Merck

Prostaglandin E2 mediates connecting tubule glomerular feedback.

Hypertension (Dallas, Tex. : 1979) (2013-09-26)
Yilin Ren, Martin A D'Ambrosio, Jeffrey L Garvin, Hong Wang, Oscar A Carretero
ABSTRACT

Connecting tubule glomerular feedback (CTGF) is a mechanism in which Na reabsorption in the connecting tubule (CNT) causes afferent arteriole (Af-Art) dilation. CTGF is mediated by eicosanoids, including prostaglandins and epoxyeicosatrienoic acids; however, their exact nature and source remain unknown. We hypothesized that during CTGF, the CNT releases prostaglandin E2, which binds its type 4 receptor (EP4) and dilates the Af-Art. Rabbit Af-Arts with the adherent CNT intact were microdissected, perfused, and preconstricted with norepinephrine. CTGF was elicited by increasing luminal NaCl in the CNT from 10 to 80 mmol/L. We induced CTGF with or without the EP4 receptor blocker ONO-AE3-208 added to the bath in the presence of the epoxyeicosatrienoic acid synthesis inhibitor MS-PPOH. ONO-AE3-208 abolished CTGF (control, 9.4 ± 0.5; MS-PPOH+ONO-AE3-208, -0.6 ± 0.2 μm; P<0.001; n=6). To confirm these results, we used a different, specific EP4 blocker, L161982 (10(-5) mol/L), that also abolished CTGF (control, 8.5 ± 0.9; MS-PPOH+L161982, 0.8 ± 0.4 μm; P<0.001; n=6). To confirm that the eicosanoids that mediate CTGF are released from the CNT rather than the Af-Art, we first disrupted the Af-Art endothelium with an antibody and complement. Endothelial disruption did not affect CTGF (7.9 ± 0.9 versus 8.6 ± 0.6 μm; P=NS; n=7). We then added arachidonic acid to the lumen of the CNT while maintaining zero NaCl in the perfusate. Arachidonic acid caused dose-dependent dilation of the attached Af-Art (from 8.6 ± 1.2 to 15.3 ± 0.7 μm; P<0.001; n=6), and this effect was blocked by ONO-AE3-208 (10(-7) mol/L). We conclude that during CTGF, the CNT releases prostaglandin E2, which acts on EP4 on the Af-Art inducing endothelium-independent dilation.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
DL-Norepinephrine hydrochloride, crystalline, ≥97% (TLC)
Sigma-Aldrich
L-Norepinephrine hydrochloride, ≥98.0% (sum of enantiomers, HPLC)
Sigma-Aldrich
(−)-Norepinephrine, ≥98%, crystalline
Sigma-Aldrich
(±)-Norepinephrine (+)-bitartrate salt
Sigma-Aldrich
Arachidonic acid, from non-animal source, ≥98.5% (GC)
Sigma-Aldrich
Arachidonic acid sodium salt, from Porcine liver, ≥99% (capillary GC), waxy solid
Sigma-Aldrich
Arachidonic acid, >95.0% (GC)
Sigma-Aldrich
(S)-(+)-Norepinephrine L-bitartrate, 99%