TY - JOUR

T1 - Lipopolysaccharide-induced acute renal failure in conscious rats

T2 - effects of specific phosphodiesterase type 3 and 4 inhibition

AU - Jonassen, Thomas E N

AU - Graebe, Martin

AU - Promeneur, Dominique

AU - Nielsen, Søren

AU - Christensen, Sten

AU - Olsen, Niels Vidiendal

PY - 2002/10

Y1 - 2002/10

N2 - 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.

AB - 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.

KW - 3',5'-Cyclic-AMP Phosphodiesterases

KW - 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone

KW - Acute Kidney Injury

KW - Animals

KW - Arginine Vasopressin

KW - Blood Glucose

KW - Blood Pressure

KW - Cyclic Nucleotide Phosphodiesterases, Type 3

KW - Cyclic Nucleotide Phosphodiesterases, Type 4

KW - Female

KW - Glomerular Filtration Rate

KW - Heart Rate

KW - Lipopolysaccharides

KW - Phosphodiesterase Inhibitors

KW - Rats

KW - Rats, Wistar

U2 - 10.1124/jpet.102.036194

DO - 10.1124/jpet.102.036194

M3 - Journal article

C2 - 12235272

VL - 303

SP - 364

EP - 374

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -