INHIBITORY EFFECTS OF ENDOGENOUS l‐ARGININE ANALOGUES ON NITRIC OXIDE SYNTHESIS IN PLATELETS: ROLE IN PLATELET HYPERAGGREGABILITY IN HYPERTENSION

Abstract

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.

Platelet activation, oxidative stress and overexpression of inducible nitric oxide synthase in moderate heart failure

“…Plasma samples were isolated and the concentration of fibrinogen was measured by the Clauss method, as described previously 22 . C‐Reactive protein (CRP) levels were determined by a highly sensitive immunoturbidimetric assay (DiaSys Diagnostic Systems, Holzheim, Germany) 20 …”

Asymmetric Dimethylarginine (ADMA) Levels Display a Morning Peak in Patients with Acute Myocardial Infarction

“…ADMA is an endogenous analogue of L-arginine that competitively inhibits NO synthase in all human cells including endothelium [15] and platelets [14]. It decreases, as a result, the NO production of cells such as endothelial cells and platelets.…”

“…It decreases, as a result, the NO production of cells such as endothelial cells and platelets. Since NO normally inhibits platelet aggregation and adhesion [14,16], any decrease in NO levels may trigger thrombus formation and development on a ruptured plaque. It is documented that NO generated from activated platelets inhibits further platelet recruitment to the developing thrombus [17].…”

“…Decreased NO availability determines enhanced platelet activation and aggregation [14,16,17]. High ADMA levels are also associated with elevated blood pressure, vasoconstriction, impaired endothelium-dependent relaxation and increased endothelial adhesiveness for monocytes [18][19][20].…”

“…After protein degradation ADMA is liberated leading to low reference levels of ADMA in serum. Because it is structurally similar to L-arginine (the substrate of nitric oxide (NO) synthase for the formation of NO), ADMA competitively inhibits the NO synthases in cells [12][13][14][15][16].…”