Late-onset endothelin receptor blockade in hypertensive heterozygous REN-2 transgenic rats

Abstract

Our previous studies in heterozygous Ren-2 transgenic rats (TGR) have shown that early treatment with selective endothelin (ET)(A) receptor blockade is superior to nonselective ET(A/B) receptor blockade. The aim of this study was to evaluate the role of the ET system in male heterozygous TGR with established hypertension (late-onset treatment). TGR and control Hannover Sprague-Dawley (HanSD) rats were fed a high-salt diet and were treated concomitantly with the nonselective ET(A/B) receptor blocker bosentan or the selective ET(A) receptor blocker atrasentan from day 52 of age on. Survival rate was partly increased by bosentan and fully normalized with atrasentan. Bosentan transiently decreased blood pressure (BP), whereas atrasentan significantly reduced BP as early as one week after the start of the treatment. This effect persisted for the whole experimental period. Atrasentan also substantially reduced cardiac hypertrophy, proteinuria, glomerulosclerosis and left ventricle ET-1 content. Bosentan improved and atrasentan almost restored podocyte architecture and reversed changes in podocyte phenotype represented by the expression of CD 10, desmin and vimentin. Our results demonstrate that selective ET(A) receptor blockade has more favorable effects than nonselective ET(A/B) receptor blockade and, unlike observed in homozygous TGR, ET(A) receptor blockade has similar effects in heterozygous rats with established hypertension as in young animals with developing hypertension.