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 (AT1) receptor 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(mRen2)27) were treated between 10 and 30 weeks of age with the angiotensin II subtype 1 (AT1) receptor antagonist, eprosartan, in an antihypertensive (Ren2-E60, 60 mg/kg per day) and a non-antihypertensive (Ren2-E6, 6 mg/kg per day) dose applied intraperitoneally via osmotic-mini-pumps. They were compared to age-matched Ren2 and Sprague-Dawley (SD) control rats receiving 0.9% NaCl as vehicle via osmotic mini-pumps (Ren2-Vehicle, SD-Vehicle, respectively).


RESULTS
Systolic blood pressure (SBP), LV weight, LV end-diastolic pressure (LVEDP), and cardiac fibrosis were elevated in Ren2-Vehicle, while diastolic function (-dP/dt(max)) and sarcoplasmic reticulum (SR) Ca2+ uptake were decreased in Ren2-Vehicle compared to SD-Vehicle (P < 0.05, respectively). SBP was not altered in Ren2-E6, but reduced to normotensive levels in Ren2-E60 compared to Ren2-Vehicle and SD-Vehicle (P < 0.0001). In both Ren2-E6 and Ren2-E60, LV weights were reduced and LVEDP and -dP/dt(max)normalized compared to Ren2-Vehicle (P < 0.05). SR Ca2+ uptake was normalized in both Ren2-E6 and Ren2-E60. Cardiac fibrosis did not change in Ren2-E6, but perivascular LV fibrosis and hydroxyprolin content were reduced in Ren2-E60 compared to Ren2-Vehicle (P < 0.05, respectively).


CONCLUSIONS
Normalization of LV SR Ca2+ uptake is an important mechanism by which AT1 receptor antagonism improves LV diastolic dysfunction independent from a reduction of SBP and cardiac fibrosis in the TGR (mRen2)27 model.
Rothermund
L
L
Institut für Klinische Pharmakologie und Toxikologie, Benjamin Franklin Hospital, Freie Universität Berlin, Germany.
Pinto
Y M
YM
Vetter
R
R
Herfort
N
N
Kossmehl
P
P
Neumayer
H H
HH
Paul
M
M
Kreutz
R
R
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism*; D005355:Fibrosis; D006352:Heart Ventricles; D006973:Hypertension / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D009929:Organ Size; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D044139:Receptor, Angiotensin, Type 2; D012083:Renin / Q000235:genetics*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D016277:Ventricular Function, Left
D057911:Angiotensin Receptor Antagonists; D020033:Protein Isoforms; D012333:RNA, Messenger; D044139:Receptor, Angiotensin, Type 2; D009320:Atrial Natriuretic Factor; D012083:Renin; D002118:Calcium