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Title: Regulation of urinary thromboxane B2 in man: influence of urinary flow rate and tubular transport

Abstract

Thromboxane B2 (TxB) is excreted in human urine, but the mechanism of renal excretion and the quantitative relationship of urinary TxB to the active parent compound, thromboxane A2, of renal or extrarenal origin is not established. To determine the effects of vasoactive hormones, uricosuric agents and urinary flow rate on TxB excretion, urinary TxB was measured by radioimmunoassay and mass spectrometry, and renal metabolism of blood TxB was determined by radiochromatography of urine after i.v. (3H)-TxB infusions. Basal TxB was 6.7 +/- 1.1 ng/h during an oral water load, and TxB fell with s.g. antidiuretic hormone (to 3.4 +/- 0.4 ng/h, P less than 0.01) and with fluid restriction (to 2.6 +/- 0.5 ng/hr, P . 0.001) in parallel with urinary volume. Urinary excretion of unmetabolized (3H)-TxB also fell (by 56%) with fluid restriction, implicating altered metabolism rather than synthesis as the mechanism of the urinary flow effect. Angiotensin II infusions slightly reduced both TxB and urine volume, consistent with a flow effect. In contrast, probenecid did not alter urine volume, but increased urinary uric acid (by 244%), TxB (from 5.6 +/- 0.9 to 11.1 +/- 2.9 ng/h) and urinary excretion of blood (3H)-TxB (by 243%) by similar amounts (allmore » P less than 0.05), suggesting that TxB is actively reabsorbed in the proximal tubule, similarly to uric acid. Thus, urinary excretion of TxB of renal and extrarenal origin is regulated by proximal and distal tubule factors.« less

Authors:
;
Publication Date:
Research Org.:
Department of Medicine, University of Southern California, Los Angeles County Medical Center
OSTI Identifier:
6746960
Resource Type:
Journal Article
Resource Relation:
Journal Name: Prostaglandins; (United States); Journal Volume: 27:2
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ARACHIDONIC ACID; METABOLITES; EXCRETION; RADIOCHROMATOGRAPHY; RADIOIMMUNOASSAY; ANGIOTENSIN; MASS SPECTROSCOPY; METABOLISM; PROSTAGLANDINS; RENAL CLEARANCE; TRITIUM COMPOUNDS; URINE; BIOLOGICAL MATERIALS; BIOLOGICAL WASTES; BODY FLUIDS; CARBOXYLIC ACIDS; CARDIOVASCULAR AGENTS; CHROMATOGRAPHY; CLEARANCE; DRUGS; GLOBULINS; ISOTOPE APPLICATIONS; LABELLED COMPOUNDS; MATERIALS; MONOCARBOXYLIC ACIDS; ORGANIC ACIDS; ORGANIC COMPOUNDS; PROTEINS; RADIOASSAY; SEPARATION PROCESSES; SPECTROSCOPY; TRACER TECHNIQUES; VASOCONSTRICTORS; WASTES 550601* -- Medicine-- Unsealed Radionuclides in Diagnostics

