanne Hansen, Lis Teusch, and Inger Nissen are thanked for assistance. We thank Drs Peter Sandner and Andreas Knorr from Bayer Schering Pharma for providing the IP antagonist BR5064 and Dr Tony Verbeuren from Servier for providing S18886.

Novelty and Significance

What Is New?

•
Prostanoids prostaglandin E2 (PGE2) and prostacyclin (PGI2) relax human microdissected intrarenal artery rings in nanomolar concentration range through receptors EP4 and IP. At concentrations >10–5 mol/L, PGE2 and PGI2 increase tension through thromboxane receptors.

What Is Relevant?

•
The clinical use of cyclooxygenase inhibitors is associated with renal adverse effects: decline in renal perfusion and glomerular filtration rate, NaCl retention, and hypertension. The set of data shows that PGE2 and PGI2 may preserve renal perfusion through vasodilator receptors associated with human intrarenal resistance vessels. The contraction by PGE2 and PGI2 at high micromolar concentrations through TP may contribute to ischemic renal failure in, for example, endotoxemia/sepsis with large synthesis of cyclooxygenase products.

Summary

Through force recordings in myographs, human intrarenal artery rings display functional expression of PGE2, PGI2, and TxA2 receptors EP4, IP, and TP. Although PGE2 and PGI2 exert relaxation in nanomolar concentrations, they induce force generation though TP and thus are low-affinity TP receptor agonists in high micromolar concentrations. Intrarenal generation of prostanoids may exert dual and concentration-dependent effects directly on the renal resistance arteries.

Supplemental Material

File (hyp_hype201303051_supp1.pdf)

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Published In

Go to Hypertension
Go to Hypertension
Hypertension
Volume 64 • Number 3 • September 2014
Pages: 551 - 556
PubMed: 24914192

Copyright

© 2014 American Heart Association, Inc.

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History

Received: 30 December 2013
Revision received: 17 January 2014
Accepted: 9 May 2014
Published online: 9 June 2014
Published in print: September 2014

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Keywords

  1. epoprostenol
  2. kidney
  3. norepinephrine
  4. prostaglandin-endoperoxide synthases

Subjects

  1. Cardiorenal Syndrome
  2. Endothelium/Vascular Type/Nitric Oxide
  3. Platelets

Authors

Affiliations

Morten P. Eskildsen
From the Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark (M.P.E., P.B.L.H., J.S., B.L.J.); State Key Laboratory for Pharmaceutical Biotechnologies and Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong (P.M.V.); and Departments of Urology, Biochemistry and Clinical Pathology, Odense University Hospital, Odense, Denmark (M.P.E., P.B.L.H., J.S., A.T., S.W., N.M., L.M.R.).
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Pernille B.L. Hansen
From the Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark (M.P.E., P.B.L.H., J.S., B.L.J.); State Key Laboratory for Pharmaceutical Biotechnologies and Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong (P.M.V.); and Departments of Urology, Biochemistry and Clinical Pathology, Odense University Hospital, Odense, Denmark (M.P.E., P.B.L.H., J.S., A.T., S.W., N.M., L.M.R.).
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Jane Stubbe
From the Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark (M.P.E., P.B.L.H., J.S., B.L.J.); State Key Laboratory for Pharmaceutical Biotechnologies and Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong (P.M.V.); and Departments of Urology, Biochemistry and Clinical Pathology, Odense University Hospital, Odense, Denmark (M.P.E., P.B.L.H., J.S., A.T., S.W., N.M., L.M.R.).
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Anja Toft
From the Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark (M.P.E., P.B.L.H., J.S., B.L.J.); State Key Laboratory for Pharmaceutical Biotechnologies and Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong (P.M.V.); and Departments of Urology, Biochemistry and Clinical Pathology, Odense University Hospital, Odense, Denmark (M.P.E., P.B.L.H., J.S., A.T., S.W., N.M., L.M.R.).
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Steen Walter
From the Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark (M.P.E., P.B.L.H., J.S., B.L.J.); State Key Laboratory for Pharmaceutical Biotechnologies and Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong (P.M.V.); and Departments of Urology, Biochemistry and Clinical Pathology, Odense University Hospital, Odense, Denmark (M.P.E., P.B.L.H., J.S., A.T., S.W., N.M., L.M.R.).
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Niels Marcussen
From the Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark (M.P.E., P.B.L.H., J.S., B.L.J.); State Key Laboratory for Pharmaceutical Biotechnologies and Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong (P.M.V.); and Departments of Urology, Biochemistry and Clinical Pathology, Odense University Hospital, Odense, Denmark (M.P.E., P.B.L.H., J.S., A.T., S.W., N.M., L.M.R.).
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Lars M. Rasmussen
From the Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark (M.P.E., P.B.L.H., J.S., B.L.J.); State Key Laboratory for Pharmaceutical Biotechnologies and Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong (P.M.V.); and Departments of Urology, Biochemistry and Clinical Pathology, Odense University Hospital, Odense, Denmark (M.P.E., P.B.L.H., J.S., A.T., S.W., N.M., L.M.R.).
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Paul M. Vanhoutte
From the Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark (M.P.E., P.B.L.H., J.S., B.L.J.); State Key Laboratory for Pharmaceutical Biotechnologies and Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong (P.M.V.); and Departments of Urology, Biochemistry and Clinical Pathology, Odense University Hospital, Odense, Denmark (M.P.E., P.B.L.H., J.S., A.T., S.W., N.M., L.M.R.).
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Boye L. Jensen
From the Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark (M.P.E., P.B.L.H., J.S., B.L.J.); State Key Laboratory for Pharmaceutical Biotechnologies and Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong (P.M.V.); and Departments of Urology, Biochemistry and Clinical Pathology, Odense University Hospital, Odense, Denmark (M.P.E., P.B.L.H., J.S., A.T., S.W., N.M., L.M.R.).
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Notes

The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.113.03051/-/DC1.
Correspondence to Boye L. Jensen, Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winslowsvej 21, 3. DK-5000, Odense C, Denmark. E-mail [email protected]

Disclosures

None.

Sources of Funding

The study was supported by the Research Council for Health and Disease, The Danish Society of Nephrology, LEO Pharma travel stipend, The AP Moeller Foundation, and The NOVO Nordisk Foundation.

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Prostaglandin I2 and Prostaglandin E2 Modulate Human Intrarenal Artery Contractility Through Prostaglandin E2-EP4, Prostacyclin-IP, and Thromboxane A2-TP Receptors
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