EPR investigation of in vivo inhibitory effect of guanidine compounds on nitric oxide production in rat tissues.
The aim of the present study was to evaluate in vivo effects on NO production of pharmacologically widely used, commercially available NOS inhibitors, structurally related to guanidine. We compared the NO inhibitory potency and selectivity of L-NAME, aminoguanidine and guanabenz in tissues of normal and LPS-stimulated rats using ex vivo EPR measurements of the NO radical in its complex with dithiocarbamate-Fe(II). The tissues studied were the brain cortex, kidney, liver, heart and testis. Differential inhibitory effects were seen for L-NAME, aminoguanidine and guanabenz when applied during basal or LPS-stimulated conditions. Aminoguanidine exerted inhibition of NO only after stimulation with LPS. Guanabenz had little effect on NO in liver, kidney, testis and heart under normal conditions, while it reduced the basal NO in brain cortex. After stimulation with LPS guanabenz afforded a partial inhibition of the NO formation in all tissues studied. L-NAME was a potent inhibitor of NO synthesis in all tested tissues, both during basal and LPS stimulated conditions. Our results show that compounds containing a guanidine moiety might possess different NOS inhibitory profiles in vivo.
Dambrova
M
M
Latvian Institute of Organic Synthesis, Aizkraukles St 21, Riga, LV-1006, Latvia. dambrova@biomed.lu.lv
Kirjanova
O
O
Baumane
L
L
Liepinsh
E
E
Zvejniece
L
L
Muceniece
R
R
Kalvinsh
I
I
Wikberg
J E S
JE
D000818:Animals; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D019343:Citric Acid; D004050:Ditiocarb / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods*; D005296:Ferrous Compounds / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D006143:Guanabenz / Q000494:pharmacology; D006146:Guanidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007668:Kidney / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D013737:Testis / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism
D005296:Ferrous Compounds; D006146:Guanidines; D008070:Lipopolysaccharides; C085124:diethyldithiocarbamate iron(II); D019343:Citric Acid; D009569:Nitric Oxide; C016600:ferrous citrate; D004050:Ditiocarb; D006143:Guanabenz; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester