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(m) value from 22+/-2 to 86+/-6 microM. The K(i) value was 158 microM at pH 7.4 and 37 degrees. Furthermore, gabexate mesylate decreased dose and time-dependent nitrite and nitrate formation (NO(x) 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.
Leoncini
Giuliana
G
Department of Experimental Medicine, Biochemistry Section, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, Italy. leoncini@unige.it
Pascale
Raffaele
R
Signorello
Maria Grazia
MG
D000925:Anticoagulants / Q000494:pharmacology*; D001120:Arginine / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002474:Cell-Free System; D006152:Cyclic GMP / Q000378:metabolism; D016670:Gabexate / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I
D000925:Anticoagulants; D009569:Nitric Oxide; D016670:Gabexate; D001120:Arginine; C496320:NOS1 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D006152:Cyclic GMP