sq-29548 and nimesulide

We have examined the effects of the selective cyclooxygenase-2 inhibitor nimesulide and the non-selective cyclooxygenase inhibitor indomethacin on vascular responsiveness of endothelium-denuded rat aorta. Isometric contractions were obtained to the alpha-adrenoceptor agonists phenylephrine (full agonist) and clonidine (partial agonist relative to phenylephrine) and to endothelin-1 and KCl. Maximum contractile responses to the partial agonist clonidine were significantly reduced by nimesulide (10 microM) and by indomethacin (10 microM) to 60.8 +/- 8.5% (n = 8) and 69.0 +/- 9.6% (n = 12) of control, respectively, as compared with the effects of vehicle (99.0 +/- 5.8%; n = 17). The inhibitors had lesser effects against contractions to phenylephrine: nimesulide had no significant effect, whereas indomethacin caused a small but significant reduction 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 the effects of the Ca2+ entry blocker nifedipine, which significantly reduced contractions to clonidine and KCl to a similar extent. The maximum contraction to clonidine was also significantly reduced by the thromboxane receptor antagonist SQ 29548 (1 microM) to 83.4 +/- 6.4% of control (n = 7) (vehicle 115.5 +/- 7.5%, n = 7). It is concluded that the cyclooxygenase inhibitors nimesulide or indomethacin reduce vascular responsiveness to alpha-adrenoceptor agonists in endothelium-denuded rat aorta, presumably by preventing the formation of vasoconstrictor prostaglandins in aortic smooth muscle by cyclooxygenase-2. This reduced vascular responsiveness was most clearly seen with the partial agonist clonidine.

Topics: Animals; Aorta; Bridged Bicyclo Compounds, Heterocyclic; Clonidine; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Endothelin-1; Endothelium, Vascular; Fatty Acids, Unsaturated; Hydrazines; In Vitro Techniques; Indomethacin; Isoenzymes; Male; Muscle Contraction; Nifedipine; Phenylephrine; Potassium Chloride; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Sulfonamides