Modulating role for thromboxane in the tubuloglomerular feedback response in the rat.
Some studies have indicated that PGs can modulate the single nephron tubuloglomerular feedback (TGF) response. The aim of this study was to define the specific role of the vasoconstrictor PG, TX, by administration to rats of either vehicle (group 1; n = 20) or drugs that inhibit either cyclooxygenase (indomethacin [indo], 5 mg.kg-1, group 2, n = 17), TX synthetase (UK-38,485 [UK], 100 mg.kg-1, group 3, n = 19), or TX receptors (SQ-29,548 [SQ], 8 mg.kg-1, group 4, n = 14, or L-641,953 [L], 50 mg.kg-1, group 5, n = 8). Indo reduced excretion of the prostacyclin derivative 6-keto-PGF1 alpha and TXB2 and lowered whole kidney GFR and renal plasma flow, whereas UK lowered excretion of TXB2 only and did not change basal renal hemodynamics. The TGF response (assessed from reduction in proximal tubule stop-flow pressure (Psf, mmHg) during increases in perfusion of the loop of Henle (LH) from 0 to 40 nl.min-1) was unchanged after vehicle (9.8 +/- 0.5-10.9 +/- 1.0, NS) but blunted (P less than 0.001) by 40-65% in rats of groups 2-5 (indo, 11.1 +/- 1.0-4.4 +/- 0.7; UK, 9.0 +/- 0.8-4.8 +/- 0.7; SQ, 10.3 +/- 0.6-4.8 +/- 0.6; L, 10.7 +/- 0.5-6.7 +/- 1.3). This blunting was due to lower values for Psf at zero LH flow after indo, SQ, and L, and higher values of Psf at 40 nl.min-1 LH flow after indo and UK. The fall in single nephron GFR (SNGFR, nl.min-1) with increasing LH perfusion was unchanged after vehicle (10.9 +/- 2.8-11.2 +/- 0.8) but was blunted (P less than 0.05) by 45-55% in rats given indo (13.9 +/- 1.2-6.2 +/- 2.2) or UK (12.8 +/- 2.1-7.0 +/- 1.5). UK produced dose-dependent reductions in TXB2 excretion (IC50, 15 mg.kg-1) and inhibition of the TGF response (IC50: 30 mg.kg-1). After blockade of TX receptors by SQ, UK had no further affect on the TGF response. The fall in Psf at high LH flow was blunted (P less than 0.05) by indo and UK, whereas the rise in Psf at zero LH flow was blunted by indo, SQ, and L. In conclusion, endogenous TX generation can modulate the reductions in Psf and SNGFR during increased delivery of NaCl to the LH.
Welch
W J
WJ
Department of Medicine, University of Florida College of Medicine, Gainesville 32610.
Wilcox
C S
CS
D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016861:Cyclooxygenase Inhibitors; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated; D005919:Glomerular Filtration Rate; D006834:Hydrazines / Q000494:pharmacology; D006874:Hydrostatic Pressure; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000502:physiology*; D007684:Kidney Tubules / Q000187:drug effects / Q000502:physiology*; D008297:Male; D011460:Prostaglandins F / Q000652:urine; D051381:Rats; D011919:Rats, Inbred Strains; D011982:Receptors, Prostaglandin / Q000187:drug effects; D017482:Receptors, Thromboxane; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors; D013929:Thromboxane B2 / Q000502:physiology* / Q000652:urine; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D019086:Bridged Bicyclo Compounds, Heterocyclic; D016861:Cyclooxygenase Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007093:Imidazoles; D011460:Prostaglandins F; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; C039242:dazmegrel; D013929:Thromboxane B2; D013928:Thromboxane A2; C045749:SQ 29548; D013930:Thromboxane-A Synthase; C100006:prostaglandin F1; D007213:Indomethacin