Modulation of L-arginine transport and nitric oxide production by gabexate mesylate

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 K-i value from 22 +/- 2 to 86 +/- 6 muM. The K-i value was 158 muM 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. (C) 2002 Elsevier Science Inc. All rights reserved.