ENDOGENOUS NITRIC-OXIDE ENHANCES PROSTAGLANDIN PRODUCTION IN A MODEL OF RENAL INFLAMMATION

The interaction between nitric oxide (NO) and cyclooxygenase (COX) was studied in a rabbit model of renal inflammation, the ureteral obstruc ted hydronephrotic kidney (HNK). Ex vivo perfusion of the HNK but not the control kidney (e.g., unobstructed contralateral kidney, CLK), led to a time-dependent release of nitrite (NO2-), a breakdown product of NO. Stimulation of the HNK with bradykinin (BK) evoked a time-depende nt increase in prostaglandin E(2) (PGE(2)) production. N-G-monomethyl- L-arginine (L-NMMA), which blocks the activity of both constitutive an d inducible nitric oxide synthase (cNOS and iNOS), aminoguanidine, a r ecently described selective iNOS inhibitor, dexamethasone, or cyclohex imide abolished the release of NO2- and attenuated the exaggerated BK- induced PGE(2) production. This supports the existance of iNOS and COX -2 in the HNK. In the CLK, BK elicited release of both NO2- and PGE(2) but this did not augment with time. L-NMMA but not aminoguanidine, de xamethasone, or cycloheximide attenuated NO2- and PGE(2) release indic ative of the presence of constitutive but not inducible NOS or COX. Th e current study suggests that the endogenous release of NO from cNOS i n the CLK activates a constitutive COX resulting in optimal PGE(2) rel ease by BK. In addition, in the HNK, NO release from iNOS activates th e induced COX resulting in markedly increased release of proinflammato ry prostaglandin. The broader implication of this study is that the cy clooxygenase isozymes are potential receptor targets for nitric oxide.