Anti-inflammatory effects of carprofen, carprofen enantiomers, and NG-nitro-L-arginine methyl ester in sheep

Objective-To assess anti-inflammatory effects of carprofen (CPF), CPF enantiomers, and N(G)-nitro-L-arginine methyl ester (L-NAME) in sheep. Animals-8 sheep. Procedure-Sheep with SC tissue cages were used. After intracaveal injection of 1% carrageenan, sheep were given single doses of racemic (Rac; 50:50 mixture of S[+] and R[-] enantiomers)-CPF (4.0 mg/kg), R(-)CPF (2.0 mg/kg), S(+)CPF (2.0 mg/kg), L-NAME (25 mg/kg), and placebo (PLB) IV in a crossover design. Results-Rac-CPF and S(+)CPF inhibited serum thromboxane(2) (TXB(2)) and exudate prostaglandin (PG)E(2) generation significantly for 32 hours. Maximal inhibitory effect for serum TXB(2) was 79 +/- 3% for Rac-CPF and 68 +/- 6% for S(+)CPF The Rac-CPF and S(+)CPF induced 50 to 98% reversible inhibitory effect for exudate PGE(2) generation during a 4- to 32-hour period. The R(-)CPF and L-NAME attenuated serum TXB(2) generation significantly. The R(-)CPF did not affect exudate PGE(2) production, whereas L-NAME potentiated exudate, PGE(2) generation by 30% during 4 to 32 hours. The S(+)CPF and L-NAME increased leukotriene B(4) generation and WBC recruitment in exudate although significance was achieved only at a few time points. Increase in skin temperature over inflammatory cages was effectively inhibited by Rac-CPF and S(+)CPF but not by R(-)CPF Conclusions and Clinical Relevance-Carprofen is a potent cyclooxygenase inhibitor in vivo in sheep, and its anti-inflammatory effects are attributable only to S(+)CPF in Rac-CPF. Nitric oxide may enhance eicosanoid production and accelerate the acute inflammatory process.