Anti-inflammatory effects of carprofen, carprofen enantiomers, and N(G)-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 (LNAME) in sheep.


METHODS
8 sheep.


METHODS
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), LNAME (25 mg/kg), and placebo (PLB) IV in a crossover design.


RESULTS
Rac-CPF and S(+)CPF inhibited serum thromboxane2 (TXB2) and exudate prostaglandin (PG)E2 generation significantly for 32 hours. Maximal inhibitory effect for serum TXB2 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 PGE2 generation during a 4- to 32-hour period. The R(-)CPF and LNAME attenuated serum TXB2 generation significantly. The R(-)CPF did not affect exudate PGE2 production, whereas L-NAME potentiated exudate, PGE2 generation by 30% during 4 to 32 hours. The S(+)CPF and LNAME increased leukotriene B4 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.
Cheng
Zhangrui
Z
Department of Veterinary Preclinical Studies, Veterinary School, University of Glasgow, UK.
Nolan
Andrea
A
McKellar
Quintin A
QA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D002351:Carrageenan / Q000378:metabolism; D018592:Cross-Over Studies; D015232:Dinoprostone / Q000032:analysis / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005122:Exudates and Transudates / Q000737:chemistry; D007975:Leukotriene B4 / Q000032:analysis / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D012756:Sheep / Q000378:metabolism*; D013237:Stereoisomerism; D013929:Thromboxane B2 / Q000097:blood / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007975:Leukotriene B4; D009569:Nitric Oxide; D013929:Thromboxane B2; D002351:Carrageenan; C007005:carprofen; D015232:Dinoprostone; D019331:NG-Nitroarginine Methyl Ester