Cabral Pablo D, Silva Guillermo B, Baigorria Sandra T, Juncos Luis I, Ajayi Ebenezer I O, García Néstor H
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA.
Department of Renal Physiology, J. Robert Cade Foundation, Córdoba, Argentina.
Kidney Res Clin Pract. 2022 Nov;41(6):699-706. doi: 10.23876/j.krcp.21.243. Epub 2022 Aug 17.
Sodium chloride (NaCl) reabsorption in the cortical thick ascending limb (cTAL) is regulated by opposing effects. Nitric oxide (NO) inhibits NaCl reabsorption while 8-iso-prostaglandin-F2α (8-iso-PGF2α) stimulates it. Their interaction has not been evaluated in the cTAL. Because 8-iso-PGF2α has considerable stability while NO is a free radical with a short half-life, we hypothesized that, in the cTAL, the inhibition of NaCl absorption will be reversed by 8-iso-PGF2α.
Chloride absorption (JCl) was measured in isolated perfused cTALs and whether the activation of protein kinase A (PKA) is required for this interaction. Since cyclic adenosine monophosphate (cAMP) is a major messenger for the 8-iso-PGF2α signaling cascade, and NO inhibits JCl by decreasing cAMP bioavailability, we measured 8-iso-PGF2α-stimulated cAMP in the presence of sodium nitroprusside (SNP).
The NO donor, SNP (10-6 M), decreased JCl by 41%, while luminal 8-iso-PGF2α (100 μM) increased JCl to 315 ± 46 pmol/ min/mm (p < 0.003), reversing the effects of the NO donor. SNP inhibited JCl, 8-iso-PGF2α failed to increase JCl in the presence of H89. Basal cAMP was 56 ± 13 fmol/min/mm, in the presence of SNP 57 ± 6 fmol/min/mm, and 8-iso-PGF2α increased it to 92 ± 2 fmol/min/mm (p < 0.04).
We concluded that 1) NO-induced inhibition of JCl in the cTAL can be reversed by 8-iso-PGF2α, 2) 8-iso-PGF2α and NO interaction requires PKA to control JCl, and 3) in the presence of NO, 8-iso-PGF2α continues to stimulate JCl because NO cannot reverse 8-iso-PGF2α-stimulated cAMP level.
皮质厚升支（cTAL）中氯化钠（NaCl）的重吸收受相反作用调节。一氧化氮（NO）抑制NaCl重吸收，而8-异前列腺素-F2α（8-异-PGF2α）则刺激其重吸收。它们在cTAL中的相互作用尚未得到评估。由于8-异-PGF2α具有相当的稳定性，而NO是一种半衰期短的自由基，我们推测在cTAL中，8-异-PGF2α会逆转NaCl吸收的抑制作用。
在分离灌注的cTAL中测量氯离子吸收（JCl），并确定这种相互作用是否需要蛋白激酶A（PKA）的激活。由于环磷酸腺苷（cAMP）是8-异-PGF2α信号级联反应的主要信使，且NO通过降低cAMP的生物利用度来抑制JCl，我们在硝普钠（SNP）存在的情况下测量了8-异-PGF2α刺激的cAMP。
NO供体SNP（10-6 M）使JCl降低41%，而管腔8-异-PGF2α（100 μM）使JCl增加到315±46 pmol/分钟/毫米（p<0.003），逆转了NO供体的作用。SNP抑制JCl，在H89存在的情况下，8-异-PGF2α未能增加JCl。基础cAMP为56±13 fmol/分钟/毫米，在SNP存在的情况下为57±6 fmol/分钟/毫米，8-异-PGF2α使其增加到92±2 fmol/分钟/毫米（p<0.04）。
我们得出结论：1）cTAL中NO诱导的JCl抑制可被8-异-PGF2α逆转；2）8-异-PGF2α与NO的相互作用需要PKA来控制JCl；3）在NO存在的情况下，8-异-PGF2α继续刺激JCl，因为NO不能逆转8-异-PGF2α刺激的cAMP水平。
