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.