Endothelin induces diuresis and natriuresis in the rat by acting on proximal tubular cells through a mechanism mediated by lipoxygenase products

Norberto Perico, Raul Plata Cornejo, Ariela Benigni, Barbara Malanchini, Jerzy Robert Ladny, Giuseppe Remuzzi

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Abstract

Besides being a potent renal vasoconstrictor, endothelin causes diuresis and natriuresis. At which site along the nephron and how endothelin alters water and sodium handling in the tubule remain to be clarified. It was found that endothelin (75 pmol) given as an i.v. infusion in vivo to rats caused diuresis and urinary sodium excretion to double but did not affect glomerular filtration rate and renal plasma flow. On raising the dose of endothelin to 150 pmol, a further increase in diuresis and natriuresis was found, whereas glomerular filtration rate fell 33% and renal plasma flow fell 36%; 300 pmol of endothelin reduced glomerular filtration rate by 73% and renal plasma flow by 77% but did not significantly affect diuresis and absolute sodium excretion. It did, however, increase fractional sodium excretion eightfold. Lithium clearance studies of changes in tubular handling of water and sodium indicated that infusion of 150 pmol of endothelin to rats caused a reduction in absolute (pre, 84.7 ± 5.9; post, 47.9 ± 6.1 μEq/min/ 100 g) and fractional (pre, 85.7 ± 3.0; post, 64.7 ± 6.4%) proximal reabsorption of sodium. Endothelin infusion (150 pmol) was not associated with any significant change in plasma atrial natriuretic peptide levels, which on average remained comparable to those in rats given the vehicle alone (49.7 ± 8.4 versus 46.3 ±5.6 pg/mL). In the isolated perfused rat kidney preparation, exposure to 150 pmol of endothelin significantly increased fractional sodium excretion over preinjection values (pre, 2.2 ± 0.2; post, 7.3 ± 1.0%) despite a marked decrease in glomerular filtration rate and renal perfusate flow. Additional in vivo experiments showed that oral administration of the specific 5-lipoxygenase inhibitor L-651,392 to rats prevented the increase in urine flow rate (pre, 5.7 ± 0.1; post, 6.6 ± 0.8 μL/min), and in absolute (pre, 0.33 ± 0.04; post, 0.37 ± 0.05 μEq/min) and fractional (pre, 0.10 ± 0.02; post, 0.11 ± 0.03%) sodium excretion caused by bolus i.v. infusion of endothelin (150 pmol). Similarly, a specific leukotriene C4/D4 receptor antagonist, L-649,923, also prevented the diuretic and natriuretic effect of 150 pmol of endothelin i.v. infusion. These findings show that (1) endothelin has a diuretic and natriuretic effect that is independent of its action on renal hemodynamics; (2) this effect depends on a direct action on the proximal tubules; (3) atrial natriuretic peptide does not appear to be involved in this effect; and (4) the diuretic and natriuretic responses to endothelin are mediated by 5-lipoxygenase products.

Original languageEnglish
Pages (from-to)57-69
Number of pages13
JournalJournal of the American Society of Nephrology
Volume2
Issue number1
Publication statusPublished - Jul 1991

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Natriuresis
Lipoxygenase
Diuresis
Endothelins
Sodium
Renal Plasma Flow
Glomerular Filtration Rate
Diuretics
Natriuretic Agents
Kidney
Atrial Natriuretic Factor
4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one
L 649923
Arachidonate 5-Lipoxygenase
Lipoxygenase Inhibitors
Water
Nephrons
Vasoconstrictor Agents
Endothelin-1
Lithium

Keywords

  • Atrial natriuretic peptide
  • Glomerular filtration rate
  • Isolated perfused kidney
  • Lithium clearance
  • Renal plasma flow

