Key result
Selective ETA receptor blockade is superior to nonselective ETA/ETB receptor blockade in attenuating hypertension and end-organ damage in Ren-2 transgenic rats, with more pronounced effects when applied early.
In a transgenic rat model of hypertension, selective ETA receptor blockade provided superior protection against hypertension and end-organ damage compared to nonselective ETA/ETB blockade.
Cautions against clinical extrapolation from rat models; leaves open whether selective ETA blockade improves human hypertension outcomes.
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 clinical 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 ET(A) 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 ET(A) treatment substantially while ET(A)/ET(B) treatment partially improved survival rate. Significant effect on BP was found with early and late ET(A) blockade, while ET(A)/ET(B) blockade had no effect. Bosentan and atrasentan similarly decreased ET-1 levels on both regimens. In conclusion, selective ET(A) receptor blockade is superior to nonselective ET(A)/ET(B) receptor blockade in attenuating hypertension and end-organ damage. Its effect is more pronounced when applied early in the life.
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Vernerová et al. (2009) conducted a review in Hypertension and end-organ damage. Selective ETA receptor blockade vs. Nonselective ETA/ETB receptor blockade or untreated was evaluated on Survival rate and blood pressure. Selective ETA receptor blockade is superior to nonselective ETA/ETB receptor blockade in attenuating hypertension and end-organ damage in Ren-2 transgenic rats, with more pronounced effects when applied early.
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