The rat strain transgenic for the murine Ren-2 renin gene (TGR) is defined as a monogenic model of angiotensin II-dependent hypertension with endogenous activation of the renin-angiotensin system. Homozygous males TGR develop malignant hypertension with a strong salt-sensitive component. These animals show severe hypertension, proteinuria and high mortality. Morphological changes of renal parenchyma correspond to chronic ischemic glomerular changes. Heterozygous TGR develop only mild hypertension and thus provide a more suitable model of hypertension regarding to clinic al studies. Within the renal parenchyma, secondary focal segmental glomerulosclerosis (FSGS) predominates. High-salt diet in heterozygous animals induces transition from benign to malignant phase of hypertension. In this case, ischemic glomerular changes are superimposed on preexisting secondary FSGS. In the regression model of hypertension (late-onset treatment) the effect of salt intake is attenuated. In homozygous TGR, early selective ET A receptor blockade decreased blood pressure and ameliorated end-organ damage. Late selective ET A receptor blockade reduced podocyte injury despite final severe hypertension. Survival rate was markedly improved in both regimens with ETA selective blockade, while there was only partial improvement with early non-selective blockade. Both bosentan and atrasentan decreased ET-1 levels in both regimens. In heterozygous TGR, early and late ETA treatment substantially while ETA/ETB treatment partially improved survival rate. Significant effect on BP was found with early and late ETA blockade, while ETA/ETB blockade had no effect. Bosentan and at rasentan similarly decreased ET-1 levels on both regimens. In conclusion, selective ETA receptor blockade is superior to nonselective ETA/ETB receptor blockade in attenuating hypertension and end-organ damage. Its effect is more pronounced when applied early in the life., Z. Vernerová ... [et al.]., and Obsahuje seznam literatury
The present study was performed to evaluate the role of intrapulmonary activity of the two axes of the renin-angiotensin system (RAS): vasoconstrictor angiotensin-converting enzyme (ACE)/angiotensin II (ANG II)/ANG II type 1 receptor (AT 1 ) axis, and vasodilator ACE type 2 (ACE2)/angiotensin 1-7 (ANG 1-7)/ Mas receptor axis, in the development of hypoxic pulmonary hypertension in Ren-2 transgenic rats (TGR). Transgene-negative Hannover Sprague-Dawley (HanSD) ra ts served as controls. Both TGR and HanSD rats responded to two weeks' exposure to hypoxia with a significant increase in mean pulmonary arterial pressure (MPAP), however, the increase was much less pronounced in the former. The attenuation of hypoxic pulmonary hypertension in TGR as compared to HanSD rats was associated with inhibition of ACE gene expression and activity, inhibition of AT 1 receptor gene expression and suppression of ANG II levels in lung tissue. Simultaneously, there was an increase in lung ACE2 gene expression and activity and, in particular, ANG 1-7 concentrations and Mas receptor gene expression. We propose that a combination of su ppression of ACE/ANG II/AT 1 receptor axis and activation of ACE2/ANG 1-7/Mas receptor axis of the RAS in the lung tissue is the main mechanism explaining attenuation of hypoxic pulmonary hypertension in TGR as compared with HanSD rats., V. Hampl, J. Herget, J. Bíbová, A. Baňasová, Z. Husková, Z. Vaňourková, Š. Jíchová, P. Kujal, Z. Vernerová, J. Sadowski, L. Červenka., and Obsahuje bibliografii