Effect of the inducible nitric oxide synthase inhibitors aminoguanidine and L-N6-(1-iminoethyl)lysine on zymosan-induced plasma extravasation in rat skin.
The effect of nitric oxide synthase (NOS) inhibitors on plasma extravasation in a rat model of zymosan-induced inflammation has been investigated. Plasma extravasation was determined in response to intradermal test agents over 0 to 45 min or 0 to 4 h by the accumulation of i.v. injected 125I-labeled human serum albumin. Zymosan (1-100 microg/site) produced a dose- and time-dependent plasma extravasation. N(G)-nitro-L-arginine methyl ester (30-300 nmol/site), but not aminoguanidine (AG; 10-300 nmol/site) or L-N6-(1-iminoethyl)lysine (L-NIL; 10-300 nmol/site), significantly (p < 0.01) inhibited zymosan-induced (10 microg/site) plasma extravasation over 0 to 45 min. However, both AG and L-NIL produced significant (p < 0.05) inhibition over 0 to 4 h. The inhibition produced by AG was reversed by i.v. L-arginine or by coinjection of the vasodilator, calcitonin gene-related peptide. Zymosan (10-100 microg/site) induced an increase in dermal blood flow (laser-Doppler flowmetry) and this was inhibited by AG. Neutrophils were depleted selectively with antiserum, but this did not affect plasma extravasation except at the highest dose of zymosan (100 microg/site). Furthermore, zymosan-induced edema was not modified at either time point by pretreatment with the cyclooxygenase inhibitor indomethacin (30 micromol/kg, s.c., -30 min). In conclusion, in this model of dermal inflammation, it is suggested that inducible NOS inhibitors selectively remove an inducible NOS component that, at least in part, acts to increase microvascular blood flow and thus the edema formation observed during 0 to 4 h. There is no evidence of a contributory role for neutrophils or cyclooxygenase products in this model.
Ridger
V C
VC
Pharmacology Group, Division of Biomedical Sciences, King's College, London, United Kingdom.
Pettipher
E R
ER
Bryant
C E
CE
Brain
S D
SD
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006146:Guanidines / Q000008:administration & dosage*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D008239:Lysine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000187:drug effects / Q000473:pathology*; D015054:Zymosan / Q000633:toxicity*
D004791:Enzyme Inhibitors; D006146:Guanidines; C090663:N(6)-(1-iminoethyl)lysine; D015054:Zymosan; D019001:Nitric Oxide Synthase; D008239:Lysine; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester