Desensitization of soluble guanylate cyclase in renal cortex during endotoxemia in mice

Acute endotoxemic renal failure involves renal vasoconstriction, which pres umably occurs despite increased nitric oxide (NO) generation by inducible N O synthase in the kidney. The present study examined the hypothesis that th e renal vasoconstriction during endotoxemia occurs in part because of desen sitization of soluble guanylate cyclase (sGC). Endotoxic shock was induced in male B6/129F2/J mice by an intraperitoneal injection of Escherichia coli lipopolysaccharide. The endotoxemia resulted in shuck and renal failure as evidenced by a decrease in mean arterial pressure and an increase in serum creatinine and urea nitrogen. Serum NO increased in a time-dependent manne r, reaching the highest levels at 24 h, in parallel with induction of induc ible NO synthase protein in the renal cortex. In renal cortical slices obta ined from endotoxemic mice, cyclic guanosine monophosphate (cGMP) increased significantly at 6 h and 15 h as compared with control but normalized at 2 4 h after injection of lipopolysaccharide. Incubation of renal cortical sli ces in the presence of a phosphodiesterase inhibitor isobutylmethylxantine did not alter the pattern of changes in cCMP. Incubation of renal cortical slices with 2 mM sodium nitroprusside resulted in a similar accumulation of cGMP in slices taken from control and endotoxemic mice at 6 h and 15 h. Ho wever, in slices from 24-h endotoxemic mice, accumulation of cGMP in respon se to sodium nitroprusside was significantly lower. This lower stimulabilit y of sGC was not paralleled by a decrease in its abundance in renal cortex on immunoblot. Taken together, these results demonstrate a desensitization of sGC in renal cortex during endotoxemia, which may contribute to the asso ciated renal vasoconstriction.