ABSTRACT
Dengue haemorrhagic fever (DHF) is a prevalent acute disease that occurs in patients infected by an arbovirus in tropical and subtropical regions. We have previously shown increased intraplatelet nitric oxide (NO) production in patients with dengue fever associated with reduced platelet aggregation. In this study, l-arginine transport as well as expression and activity of nitric oxide synthase (NOS) isoforms in the presence or absence of l-arginine analogues were examined in 23 DHF patients. l-arginine transport and NOS activity in platelets were increased in patients with DHF compared with controls. However, platelet endothelial NOS (eNOS) and inducible (iNOS) protein levels did not differ between healthy controls and DHF patients. Endogenous or exogenous analogues did not inhibit platelet NOS activity from DHF patients. In contrast, endogenous l-arginine analogues [N(G)-monomethyl-l-arginine (l-NMMA) and asymmetric dimethylarginine (ADMA)] inhibited NOS activity in platelets from healthy subjects. These results show the first evidence that the intraplatelet l-arginine-NO pathway is activated in DHF patients. The lack of inhibition of NO formation in vitro by all l-arginine analogues tested in DHF platelets may suggest another mechanism by which NOS activity can be regulated.
Subject(s)
Arginine/analogs & derivatives , Blood Platelets/drug effects , Enzyme Inhibitors/pharmacology , Severe Dengue/drug therapy , Thrombocytopenia/drug therapy , omega-N-Methylarginine/pharmacology , Adult , Arginine/blood , Arginine/pharmacology , Brazil , Female , Humans , Male , Nitric Oxide Synthase , Platelet Aggregation , Severe Dengue/blood , Severe Dengue/complications , Thrombocytopenia/blood , Thrombocytopenia/etiologyABSTRACT
The mechanism underlying the analgesic effect of clonidine, an alpha(2)-adrenoceptor agonist, remains uncertain. Activation of alpha(2)-adrenoceptor induces the release of nitric oxide (NO) from endothelial cells, which has led us to test the hypothesis that the observed antinociceptive effect induced by the systemic administration of clonidine depends on the NO-cGMP pathway. The possible involvement of an opioid link in the antinociceptive effect of clonidine was also evaluated. The antinociceptive effect induced by systemic administration (intravenous or intraperitoneal) of clonidine was evaluated using the rat paw formalin, mice tail-flick and writhing tests. Clonidine (3-120 microg/kg) induces a dose-dependent antinociceptive effect in the formalin, tail-flick and writhing tests. The antinociceptive effect of clonidine in a dose that had no sedative effect assessed by rota rod test, was significantly reduced by NO-synthase and guanylyl cyclase inhibition. The antinociceptive effect of morphine, but not clonidine, was inhibited by naloxone. Our current results suggest that the antinociceptive effect of systemic clonidine does not involve the opioid receptor and is modulated by the NO-cGMP pathway.
