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 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.
Connolly
C
C
Department of Physiology, Royal College of Surgeons in Ireland, Dublin.
McCormick
P A
PA
Docherty
J R
JR
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003000:Clonidine / Q000494:pharmacology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000187:drug effects*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D019332:Endothelin-1; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007527:Isoenzymes; D013449:Sulfonamides; D010656:Phenylephrine; D011189:Potassium Chloride; C045749:SQ 29548; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D009543:Nifedipine; D003000:Clonidine; C012655:nimesulide; D007213:Indomethacin