AT1 receptor blockade reduces cardiac calcineurin activity in hypertensive rats.
The possible role of calcineurin in the attenuation of cardiac hypertrophy and fibrosis by blockade of the angiotensin II type 1 (AT1) receptor was investigated in Dahl salt-sensitive (DS) rats. The effect of the calcineurin inhibitor FK506 was also studied. DS rats progressively developed severe hypertension when fed a diet containing 8% NaCl from 7 weeks of age. In addition, marked cardiac hypertrophy and fibrosis were apparent and the activity of calcineurin and its mRNA expression in the myocardium was increased in these animals at 12 weeks in comparison with age-matched Dahl salt-resistant rats. The abundance of angiotensin-converting enzyme (ACE) and transforming growth factor (TGF)-beta1 mRNAs was also increased in the hearts of DS rats at 12 weeks. Treatment of DS rats with a non-antihypertensive dose of the selective AT1 receptor blocker candesartan (1 mg/kg per day) or FK506 (0.1 mg/kg per day) from 7 to 12 weeks attenuated both calcineurin activity and its mRNA expression in the heart, as well as the development of cardiac hypertrophy and fibrosis, without affecting cardiac function. Treatment with candesartan, but not FK506, prevented the upregulation of ACE and TGF-beta1 gene expression. Both candesartan and FK506 prevented the load-induced induction of fetal-type cardiac genes. These results demonstrate that AT1 receptor blockade attenuates the development of cardiac hypertrophy and fibrosis as well as the activation of calcineurin, without an antihypertensive effect, in rats with salt-sensitive hypertension. Calcineurin may be downstream from TGF-beta1 in AT1 receptor-mediated angiotensin II signaling in vivo.
Nagata
Kohzo
K
Department of Clinical Pathophysiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Somura
Fuji
F
Obata
Koji
K
Odashima
Mari
M
Izawa
Hideo
H
Ichihara
Sahoko
S
Nagasaka
Tetsuro
T
Iwase
Mitsunori
M
Yamada
Yoshiji
Y
Nakashima
Nobuo
N
Yokota
Mitsuhiro
M
D000804:Angiotensin II / Q000502:physiology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D004452:Echocardiography; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000235:genetics; D013314:Stress, Mechanical; D016559:Tacrolimus / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D019703:Calcineurin; D007703:Peptidyl-Dipeptidase A; C081643:candesartan; D016559:Tacrolimus