Citation Formats

Zipser, R.D., and Smorlesi, C.. Regulation of urinary thromboxane B2 in man: influence of urinary flow rate and tubular transport. United States: N. p., 1984. Web. doi:10.1016/0090-6980(84)90078-9.
Zipser, R.D., & Smorlesi, C.. Regulation of urinary thromboxane B2 in man: influence of urinary flow rate and tubular transport. United States. doi:10.1016/0090-6980(84)90078-9.
Zipser, R.D., and Smorlesi, C.. 1984. "Regulation of urinary thromboxane B2 in man: influence of urinary flow rate and tubular transport". United States. doi:10.1016/0090-6980(84)90078-9.
@article{osti_6746960,
title = {Regulation of urinary thromboxane B2 in man: influence of urinary flow rate and tubular transport},
author = {Zipser, R.D. and Smorlesi, C.},
abstractNote = {Thromboxane B2 (TxB) is excreted in human urine, but the mechanism of renal excretion and the quantitative relationship of urinary TxB to the active parent compound, thromboxane A2, of renal or extrarenal origin is not established. To determine the effects of vasoactive hormones, uricosuric agents and urinary flow rate on TxB excretion, urinary TxB was measured by radioimmunoassay and mass spectrometry, and renal metabolism of blood TxB was determined by radiochromatography of urine after i.v. (3H)-TxB infusions. Basal TxB was 6.7 +/- 1.1 ng/h during an oral water load, and TxB fell with s.g. antidiuretic hormone (to 3.4 +/- 0.4 ng/h, P less than 0.01) and with fluid restriction (to 2.6 +/- 0.5 ng/hr, P . 0.001) in parallel with urinary volume. Urinary excretion of unmetabolized (3H)-TxB also fell (by 56%) with fluid restriction, implicating altered metabolism rather than synthesis as the mechanism of the urinary flow effect. Angiotensin II infusions slightly reduced both TxB and urine volume, consistent with a flow effect. In contrast, probenecid did not alter urine volume, but increased urinary uric acid (by 244%), TxB (from 5.6 +/- 0.9 to 11.1 +/- 2.9 ng/h) and urinary excretion of blood (3H)-TxB (by 243%) by similar amounts (all P less than 0.05), suggesting that TxB is actively reabsorbed in the proximal tubule, similarly to uric acid. Thus, urinary excretion of TxB of renal and extrarenal origin is regulated by proximal and distal tubule factors.},
doi = {10.1016/0090-6980(84)90078-9},
journal = {Prostaglandins; (United States)},
number = ,
volume = 27:2,
place = {United States},
year = 1984,
month = 2
}
  • This paper presents the chemical reaction engineering development of the H{sub 2}O{sub 2}/VisUV photo-oxidation process for treatment of hazardous waterborne substances, that occur in groundwater, leachates, and industrial wastewater. Reaction results, on benzene (BNZ), dichlorobenzene (DCB), trichloroethene (TCE), trichloroethane (TCA), and carbon tetrachloride (CTC), have been obtained, providing engineering data and models that can be used to size full-scale equipment. A photochemical flow stirred tank reactor (pcfSTR) and a photo-chemical tubular flow reactor (pcTFR) were used in the experimental work. Two experimental discoveries were made in the course of the work: (1) conventional thermal kinetics do not apply, the ratemore » controlling variable is the photon flux, and (2) for the photo-chemical reactors used, the pcfSTR was more effective than the pcTFR. The following sub-topics are discussed: reaction mechanism, reactor hydrodynamics, photon flux effects, typical reaction data (on benzene and trichloroethane), and rate constants.« less
  • The human thromboxane synthase (TS) gene encodes a microsomal enzyme catalyzing the conversion of prostaglandin endoperoxide into thromboxane A{sub 2}(TxA{sub 2}), a potent inducer of vasoconstriction and platelet aggregation. A deficiency in platelet TS activity results in bleeding disorders, but the underlying molecular mechanism remains to be elucidated. Increased TxA{sub 2} has been associated with many pathophysiological conditions such as cardiovascular disease, pulmonary hypertension, pre-eclampsia, and thrombosis in sickle cell patients. Since the formation of TxA{sub 2} is dependent upon TS, the regulation of TS gene expression may presumably play a crucial role in vivo. Abrogation of the regulatory mechanismmore » in TS gene expression might contribute, in part, to the above clinical manifestations. To gain insight into TS gene regulation, a 1.7 kb promoter of the human TS gene was cloned and sequenced. RNase protection assay and 5{prime} RACE protocols were used to map the transcription initiation site to nucleotide A, 30 bp downstream from a canonical TATA box. Several transcription factor binding sites, including AP-1, PU.1, and PEA3, were identified within this sequence. Transient expression studies in HL-60 cells transfected with constructs containing various lengths (0.2 to 5.5 kb) of the TS promoter/luciferase fusion gene indicated the presence of multiple repressor elements within the 5.5 kb TS promoter. However, a lineage-specific up-regulation of TS gene expression was observed in HL-60 cells induced by TPA to differentiate along the macrophage lineage. The increase in TS transcription was not detectable until 36 hr after addition of the inducer. These results suggest that expression of the human TS gene may be regulated by a mechanism involving repression and derepression of the TS promoter.« less
