title: Inhibition of the Prostaglandin Transporter PGT Lowers Blood Pressure in Hypertensive Rats and Mice.
abstract: Inhibiting the synthesis of endogenous prostaglandins with nonsteroidal anti-inflammatory drugs exacerbates arterial hypertension. We hypothesized that the converse, i.e., raising the level of endogenous prostaglandins, might have anti-hypertensive effects. To accomplish this, we focused on inhibiting the prostaglandin transporter PGT (SLCO2A1), which is the obligatory first step in the inactivation of several common PGs. We first examined the role of PGT in controlling arterial blood pressure blood pressure using anesthetized rats. The high-affinity PGT inhibitor T26A sensitized the ability of exogenous PGE2 to lower blood pressure, confirming both inhibition of PGT by T26A and the vasodepressor action of PGE2 T26A administered alone to anesthetized rats dose-dependently lowered blood pressure, and did so to a greater degree in spontaneously hypertensive rats than in Wistar-Kyoto control rats. In mice, T26A added chronically to the drinking water increased the urinary excretion and plasma concentration of PGE2 over several days, confirming that T26A is orally active in antagonizing PGT. T26A given orally to hypertensive mice normalized blood pressure. T26A increased urinary sodium excretion in mice and, when added to the medium bathing isolated mouse aortas, T26A increased the net release of PGE2 induced by arachidonic acid, inhibited serotonin-induced vasoconstriction, and potentiated vasodilation induced by exogenous PGE2. We conclude that pharmacologically inhibiting PGT-mediated prostaglandin metabolism lowers blood pressure, probably by prostaglandin-induced natriuresis and vasodilation. PGT is a novel therapeutic target for treating hypertension.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States of America.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Chi
authors.affiliation: Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, Philadelphia, PA, United States of America.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Jasmin
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, United States of America.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Seki
authors.affiliation: Institute of Cancer Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States of America; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, United States of America; Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY, United States of America.
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Charron
authors.affiliation: Department of Physiology, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States of America; Department of Physiology & Biophysics, Albert Einstein College of Medicine, Bronx, NY, United States of America.
authors.forename: Victor L
authors.initials: VL
authors.lastname: Schuster
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D051379:Mice; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D012964:Sodium / Q000378:metabolism / Q000652:urine; D013931:Thromboxanes / Q000378:metabolism; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D062366:para-Aminobenzoates / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: C569290:N-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-4-((4-((2-(2-(2-benzamidoethoxy)ethoxy)ethyl)amino)-6-((4-hydroxyphenyl)amino)-1,3,5-triazin-2-yl)amino)benzamide; D027361:Organic Anion Transporters; D011453:Prostaglandins; C503528:Slco2a1 protein, rat; D013931:Thromboxanes; D014227:Triazines; D062366:para-Aminobenzoates; D012964:Sodium