ASJC Scopus subject areas

  • Nephrology

Cite this

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title = "Endothelin induces diuresis and natriuresis in the rat by acting on proximal tubular cells through a mechanism mediated by lipoxygenase products",
abstract = "Besides being a potent renal vasoconstrictor, endothelin causes diuresis and natriuresis. At which site along the nephron and how endothelin alters water and sodium handling in the tubule remain to be clarified. It was found that endothelin (75 pmol) given as an i.v. infusion in vivo to rats caused diuresis and urinary sodium excretion to double but did not affect glomerular filtration rate and renal plasma flow. On raising the dose of endothelin to 150 pmol, a further increase in diuresis and natriuresis was found, whereas glomerular filtration rate fell 33{\%} and renal plasma flow fell 36{\%}; 300 pmol of endothelin reduced glomerular filtration rate by 73{\%} and renal plasma flow by 77{\%} but did not significantly affect diuresis and absolute sodium excretion. It did, however, increase fractional sodium excretion eightfold. Lithium clearance studies of changes in tubular handling of water and sodium indicated that infusion of 150 pmol of endothelin to rats caused a reduction in absolute (pre, 84.7 ± 5.9; post, 47.9 ± 6.1 μEq/min/ 100 g) and fractional (pre, 85.7 ± 3.0; post, 64.7 ± 6.4{\%}) proximal reabsorption of sodium. Endothelin infusion (150 pmol) was not associated with any significant change in plasma atrial natriuretic peptide levels, which on average remained comparable to those in rats given the vehicle alone (49.7 ± 8.4 versus 46.3 ±5.6 pg/mL). In the isolated perfused rat kidney preparation, exposure to 150 pmol of endothelin significantly increased fractional sodium excretion over preinjection values (pre, 2.2 ± 0.2; post, 7.3 ± 1.0{\%}) despite a marked decrease in glomerular filtration rate and renal perfusate flow. Additional in vivo experiments showed that oral administration of the specific 5-lipoxygenase inhibitor L-651,392 to rats prevented the increase in urine flow rate (pre, 5.7 ± 0.1; post, 6.6 ± 0.8 μL/min), and in absolute (pre, 0.33 ± 0.04; post, 0.37 ± 0.05 μEq/min) and fractional (pre, 0.10 ± 0.02; post, 0.11 ± 0.03{\%}) sodium excretion caused by bolus i.v. infusion of endothelin (150 pmol). Similarly, a specific leukotriene C4/D4 receptor antagonist, L-649,923, also prevented the diuretic and natriuretic effect of 150 pmol of endothelin i.v. infusion. These findings show that (1) endothelin has a diuretic and natriuretic effect that is independent of its action on renal hemodynamics; (2) this effect depends on a direct action on the proximal tubules; (3) atrial natriuretic peptide does not appear to be involved in this effect; and (4) the diuretic and natriuretic responses to endothelin are mediated by 5-lipoxygenase products.",
keywords = "Atrial natriuretic peptide, Glomerular filtration rate, Isolated perfused kidney, Lithium clearance, Renal plasma flow",
author = "Norberto Perico and Cornejo, {Raul Plata} and Ariela Benigni and Barbara Malanchini and Ladny, {Jerzy Robert} and Giuseppe Remuzzi",
year = "1991",
month = "7",
language = "English",
volume = "2",
pages = "57--69",
journal = "Journal of the American Society of Nephrology : JASN",
issn = "1046-6673",
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TY - JOUR

T1 - Endothelin induces diuresis and natriuresis in the rat by acting on proximal tubular cells through a mechanism mediated by lipoxygenase products

