Cardiac endothelin system impairs left ventricular function in renin-dependent hypertension via decreased sarcoplasmic reticulum Ca2+ uptake

Background-We evaluated the role of the cardiac endothelin (ET) system in c ompensated hypertensive left ventricular (LV) hypertrophy (LVH) and after t he transition toward LV dysfunction. Methods and Results-Hypertensive transgenic rats overexpressing the Ren2 ge ne (Ren2 rats) were investigated between the ages of 10 and 30 weeks (Ren2- 10 and Ren2-30 groups, respectively) and compared with age-matched normoten sive Sprague-Dawley (SD) rats (SD-10 and SD-30 groups, respectively). Systo lic blood pressure and LV weight were elevated in both Ren2 groups compared with their age-matched SD control groups (P<0.0001). in Ren2-30 rats, LV e nd-diastolic pressure increased and -dP/dt(max) decreased compared with the values in SD-30 and Ren2-10 rats (P<0.05). This was paralleled by an activ ation of LV mRNA expression of preproET-1 and ET-converting enzyme-1 and ET subtype A (ETA) receptor binding in Ren2-30 compared with Ren2-10 rats (P< 0.001), Cardiac fibrosis was increased and sarcoplasmic reticulum (SR) Ca2 reuptake was reduced in Ren2-30 compared with SD-30 and Ren2-10 rats (P<0. 05). Treatment of Ren2 rats with the selective ETA receptor antagonist Lu13 5252 between 10 and 30 weeks of age did not lower systolic blood pressure, heart weight, or cardiac fibrosis but completely prevented the deterioratio n of LV end-diastolic pressure and abolished alterations in -dP/dt(max) and SR Ca2+ reuptake compared with no treatment in Ren2-30 and SD-30 rats (P<0 .05). Conclusions-Activation of the cardiac ET system accounts at Least in part f or the LV dysfunction that gradually develops in LVH. The protective effect of ETA antagonism can be attributed to the improvement of diastolic LV fun ction that is due to normalization of impaired SR Ca2+ uptake.