EFFECTS OF THE SELECTIVE CYCLOOXYGENASE-2 INHIBITOR NIMESULIDE ON VASCULAR CONTRACTIONS IN ENDOTHELIUM-DENUDED RAT AORTA

We have examined the effects of the selective cyclooxygenase-2 inhibit or nimesulide and the non-selective cyclooxygenase inhibitor indometha cin on vascular responsiveness of endothelium-denuded rat aorta. Isome tric contractions were obtained to the a-adrenoceptor agonists phenyle phrine (full agonist) and clonidine (partial agonist relative to pheny lephrine) and to endothelin-1 and KCl. Maximum contractile responses t o the partial agonist clonidine were significantly reduced by nimesuli de (10 mu M) and by indomethacin (10 mu M) to 60.8 +/- 8.5% (n = 8) an d 69.0 +/- 9.6% (n = 12) of control, respectively, as compared with th e effects of vehicle (99.0 +/- 5.8%; n = 17). The inhibitors had lesse r effects against contractions to phenylephrine: nimesulide had no sig nificant effect, whereas indomethacin caused a small but significant r eduction in the maximum contraction to phenylephrine to 90.3 +/- 5.0% (n = 12) of control (vehicle: 108.0 +/- 5.2%, n = 15 nimesulide: 111.8 +/- 5.9%, n = 5). Neither nimesulide nor indomethacin had any effect on contractions to endothelin-1 or KCl. These actions differed from th e effects of the Ca2+ entry blocker nifedipine, which significantly re duced contractions to clonidine and KCl to a similar extent. The maxim um contraction to clonidine was also significantly reduced by the thro mboxane receptor antagonist SQ 29548 (1 mu M) to 83.4 +/- 6.4% of cont rol (n = 7) (vehicle 115.5 +/- 7.5%, n = 7). It is concluded that the cyclooxygenase inhibitors nimesulide or indomethacin reduce Vascular r esponsiveness to alpha-adrenoceptor agonists in endothelium-denuded ra t aorta, presumably by preventing the formation of vasoconstrictor pro staglandins in aortic smooth muscle by cyclooxygenase-2. This reduced vascular responsiveness was most clearly seen with the partial agonist clonidine. (C) 1998 Elsevier Science B.V. All rights reserved.