Inhibitory effects of endogenous L-arginine analogues on nitric oxide synthesis in platelets: role in platelet hyperaggregability in hypertension.
1. An increase in plasma concentrations of endogenous L-arginine analogues, which are inhibitors of nitric oxide (NO) synthesis, may be involved in platelet activation and the increased risk of thrombosis in essential hypertension. Nitric oxide is synthesised in platelets from the amino acid L-arginine by inducible and constitutive isoforms of NO synthase (NOS), which leads to increased levels of cGMP. 2. In the present study, we investigated basal intraplatelet cGMP levels, platelet aggregation and pro-inflammatory biomarkers in hypertensive patients. The effects of endogenous (N(G)-monomethyl-L-arginine (L-NMMA) and asymmetric dimethylarginine (ADMA); both at 1 mmol/L) and exogenous (aminoguanidine and N(G)-nitro-L-arginine; both at 1 mmol/L) L-arginine analogues and the neutral amino acid L-leucine (1 mmol/L) in inhibiting NOS activity in platelets were also investigated. 3. Twelve healthy controls and 18 hypertensive patients participated in the study. Platelet aggregation induced by collagen was increased in hypertensive patients (95 +/- 5%) compared with controls (72 +/- 5%). Basal NOS activity and intraplatelet cGMP levels were reduced in hypertensive platelets. Moreover, ADMA, L-NMMA and L-leucine were effective inhibitors of NO synthesis in both hypertensive and control platelets. Essential hypertension led to an inflammatory response, with increased plasma concentrations of fibrinogen, C-reactive protein and cytokines. 4. These findings provide evidence that, in essential arterial hypertension, the enhanced plasma levels of endogenous L-arginine analogues ADMA and L-NMMA, potent inhibitors of L-arginine transport and NO synthesis in platelets, may play a role in increased platelet aggregation via a cGMP-dependent mechanism.
de Meirelles
Luisa R
LR
Pharmacology Department, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
Mendes-Ribeiro
Antônio C
AC
Santoro
Marcelle M
MM
Mendes
Michely A P
MA
da Silva
Michele N S B
MN
Mann
Giovanni E
GE
Brunini
Tatiana M C
TM
D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002097:C-Reactive Protein / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000378:metabolism*; D015850:Interleukin-6 / Q000097:blood; D007930:Leucine / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D005340:Fibrinogen; D002097:C-Reactive Protein; D001120:Arginine; D019001:Nitric Oxide Synthase; D007930:Leucine; D006152:Cyclic GMP