Inverse relationship between severity of experimental pyelonephritis and nitric oxide production in C3H/HeJ mice

The contribution of nitric oxide to host resistance to experimental pyelone phritis is not well understood. We examined whether the inhibition of nitri c oxide synthesis alters the sensitivity of lipopolysaccharide (LPS) respon der (C3H/HeN) and nonresponder (C3H/HeJ) mice to experimental Escherichia c oli pyelonephritis. C3H/HeJ and C3H/HeN mice were implanted subcutaneously with minipumps containing an inhibitor of nitric oxide, N-G-nitro-L-arginin e methyl ester (L-NAME), or a corresponding vehicle. Ascending urinary trac t infection by bladder catheterization with two strains off. coli, an O75 s train bearing Dr fimbriae and an O75 strain bearing P fimbriae, was develop ed in tested animals. Twenty-four hours following bladder infection, the ki dneys of C3H/HeN and C3H/HeJ mice were colonized at a similar rate. However , 5 weeks postinoculation, C3H/HeN mice cleared infection while C3H/HeJ mic e showed persistent colonization. Twenty-four hours following infection, C3 H/HeN mice treated with L-NAME showed no significant increase of renal tiss ue infection compared to the saline-treated control group. However, L-NAME- treated C3H/HeJ mice showed an approximately 100-fold increase in E. coli i nfection rate compared to the saline-treated controls in the Dr(+) group bu t showed no change compared to those in the P+ group. Dissemination of Dr() E. coli but not P+ E. coli to the liver and uterus was significantly enha nced with L-NAME treatment in C3H/HeJ mice only. Nitric oxide had no direct killing effect on E, coli in vitro. Nitrite production by various organs w as found to be significantly lower in C3H/HeJ mice than in C3H/HeN mice. Al teration of nitric oxide and LPS responsiveness was significantly associate d with the increased sensitivity of C3H/HeJ mice to experimental Dr(+) but not to P+ E. coli pyelonephritis. These findings are consistent with the hy pothesis that nitric oxide synthase activity in concert with LPS responsive ness may participate in the antibacterial defense mechanisms of the C3H mou se urinary tract. This phenomenon is strain dependent and possibly related to the invasive properties of E. coli.