Effect of combination of nitric oxide synthase and cyclooxygenase inhibitors on carrageenan-induced pleurisy in rats.
In the present study, we examined the effects of L-nitroarginine methylester (L-NAME), a non-selective nitric oxide synthase (NOS) inhibitor, indomethacin (IND), a non-selective COX inhibitor and a combination of these agents (L-NAME+IND) on carrageenan-induced pleurisy in rats. Exudate volume, albumin leakage, leukocyte influx, exudate and plasma nitrite/nitrate (NO(x)) levels and exudate PGE(2) levels increased markedly 6 h after an intrapleural injection of 2% carrageenan. First, the effects of L-NAME and IND alone were investigated. L-NAME non-significantly reduced exudate volume by 26% at 10 mg/kg (i.p.), and significantly by 45% at 30 mg/kg. IND dose-dependently decreased the exudate volume at 0.3-10 mg/kg (p.o.) and the effect reached the maximal level at 1 mg/kg (33%). Second, the effects of L-NAME (10 mg/kg, i.p.), IND (1 mg/kg, p.o.) and L-NAME+IND were examined. L-NAME and IND alone at the dose employed significantly reduced the exudate volume and albumin levels by 21-26%. L-NAME but not IND tended to reduce the increased exudate and plasma NO(x) by 18% and 19%, respectively. IND but not L-NAME significantly reduced leukocyte numbers and PGE(2) levels in the exudates by 25% and 77%, respectively. L-NAME+IND significantly reduced exudate volume, albumin leakage, leukocyte number, PGE(2) and NO(x) by 43%, 41%, 31%, 80% and 37%, respectively. The inhibitory effects of L-NAME+IND on exudate volume, albumin leakage and NO(x) levels were greater than those of L-NAME and IND alone. In conclusion, a non-selective NOS inhibitor and COX inhibitor showed anti-inflammatory effects at the early phase of carrageenan-induced pleurisy, and a combination of both inhibitors had a greater effect than each alone probably via the potentiation of NOS inhibition. The simultaneous inhibition of NOS and COX could be a useful approach in therapy for acute inflammation.
Fuji Biomedix, Co. Ltd., Yamanashi Prefecture 408-0044, Japan.
Yasue
Y
Sakaguchi
Hiroaki
H
Shirahase
Kazuyoshi
K
Kunishiro
Atsuko
A
Ichikawa
Mamoru
M
Kanda
Yoshio
Y
Uehara
D000418:Albumins / Q000378:metabolism; D000818:Animals; D002351:Carrageenan / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000097:blood; D004347:Drug Interactions; D005122:Exudates and Transudates / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D007958:Leukocyte Count; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D010998:Pleurisy / Q000097:blood / Q000139:chemically induced*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000418:Albumins; D016861:Cyclooxygenase Inhibitors; D009566:Nitrates; D009573:Nitrites; D002351:Carrageenan; D019001:Nitric Oxide Synthase; D015232:Dinoprostone; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin