EFFECT OF A NITRIC-OXIDE SYNTHASE INHIBITOR, S-ETHYLISOTHIOUREA, ON CULTURED-CELLS AND CARDIOVASCULAR FUNCTIONS OF NORMAL AND LIPOPOLYSACCHARIDE-TREATED RABBITS

Nitric oxide (NO) is synthesized from L-arginine by three isoforms of NO synthase (NOS). It is essential to suppress the function of the ind ucible isoform (macNOS) for amelioration of some inflammatory diseases in which the cytotoxic effect of NO is involved. S-Ethylisothiourea ( S-EIU) was reported to be a potent and specific inhibitor of macNOS, W e also confirmed that it rather specifically inhibited the activity of the purified macNOS and the formation of nitrite by RAW264.7 cells co mpared to N-G-monomethyl-L-arginine (L-NMA) and NC-nitro-L-arginine (L -NNA), the other isoforms being less effective. S-EIU suppressed the r elease of nitrite and lactate dehydrogenase from rat vascular smooth m uscle cells treated with interleukin-1 beta and forskolin more potentl y than L-NMA or L-NNA. S-EIU also slightly suppressed internucleosomal DNA cleavage in pancreatic beta-cells induced by NO produced by macNO S, Intravenous administration of either S-EIU at 0.1 mg/kg/min or L-NM A at 1 mg/kg/min increased the blood pressure but decreased the heart rate in normal rabbits, while aminoguanidine at 1 mg/kg/min affected n either cardiovascular function, These inhibitors at these doses caused recovery of the blood pressure in lipopolysaccharide-treated rabbits that exhibited lowered blood pressure similar to that in the case of s eptic shock. Although S-EIU seemed not to be an adequate inhibitor for therapeutic use in vivo due to its side effects on cardiovascular fun ctions, it is one of the most potent inhibitors of macNOS among report ed inhibitors in vitro.