Pré-eclâmpsia precoce e tardia: avaliação de ADMA, GMPc e polimorfismos da sintase do óxido nítrico

Abstract

Preeclampsia is characterized by the development of hypertension and proteinuria from the twentieth week of pregnancy. The disease progresses with generalized vasoconstriction and endothelial dysfunction. Nitric oxide is an intercellular and intracellular messenger and participates in several physiological and pathophysiological reactions occurring in various cell types. It is produced from L-arginine in a reaction catalyzed by a family of nitric oxide synthases. In endothelial cells and platelets, nitric oxide activates the enzyme guanylate cyclase, which leads to increased cyclic guanosine monophosphate (cGMP) resulting in vascular relaxation and inhibition of platelet activation. L-Arginine Asymmetric Dimethyl (ADMA),an amino acid of intracellular source formed from the methylation of arginine residues of the protein, competes with L-arginine reducing nitric oxide synthesis. The polymorphisms G894T, VNTR b / a and T-786C gene of the enzyme endothelial nitric oxide synthase are associated with impaired nitric oxide synthesis in several clinical conditions. The objective of this study was to investigate the role of nitric oxide in the physiopathology of preeclampsia. Plasma levels of ADMA (ELISA Diagnostika GMBH), intraplatelet cGMP (ELISA, Amersham) levels and polymorphisms G894T, VNTR b / a and T-786C mutation in the endothelial nitric oxide synthase were assessed in early onset severe preeclampsia (gestational age <34 weeks) and late (gestational age 34 weeks). A total of 201 women were evaluated, 53 with early severe preeclampsia (group I), 45 with late severe preeclampsia (group II) and 103 normotensive pregnant women (group III). Plasma levels of ADMA, were higher in group I than in group II and III (P<0.001 for both). Intraplatelet levels of cGMP were not different when comparing the groups in pairs. VNTR polymorphism b/a had a higher frequency of allele a and genotype aa in group I. The frequency of women homozygous (894TT) (recessive model) was higher in group I than in group II and group II than in group III (P=0.042 and P=0.002, respectively). The frequency of homozygous women (VNTR b/a) (recessive model) was higher in group I than in group III (P=0.011). Higher frequencies of genotypes aa and ab for VNTR b/a polymorphism (dominant model) were observed comparing the groups I and II, as well as the groups I and III (P=0.042, P=0.049, respectively). The frequency of haplotype T-b-C was higher in group II compared to groups I and III (P=0.0056 and P=0.036, respectively). The correlation analysis of the polymorphism T-786C and intraplatelet cGMP levels revealed that these are poorly correlated (P=0.036, r=0.430). It was concluded that could be an impairment of the L-arginine: NO pathway in early and late-onset preeclampsia. ADMA plasma levels and nitric oxide synthase gene polymorphisms suggest that early and late forms of preeclampsia are different diseases. Intraplatelet cGMP is not a reliable marker to assess inhibition of platelet activation in preeclampsia.