Inflammation modifies the role of cyclooxygenases in the contractile responses of the rat detrusor smooth muscle to kinin agonists

The contractile responses elicited by the selective kinin B-1 and B-2 receptor agonists [desArg(9)]-bradykinin ([desArg(9)]-BK) and [Hyp(3), Tyr(Me)(8)]-bradykinin ([Hyp(3), Tyr(Me)(8)]-BK) (1 nM-10 mu M), respectively, were evaluated in control vs. inflamed (cyclophosphamide 150 mg kg(-1) i.p., 48 h before the sacrifice) rat isolated urinary bladder strips. The contractile responses to the B-2 receptor agonist did not differ in control vs. inflamed bladders, whereas the contractile responses to [desArg(9)]-BK were potentiated in inflamed bladders. The selective B-1 and B-2 receptor antagonists B 9858 (H-Lys-Lys-Arg-Pro-Hyp-Gly-lgl-Ser-Dlgl-Oic-OH) and Hoe 140 (H-DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-Oic-Arg-OH), both at 1 mu M, inhibited the response to the B, and B, receptor agonists, respectively, in both control and inflamed bladders. In addition, the concentration-response curve to [Hyp(3), Tyr(Me)(8)]-BK was shifted to the right and depressed by B 9858 in inflamed bladders. The nonselective cyclooxygenase (COX) inhibitors S-(-)-ketoprofen (10 mu M) and piroxicam (30 mu M) markedly depressed the concentration-response curves to [desArg(9)]-BK and [Hyp(3), Tyr(Me)(8)]-BK in control bladders, but neither drug affected the B, or B, receptor agonist-mediated responses in inflamed bladders. The selective inhibitor of the inducible COX-2 isoenzyme, NS-398 (1 mu M), did not inhibit the contractile responses to [desArg(9)]-BK and [Hyp(3), Tyr(Me)(8)]-BK in either control or inflamed bladders, whereas it significantly potentiated the response to the B, receptor agonist in inflamed bladders. The exogenous administration of prostaglandin E-2 (PGE(2)) induced S-(-)-ketoprofen-resistant contractile responses that were depressed in inflamed bladders. Pretreatment with S-(-)-ketoprofen restored the PGE(2)-mediated contractile responses of inflamed bladders to control values. PGE, assay revealed that the basal production of PGE, is significantly higher after inflammation than in control conditions. [desArg(9)]-BK and [Hyp(3), Tyr(Me)(8)]-BK(1 mu M each) both stimulated PGE, production, and their effect was larger in inflamed than in control bladders. Piroxicam (30 mu M) prevented the PGE, production evoked by [desArg(9)]-BK in both control and inflamed bladders and likewise abolished that produced by [Hyp(3), Tyr(Me)(8)]-BK. NS-398 (1 mu M) reduced the PGE, production elicited by [desArg(9)]-BK in control and inflamed bladders. When NS-398 was tested on the [Hyp(3), Tyr(Me)(8)]-BK-induced PGE, production, it inhibited PGE, production in the inflamed bladders only, without significantly modifying the response obtained in controls. These findings demonstrate that 1) in normal bladders, the activation of B-1 and B-2 receptors evokes contraction that is largely mediated by COX-I metabolites, whereas the COX-2 appears to be involved in PGE, production after the activation of B-1 receptor only, without interfering with contraction, and 2) in inflamed bladders, the activation of B-1 and B-2 receptors still produce PGE,, but the contractile response is not reduced by COX inhibitors, a result that indicates that additional mechanisms play a compensatory role.