Lipopolysaccharide-induced acute renal failure in conscious rats

Effects of specific phosphodiesterase type 3 and 4 inhibition

Thomas E N Jonassen, Martin Græbe, Dominique Promeneur, Søren Nielsen, Sten Christensen, Niels V. Olsen

Research output: Contribution to journalArticle

Abstract

In conscious, chronically instrumented rats we examined 1) renal tubular functional changes involved in lipopolysaccharide (LPS)-induced acute renal failure; 2) the effects of LPS on the expression of selected renal tubular water and sodium transporters; and 3) effects of milrinone, a phosphodiesterase type 3 (PDE3) inhibitor, and Ro-20-1724, a PDE4 inhibitor, on LPS-induced changes in renal function. Intravenous infusion of LPS (4 mg/kg b.wt. over 1 h) caused an immediate decrease in glomerular filtration rate (GFR) and proximal tubular outflow without changes in mean arterial pressure (MAP), LPS-induced fall in GFR and proximal tubular outflow were sustained on day 2. Furthermore, LPS-treated rats showed a marked increase in fractional distal water excretion, despite significantly elevated levels of plasma vasopressin (AVP). Semiquantitative immunoblotting showed that LPS increased the expression of the Na+,K+,2Cl--cotransporter (BSC1) in the thick ascending limb, whereas the expression of the AVP-regulated water channel aquaporin-2 in the collecting duct (CD) was unchanged. Pretreatment with milrinone or Ro-20-1724 enhanced LPS-induced increases in plasma tumor necrosis factor-α and lactate, inhibited the LPS-induced tachycardia, and exacerbated the acute LPS-induced fall in GFR. Furthermore, Ro-20-1724-treated rats were unable to maintain MAP. We conclude 1) PDE3 or PDE4 inhibition exacerbates LPS-induced renal failure in conscious rats; and 2) LPS treated rats develop an escape from AVP in the CDs, which could be aimed to protect against water intoxication in septic conditions associated with decreased GFR and high levels of AVP.

Original languageEnglish (US)
Pages (from-to)364-374
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume303
Issue number1
DOIs
StatePublished - Oct 2002
Externally publishedYes

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Type 4 Cyclic Nucleotide Phosphodiesterase
Acute Kidney Injury
Lipopolysaccharides
4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone
Glomerular Filtration Rate
Milrinone
Kidney
Arterial Pressure
Phosphodiesterase 3 Inhibitors
Water Intoxication
Aquaporin 2
Phosphodiesterase 4 Inhibitors
Aquaporins
Water
Phosphoric Diester Hydrolases
Vasopressins
Immunoblotting
Intravenous Infusions
Tachycardia
Renal Insufficiency

ASJC Scopus subject areas

  • Pharmacology

Cite this

Lipopolysaccharide-induced acute renal failure in conscious rats : Effects of specific phosphodiesterase type 3 and 4 inhibition. / Jonassen, Thomas E N; Græbe, Martin; Promeneur, Dominique; Nielsen, Søren; Christensen, Sten; Olsen, Niels V.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 303, No. 1, 10.2002, p. 364-374.

Research output: Contribution to journalArticle

Jonassen, Thomas E N ; Græbe, Martin ; Promeneur, Dominique ; Nielsen, Søren ; Christensen, Sten ; Olsen, Niels V. / Lipopolysaccharide-induced acute renal failure in conscious rats : Effects of specific phosphodiesterase type 3 and 4 inhibition. In: Journal of Pharmacology and Experimental Therapeutics. 2002 ; Vol. 303, No. 1. pp. 364-374.
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