Lipopolysaccharide-induced acute renal failure in conscious rats: effects of specific phosphodiesterase type 3 and 4 inhibition.
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-alpha 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.
Jonassen
Thomas E N
TE
Department of Pharmacology, The Panum Institute, University of Copenhagen, Denmark. fitj@farmakol.ku.dk
Graebe
Martin
M
Promeneur
Dominique
D
Nielsen
Søren
S
Christensen
Sten
S
Olsen
Niels V
NV
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology*; D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000503:physiopathology; D000818:Animals; D001127:Arginine Vasopressin / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D001786:Blood Glucose; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D001127:Arginine Vasopressin; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4