  • The thromboxane (TX) A{sub 2} receptor (TP) encompasses two alternatively spliced forms, termed the platelet/placental (TP-P) and endothelial (TP-E) type receptors. Experimental evidence suggests that TP activity may be modulated by novel ligands, termed the isoprostanes, that paradoxically act as TP agonists in smooth muscle and TP antagonists in platelet preparations. Here we have investigated whether prototypical isoprostanes 8-iso-prostaglandin (PG)F{sub 2{alpha}} and 8-iso-PGE{sub 2} regulate the activity of TP isoforms expressed in Chinese hamster ovary (CHO) cells using activator protein-1 (AP-1)-luciferase activity as a reporter. AP-1-luciferase activity was increased by a TP agonist [9,11-dideoxy-9{alpha},11{alpha}-methanoepoxy PGF{sub 2{alpha}} (U46619)] in CHO cellsmore » transfected with the human TP-P and TP-E receptors, and this response was fully inhibited by TP antagonists [1S-[1{alpha},2{beta}(Z),3{alpha},5{alpha}]]-7-[3-[[(4-iodophenyl)sulfonyl]amino]-6,6-dimethylbicyclo[3.1.1]hept-2-yl]-5-heptenoic acid (I-SAP) and [1S-[1{alpha},2{alpha}(Z),3{alpha},4{alpha}]]-7-[[2-[(phenylamino) carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1] [hept-2-yl-5-heptenoic acid (SQ 29,548)]. AP-1-luciferase activity was potently (nanomolar concentrations) increased by 8-iso-PGE{sub 2} in CHO TP-P and TP-E cells, and this response was partially inhibited by cotreatment of cells with TP antagonists, whereas 8-iso-PGF{sub 2{alpha}}, was without effect. Cyclooxygenase inhibitors did not abolish 8-iso-PGE{sub 2} mediated AP-1-luciferase activity, indicating that this response is not dependent on de novo TXA{sub 2} biosynthesis. Interestingly, 8-iso-PGE{sub 2}-mediated AP-1-luciferase activity was near maximal in naive cells between 1 and 10 nM concentrations, and this response was not inhibited by TP antagonist or reproduced by agonists for TP or EP{sub 1}/EP{sub 3} receptors. These observations (1) support a role for novel ligands in the regulation of TP-dependent signaling, (2) indicate that TP-P and TP-E couple to AP-1, (3) provide further evidence that isoprostanes function as TP agonists in a cell-type specific fashion, and (4) indicate that additional targets regulated by 8-iso-PGE{sub 2} couple to AP-1.« less
  • The thromboxane A{sub 2} (TXA{sub 2}) receptor (TP) is represented by two alternatively spliced forms, termed the platelet/placental (TP-P) and endothelial (TP-E) type receptors. Experimental evidence suggests that TP isoforms may be regulated by novel ligands termed the isoprostanes, which paradoxically act as TP agonists in smooth muscle and TP antagonists in platelet preparations. Here we have investigated whether prototypical isoprostanes (8-iso-PG{sub 2{sub {alpha}}} and 8-iso-PGE{sub 2}) regulate the activity of TP isoforms expressed in Chinese Hamster Ovary (CHO) cells using activator protein-1 (AP-1)-luciferase activity as a reporter. AP-1-luciferase activity was increased by a TP agonist (U46619) in CHO cellsmore » transfected with the human TP-P and TP-E receptors and this response was fully inhibited by TP antagonists (ISAP, SQ29,548). AP-1-luciferase activity was potently (nM) increased by 8-iso-PGE2 in CHO TP-P and TP-E cells, and this response was partially inhibited by cotreatment of cells with TP antagonists, while 8-iso-PGF{sub 2{sub {alpha}}} was without effect. Cyclooxygenase inhibitors did not abolish 8-iso-PGE{sub 2} mediated AP-1-luciferase activity, indicating that this response is not dependent on de novo TXA2 biosynthesis. Interestingly, 8-iso-PGE{sub 2}-mediated AP-1-luciferase activity was near maximal in naive cells between 1-10 nM concentrations, and this response was not inhibited by TP antagonist or reproduced by agonists for TP or EP1/EP3 receptors. These observations (1) support a role for novel ligands in the regulation of TP-dependent signaling, (2) indicate that TP-P and TP-E couple to AP-1, (3) provide further evidence that isoprostanes function as TP agonists in a cell-type specific fashion, and (4) indicate that additional targets regulated by 8-iso-PGE{sub 2} couple to AP-1.« less