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Gabexate mesylate, a non-antigenic synthetic inhibitor of trypsin-like serine proteinases, is a drug used efficiently in the treatment of pancreatitis and disseminated intravascular coagulation and as a regional anticoagulant for haemodialysis. Considering the structural similarity between l-arginine and gabexate mesylate, the effect of this drug on l-arginine transport, nitric oxide (NO) formation and constitutive NO synthase activity in human platelets was investigated. Data have shown that gabexate mesylate inhibited competitively l-arginine uptake by increasing the Km value from 22±2 to 86±6 μM. The Ki value was 158 μM at pH 7.4 and 37°. Furthermore, gabexate mesylate decreased dose and time-dependent nitrite and nitrate formation (NOx release) and cGMP accumulation in whole cells. In addition, gabexate mesylate inhibited constitutive nitric oxide synthase in a cell-free extract. We concluded that gabexate mesylate could be considered an effective modulator of cellular NO synthesis. [Copyright &y& Elsevier]