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 obstructed 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-dependent increase in prostaglandin E₂ (PGE₂) production. N(G)-monomethyl-L-arginine (L-NMMA), which blocks the activity of both constitutive and inducible nitric oxide synthase (cNOS and iNOS), aminoguanidine, a recently described selective iNOS inhibitor, dexamethasone, or cycloheximide abolished the release of NO₂^- and attenuated the exaggerated BK-induced PGE₂ production. This supports the existance of iNOS and COX-2 in the HNK. In the CLK, BK elicited release of both NO₂^- and PGE₂ but this did not augment with time. L-NMMA but not aminoguanidine, dexamethasone, or cycloheximide attenuated NO₂^- and PGE₂ release indicative of the presence of constitutive but not inducible NOS or COX. The current study suggests that the endogenous release of NO from cNOS in the CLK activates a constitutive COX resulting in optimal PGE₂ release by BK. In addition, in the HNK, NO release from iNOS activates the induced COX resulting in markedly increased release of proinflammatory prostaglandin. The broader implication of this study is that the cyclooxygenase isozymes are potential receptor targets for nitric oxide.