Cardiac Endothelin System Impairs Left Ventricular Function in Renin-Dependent Hypertension via Decreased Sarcoplasmic Reticulum Ca ²⁺ Uptake

Abstract

Background-We evaluated the role of the cardiac endothelin (ET) system in compensated hypertensive left ventricular (LV) hypertrophy (LVH) and after the transition toward LV dysfunction. Methods and Results-Hypertensive transgenic rats overexpressing the Ren2 gene (Ren2 rats) were investigated between the ages of 10 and 30 weeks (Ren2-10 and Ren2-30 groups, respectively) and compared with age-matched normotensive Sprague-Dawley (SD) rats (SD-10 and SD-30 groups, respectively). Systolic blood pressure and LV weight were elevated in both Ren2 groups compared with their age-matched SD control groups (PϽ0.0001). In Ren2-30 rats, LV end-diastolic pressure increased and ϪdP/dt max decreased compared with the values in SD-30 and Ren2-10 rats (PϽ0.05). This was paralleled by an activation 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 (PϽ0.001). Cardiac fibrosis was increased and sarcoplasmic reticulum (SR) Ca 2ϩ reuptake was reduced in Ren2-30 compared with SD-30 and Ren2-10 rats (PϽ0.05). Treatment of Ren2 rats with the selective ETA receptor antagonist Lu135252 between 10 and 30 weeks of age did not lower systolic blood pressure, heart weight, or cardiac fibrosis but completely prevented the deterioration of LV end-diastolic pressure and abolished alterations in ϪdP/dt max and SR Ca 2ϩ reuptake compared with no treatment in Ren2-30 and SD-30 rats (PϽ0.05). Conclusions-Activation of the cardiac ET system accounts at least in part for the LV dysfunction that gradually develops in LVH. The protective effect of ETA antagonism can be attributed to the improvement of diastolic LV function that is due to normalization of impaired SR Ca 2ϩ uptake. (Circulation. 2000;102:1582-1588.)

Endothelin-A Receptor Blockade Prevents Left Ventricular Hypertrophy and Dysfunction in Salt-Sensitive Experimental Hypertension

“…The latter findings are in agreement with our previous experiments in a transgenic rat model with high-renin hypertension. 5 In this former study, LV diastolic dysfunction was improved by ETA blockade without affecting hypertension or LVH. Interstitial fibrosis was also not affected by ETA blockade in transgenic rats, suggesting that cardiac fibrosis in both the high-renin transgenic model and the low-renin DOCA saltsensitive Sabra model could probably be attributed to direct cardiac effects of mineralocorticoids.…”

“…Systolic blood pressure (SBP) was determined in awake rats as reported previously. 5 At the age of 16 weeks, the rats were submitted to LV catheterization under pentobarbital anesthesia using the technique reported previously. 5 Preparation of the heart and histological evaluation of cardiac fibrosis were performed as described.…”

“…5 At the age of 16 weeks, the rats were submitted to LV catheterization under pentobarbital anesthesia using the technique reported previously. 5 Preparation of the heart and histological evaluation of cardiac fibrosis were performed as described. 5 Determination of atrial natriuretic factor (ANF) mRNA in the left ventricle and of sarcoplasmic reticulum (SR) Ca 2ϩ -reuptake was performed as reported.…”

“…5 Preparation of the heart and histological evaluation of cardiac fibrosis were performed as described. 5 Determination of atrial natriuretic factor (ANF) mRNA in the left ventricle and of sarcoplasmic reticulum (SR) Ca 2ϩ -reuptake was performed as reported. 5 Western blot analyses of SR Ca 2ϩ -ATPase (SERCA2) and phospholamban were carried out as described elsewhere.…”

Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat

“…This approach leads to systemic hypertension and remodeling in the peripheral vasculature, but not pulmonary vascular remodeling, increased AT 1 R expression, or PH (34). Third, 10-wk-old Ren2 rats exhibit LVH without elevation in LV end-diastolic pressure, as opposed to 30-wk-old Ren2 rats, which exhibit LVH with diastolic impairment (57). The Ren2 rats used in this study were ϳ9 wk of age and not yet at an age characterized by LV dysfunction.…”