Effects of L- and D-arginine and some related esters on the cytosolic mechanisms of alpha-thrombin-induced human platelet activation.
1. In Fura-2 preloaded human platelets, the increase in cytosolic calcium induced by alpha-thrombin was reduced by some L- and D-arginine ester compounds the IC50 (microM) values of which were 7.4 for TAEE, 56.9 for BAEE, 77.6 for TAME, 560 for T(d)AME, 656.3 for L-ArgOMe and 2206.7 for D-ArgOMe. alpha-tosyl-L-Arginine, L- and D-arginine were inactive. 2. The inhibitory activity of the L-arginine esters was not modified when platelets were pretreated with 100 microM N omega-monomethyl-L-arginine. 3. The L-arginine esters did not increase cyclic GMP content in platelets either in the presence or absence of indomethacin and apyrase at rest and after alpha-thrombin stimulation. 4. The kinetic parameters of platelet Na+/H+ antiporter (amiloride-inhibitable, evaluated after cytosolic nigericin-induced acidification) were modified by L- and D-arginine esters, while the native amino acids were ineffective. 5. The inhibitory effects of the L- and D-arginine esters on platelet activation appear to be mainly due to their inhibitory effect on Na+/H+ antiporter.
Failli
P
P
Dipartimento di Farmacologia Preclinica e Clinica M. Aiazzi Mancini, University of Florence, Italy.
Cecchi
E
E
Ruocco
C
C
Fazzini
A
A
Giotti
A
A
D000244:Adenosine Diphosphate / Q000494:pharmacology; D001081:Apyrase / Q000494:pharmacology; D001095:Arachidonic Acids / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D006152:Cyclic GMP / Q000097:blood; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D009599:Nitroprusside / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013237:Stereoisomerism; D013917:Thrombin / Q000494:pharmacology*
D001095:Arachidonic Acids; D010975:Platelet Aggregation Inhibitors; D017923:Sodium-Hydrogen Exchangers; D009599:Nitroprusside; D000244:Adenosine Diphosphate; D001120:Arginine; D013917:Thrombin; D001081:Apyrase; D006152:Cyclic GMP; D007213:Indomethacin