Mecanismos moleculares e celulares envolvidos na modulação da via L-arginina-óxido nítrico em hipertensão e insuficiência renal crônica.

Abstract

Chronic renal failure (CRF) and essential hypertension (EH) are diseases associated with high rates of morbidity and mortality, consuming huge amounts of money from the public health system. The endothelial dysfunction existent in both diseases, CRF and EH, contributes to the maintenance of the high peripheral resistance, and contribute to circulatory complications such as atherosclerosis. This endothelial dysfunction is part of a pro-thrombotic state, leading to cardiovascular events, which are the major cause of death in these disorders. Nitric oxide (NO) plays an important role in the modulation of platelet function. Abnormalities of NO synthesis or inactivation are described in CRF and EH. It was previously reported an inhibition of L-arginine transport in erythrocytes of hypertensive patients and in an animal model of hypertension. Moreover, we have also demonstrated an activation of L-arginine-NO pathway in platelets taken from uraemic patients. The aim of the present thesis is to investigate L-arginine-NO pathway in arterial hypertension and in different stages of chronic renal failure. It will also be evaluated urea cycle and the presence of oxidative stress markers in these patients. According to the present study it was not detected any alteration in erythrocytres NO synthesis in hypertension, however, there was an activation of urea cycle, which could be explained by an increase in L-arginine influx. The present study has not demonstrated significative difference in markers of lipid peroxidation in the serum, platelets or erythrocytes in hypertension. In platelets however, there was an inhibition of NO synthase (NOS) activity without any alterations of NOS isoforms, arginase, phosphodiesterase 5 (PDE5) or soluble guanylyl cyclase (sGC) expression. This reduction of NO synthesis may be explained by a lower influx of L-arginine that is present on hypertension. Erythrocytes from chronic renal failure patients under haemodyalysis have shown an increased influx of L-arginine associated with a higher expression and activity of arginase with no difference in NOS activity. Therefore, although it was not shown abnormalities of lipid per oxidation markers in erythrocytes and platelets, it was detected increased levels of these markers in the serum of chronic renal failure patients under hemodyalysis. On the other hand, platelets from the same patients exhibited increased expression of eNOS, iNOS and soluble guanylyl cyclase associated with reduced arginase activity, which can explain the platelet dysfunction observed in these patients. Platelets taken from patients with chronic renal failure under conservative treatment have shown increased NOS activity associated with higher expression of both iNOS and eNOS. Curiously, it was been detected a lower concentration of cyclic guanosine monophosphate (cGMP), although there was no difference in the patterns of platelet aggregation induced by collagen or adenosine diphosphate (ADP). The findings reported in this study may contribute to a better understanding of EH and CRF physiopathology.