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.
Department of Experimental Medicine, Biochemistry Section, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, Italy. leoncini@unige.it
Giuliana
G
Leoncini
Raffaele
R
Pascale
Maria Grazia
MG
Signorello
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