title: Prostaglandin I2 and prostaglandin E2 modulate human intrarenal artery contractility through prostaglandin E2-EP4, prostacyclin-IP, and thromboxane A2-TP receptors.
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.
authors.affiliation: 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.).
authors.forename: Morten P
authors.initials: MP
authors.lastname: Eskildsen
authors.affiliation: 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.).
authors.forename: Pernille B L
authors.initials: PB
authors.lastname: Hansen
authors.affiliation: 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.).
authors.forename: Jane
authors.initials: J
authors.lastname: Stubbe
authors.affiliation: 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.).
authors.forename: Anja
authors.initials: A
authors.lastname: Toft
authors.affiliation: 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.).
authors.forename: Steen
authors.initials: S
authors.lastname: Walter
authors.affiliation: 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.).
authors.forename: Niels
authors.initials: N
authors.lastname: Marcussen
authors.affiliation: 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.).
authors.forename: Lars M
authors.initials: LM
authors.lastname: Rasmussen
authors.affiliation: 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.).
authors.forename: Paul M
authors.initials: PM
authors.lastname: Vanhoutte
authors.affiliation: 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.). bljensen@health.sdu.dk.
authors.forename: Boye L
authors.initials: BL
authors.lastname: Jensen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015232:Dinoprostone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D044006:Receptors, Epoprostenol / Q000187:drug effects / Q000502:physiology*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000187:drug effects / Q000502:physiology*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000187:drug effects / Q000502:physiology*; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014655:Vascular Resistance / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D044006:Receptors, Epoprostenol; D058309:Receptors, Prostaglandin E, EP4 Subtype; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014662:Vasoconstrictor Agents; D011189:Potassium Chloride; D011464:Epoprostenol; D015232:Dinoprostone; D009638:Norepinephrine
keywords: epoprostenol; kidney; norepinephrine; prostaglandin-endoperoxide synthases