Modulation of human platelet function by L-canavanine: differential effects of low and high concentrations.
L-Canavanine is a naturally occurring L-amino acid that interferes with L-arginine-utilizing enzymes owing to its structural analogy with this L-amino acid. In macrophages and polymorphonuclear leukocytes, which express inducible nitric oxide synthase (iNOS), L-canavanine is able to prevent the L-arginine-derived synthesis of nitric oxide (NO). Its effects on constitutive NOS (cNOS) are far less clear. Because human platelets synthesize NO from L-arginine through a cNOS and because intracellular NO levels modulate platelet function, we have investigated the effects of L-canavanine on parameters potentially influenced by NO, such as platelet levels of 3',5'-cyclic guanosine monophosphate (cGMP) and responses to different aggregating agents. In our experimental conditions, L-canavanine was able to influence the response of human platelets to different aggregating agents such as catecholamines, 5-hydroxytryptamine, and ADP. Low L-canavanine concentrations (10-100 micromol/l) decreased platelet responses, whereas a high concentration (1 mmol/l) was unable to exert antiaggregating effects. In resting platelets, L-canavanine reduced the levels of cGMP, starting from a concentration of 1 mmol/l; furthermore, at the same concentrations, it was able to reduce cGMP levels at the end of the aggregation induced by collagen. In conclusion, L-canavanine exerts differential effects on human platelets in relation to the concentrations: at low levels, it exerts antiaggregating effects by actions independent of NOS inhibition, whereas, at high levels, it inhibits NO synthesis and does not exert antiaggregating effects.
Anfossi
G
G
Department of Clinical and Biological Sciences, University of Turin, Ospedale S. Luigi Gonzaga, Orbassano (TO), Italy.
Massucco
P
P
Mattiello
L
L
Cavalot
F
F
Perna
P
P
Giori
A
A
Tassone
F
F
Trovati
M
M
D000244:Adenosine Diphosphate / Q000502:physiology; D001120:Arginine / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D002172:Canavanine / Q000494:pharmacology*; D002395:Catecholamines / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010979:Platelet Function Tests; D012701:Serotonin / Q000502:physiology
D002395:Catecholamines; D010975:Platelet Aggregation Inhibitors; D012701:Serotonin; D002172:Canavanine; D000244:Adenosine Diphosphate; D001120:Arginine; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP