Inhibition of the prostaglandin transporter PGT lowers blood pressure in hypertensive rats and mice

Yuling Chi, Jean Francois Jasmin, Yoshinori Seki, Michael P. Lisanti, Maureen J. Charron, David J. Lefer, Victor L. Schuster

Research output: Contribution to journalArticle

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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 PGE<inf>2</inf> to lower blood pressure, confirming both inhibition of PGT by T26A and the vasodepressor action of PGE<inf>2</inf> 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 PGE<inf>2</inf> 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 PGE<inf>2</inf> induced by arachidonic acid, inhibited serotonin-induced vasoconstriction, and potentiated vasodilation induced by exogenous PGE<inf>2</inf>. 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.

Original languageEnglish (US)
Article numbere0131735
JournalPLoS One
Volume10
Issue number6
DOIs
StatePublished - Jun 29 2015

Fingerprint

hypotension
Blood pressure
Dinoprostone
prostaglandins
Prostaglandins
transporters
Rats
blood pressure
Blood Pressure
rats
mice
vasodilation
Vasodilation
hypertension
excretion
Hypertension
antihypertensive effect
Natriuresis
Rat control
vasoconstriction

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Inhibition of the prostaglandin transporter PGT lowers blood pressure in hypertensive rats and mice. / Chi, Yuling; Jasmin, Jean Francois; Seki, Yoshinori; Lisanti, Michael P.; Charron, Maureen J.; Lefer, David J.; Schuster, Victor L.

In: PLoS One, Vol. 10, No. 6, e0131735, 29.06.2015.

Research output: Contribution to journalArticle

Chi, Yuling ; Jasmin, Jean Francois ; Seki, Yoshinori ; Lisanti, Michael P. ; Charron, Maureen J. ; Lefer, David J. ; Schuster, Victor L. / Inhibition of the prostaglandin transporter PGT lowers blood pressure in hypertensive rats and mice. In: PLoS One. 2015 ; Vol. 10, No. 6.
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