AU - Perico, Norberto

AU - Cornejo, Raul Plata

AU - Benigni, Ariela

AU - Malanchini, Barbara

AU - Ladny, Jerzy Robert

AU - Remuzzi, Giuseppe

PY - 1991/7

Y1 - 1991/7

N2 - Besides being a potent renal vasoconstrictor, endothelin causes diuresis and natriuresis. At which site along the nephron and how endothelin alters water and sodium handling in the tubule remain to be clarified. It was found that endothelin (75 pmol) given as an i.v. infusion in vivo to rats caused diuresis and urinary sodium excretion to double but did not affect glomerular filtration rate and renal plasma flow. On raising the dose of endothelin to 150 pmol, a further increase in diuresis and natriuresis was found, whereas glomerular filtration rate fell 33% and renal plasma flow fell 36%; 300 pmol of endothelin reduced glomerular filtration rate by 73% and renal plasma flow by 77% but did not significantly affect diuresis and absolute sodium excretion. It did, however, increase fractional sodium excretion eightfold. Lithium clearance studies of changes in tubular handling of water and sodium indicated that infusion of 150 pmol of endothelin to rats caused a reduction in absolute (pre, 84.7 ± 5.9; post, 47.9 ± 6.1 μEq/min/ 100 g) and fractional (pre, 85.7 ± 3.0; post, 64.7 ± 6.4%) proximal reabsorption of sodium. Endothelin infusion (150 pmol) was not associated with any significant change in plasma atrial natriuretic peptide levels, which on average remained comparable to those in rats given the vehicle alone (49.7 ± 8.4 versus 46.3 ±5.6 pg/mL). In the isolated perfused rat kidney preparation, exposure to 150 pmol of endothelin significantly increased fractional sodium excretion over preinjection values (pre, 2.2 ± 0.2; post, 7.3 ± 1.0%) despite a marked decrease in glomerular filtration rate and renal perfusate flow. Additional in vivo experiments showed that oral administration of the specific 5-lipoxygenase inhibitor L-651,392 to rats prevented the increase in urine flow rate (pre, 5.7 ± 0.1; post, 6.6 ± 0.8 μL/min), and in absolute (pre, 0.33 ± 0.04; post, 0.37 ± 0.05 μEq/min) and fractional (pre, 0.10 ± 0.02; post, 0.11 ± 0.03%) sodium excretion caused by bolus i.v. infusion of endothelin (150 pmol). Similarly, a specific leukotriene C4/D4 receptor antagonist, L-649,923, also prevented the diuretic and natriuretic effect of 150 pmol of endothelin i.v. infusion. These findings show that (1) endothelin has a diuretic and natriuretic effect that is independent of its action on renal hemodynamics; (2) this effect depends on a direct action on the proximal tubules; (3) atrial natriuretic peptide does not appear to be involved in this effect; and (4) the diuretic and natriuretic responses to endothelin are mediated by 5-lipoxygenase products.

AB - Besides being a potent renal vasoconstrictor, endothelin causes diuresis and natriuresis. At which site along the nephron and how endothelin alters water and sodium handling in the tubule remain to be clarified. It was found that endothelin (75 pmol) given as an i.v. infusion in vivo to rats caused diuresis and urinary sodium excretion to double but did not affect glomerular filtration rate and renal plasma flow. On raising the dose of endothelin to 150 pmol, a further increase in diuresis and natriuresis was found, whereas glomerular filtration rate fell 33% and renal plasma flow fell 36%; 300 pmol of endothelin reduced glomerular filtration rate by 73% and renal plasma flow by 77% but did not significantly affect diuresis and absolute sodium excretion. It did, however, increase fractional sodium excretion eightfold. Lithium clearance studies of changes in tubular handling of water and sodium indicated that infusion of 150 pmol of endothelin to rats caused a reduction in absolute (pre, 84.7 ± 5.9; post, 47.9 ± 6.1 μEq/min/ 100 g) and fractional (pre, 85.7 ± 3.0; post, 64.7 ± 6.4%) proximal reabsorption of sodium. Endothelin infusion (150 pmol) was not associated with any significant change in plasma atrial natriuretic peptide levels, which on average remained comparable to those in rats given the vehicle alone (49.7 ± 8.4 versus 46.3 ±5.6 pg/mL). In the isolated perfused rat kidney preparation, exposure to 150 pmol of endothelin significantly increased fractional sodium excretion over preinjection values (pre, 2.2 ± 0.2; post, 7.3 ± 1.0%) despite a marked decrease in glomerular filtration rate and renal perfusate flow. Additional in vivo experiments showed that oral administration of the specific 5-lipoxygenase inhibitor L-651,392 to rats prevented the increase in urine flow rate (pre, 5.7 ± 0.1; post, 6.6 ± 0.8 μL/min), and in absolute (pre, 0.33 ± 0.04; post, 0.37 ± 0.05 μEq/min) and fractional (pre, 0.10 ± 0.02; post, 0.11 ± 0.03%) sodium excretion caused by bolus i.v. infusion of endothelin (150 pmol). Similarly, a specific leukotriene C4/D4 receptor antagonist, L-649,923, also prevented the diuretic and natriuretic effect of 150 pmol of endothelin i.v. infusion. These findings show that (1) endothelin has a diuretic and natriuretic effect that is independent of its action on renal hemodynamics; (2) this effect depends on a direct action on the proximal tubules; (3) atrial natriuretic peptide does not appear to be involved in this effect; and (4) the diuretic and natriuretic responses to endothelin are mediated by 5-lipoxygenase products.

KW - Atrial natriuretic peptide

KW - Glomerular filtration rate

KW - Isolated perfused kidney

KW - Lithium clearance

KW - Renal plasma flow

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