Prostaglandin E2 mediates connecting tubule glomerular feedback.
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.
Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202. ocarret1@hfhs.org.
Yilin
Y
Ren
Martin A
MA
D'Ambrosio
Jeffrey L
JL
Garvin
Hong
H
Wang
Oscar A
OA
Carretero
D000577:Amides / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism*; D008833:Microcirculation / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010654:Phenylbutyrates / Q000494:pharmacology; D011817:Rabbits; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
C487890:4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid; D000577:Amides; C121756:N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; D009281:Naphthalenes; D010654:Phenylbutyrates; D058309:Receptors, Prostaglandin E, EP4 Subtype; D016718:Arachidonic Acid; D015232:Dinoprostone; D009638:Norepinephrine
11,12-epoxy-5,8,14-eicosatrienoic acid; arachidonic acid; arterioles; endothelium; microcirculation; prostaglandin E2; receptors, prostaglandin E