Human umbilical vein: involvement of cyclooxygenase-2 pathway in bradykinin B₁ receptor-sensitized responses

Abstract.

In isolated human umbilical vein (HUV), the contractile response to des-Arg⁹-bradykinin (des-Arg⁹-BK), selective BK B₁ receptor agonist, increases as a function of the incubation time. Here, we evaluated whether cyclooxygenase (COX) pathway is involved in BK B₁-senzitized response obtained in 5-h incubated HUV rings. The effect of different concentrations of indomethacin, sodium salicylate, ibuprofen, meloxicam, lysine clonixinate or NS-398 administrated 30 min before concentration-response curves (CRC) was studied. All treatments produced a significant rightward shift of the CRC to des-Arg⁹-BK in a concentration-dependent manner, which provides pharmacological evidence that COX pathway is involved in the BK B₁ responses. Moreover, in this tissue, the NS-398 pK _b (5.2) observed suggests that COX-2 pathway is the most relevant. The strong correlation between published pIC₅₀ for COX-2 and the NSAIDs' pK _bs estimated further supports the hypothesis that COX-2 metabolites are involved in BK B₁ receptor-mediated responses. In other rings, indomethacin (30, 100 µmol/l) or NS-398 (10, 30 µmol/l) produced a significant rightward shift of the CRC to BK, selective BK B₂ agonist, and its pK _bs were similar to the values to inhibit BK B₁ receptor responses, suggesting that COX-2 pathway also is involved in BK B₂ receptor responses. Western blot analysis shows that COX-1 and COX-2 isoenzymes are present before and after 5-h in vitro incubation and apparently COX-2 does not suffer additional induction.