Effects of angiotensin II subtype 1 receptor blockade on cardiac fibrosis and sarcoplasmic reticulum Ca2+ handling in hypertensive transgenic rats overexpressing the Ren2 gene

Objective We evaluated the effects of angiotensin II subtype 1 (AT(1)) rece ptor antagonism on cardiac fibrosis and sarcoplasmic (SR) Ca2+ handling in a transgenic rat model of renin-dependent left ventricular (LV) hypertrophy (LVH). Methods Hypertensive transgenic rats overexpressing the Ren2 gene (TGR(mRen 2)27) were treated between 10 and 30 weeks of age with the angiotensin II s ubtype 1 (AT(1)) receptor antagonist, eprosartan, in an antihypertensive (R en2-E60, 60 mg/kg per day) and a non-a nti hypertensive (Ren2-E6, 6 mg/kg p er day) dose applied intraperitoneally via osmotic-mini-pumps. They were co mpared to age-matched Ren2 and Sprague-Dawley (SD) control rats receiving 0 .9% NaCl as vehicle via osmotic mini-pumps (Ren2-Vehicle, SD-Vehicle, respe ctively). Results Systolic blood pressure (SBP), LV weight, LV end-diastolic pressure (LVEDP), and cardiac fibrosis were elevated in Ren2-Vehicle, while diastol ic function (-dP/dt(max)) and sarcoplasmic reticulum (SR) Ca2+ uptake were decreased in Ren2-Vehicle compared to SD-Vehicle (P <0.05, respectively). S BP was not altered in Ren2-E6, but reduced to normotensive levels in Ren2-E 60 compared to Ren2-Vehicle and SID-Vehicle (P <0.0001). In both Ren2-E6 an d Ren2-E60, LV weights were reduced and LVEDP and -dP/dt(max) normalized co mpared to Ren2-Vehicle (P <0.05). SR Ca2+ uptake was normalized in both Ren 2-E6 and Ren2-E60. Cardiac fibrosis did not change in Ren2-E6, but perivasc ular LV fibrosis and hydroxyprolin content were reduced in Ren2-E60 compare d to Ren2-Vehicle (P <0.05, respectively). Conclusions Normalization of LV SR Ca2+ uptake is an important mechanism by which AT(1) receptor antagonism improves LV diastolic dysfunction independ ent from a reduction of SBP and cardiac fibrosis in the TGR (mRen2)27 model . (C) 2001 Lippincott Williams & Wilkins.