AT1 receptor blockade reduces cardiac calcineurin activity in hypertensive rats

Kohzo Nagata, Fuji Somura, Koji Obata, Mari Odashima, Hideo Izawa, Sahoko Ichihara, Tetsuro Nagasaka, Mitsunori Iwase, Yoshiji Yamada, Nobuo Nakashima, Mitsuhiro Yokota

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Abstract

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)-β1 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-β1 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-β1 in AT1 receptor-mediated angiotensin II signaling in vivo.

Original languageEnglish
Pages (from-to)168-174
Number of pages7
JournalHypertension
Volume40
Issue number2
DOIs
Publication statusPublished - 14-08-2002

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Inbred Dahl Rats
Angiotensin Type 1 Receptor
Calcineurin
Cardiomegaly
Tacrolimus
Transforming Growth Factors
Fibrosis
Peptidyl-Dipeptidase A
Messenger RNA
Hypertension
Angiotensin II Type 1 Receptor Blockers
Angiotensin II
Antihypertensive Agents
Myocardium
Up-Regulation
Salts
Diet
Gene Expression
Genes
candesartan

All Science Journal Classification (ASJC) codes

  • Internal Medicine

Cite this

Nagata, K., Somura, F., Obata, K., Odashima, M., Izawa, H., Ichihara, S., ... Yokota, M. (2002). AT1 receptor blockade reduces cardiac calcineurin activity in hypertensive rats. Hypertension, 40(2), 168-174. https://doi.org/10.1161/01.HYP.0000026668.50222.1E
Nagata, Kohzo ; Somura, Fuji ; Obata, Koji ; Odashima, Mari ; Izawa, Hideo ; Ichihara, Sahoko ; Nagasaka, Tetsuro ; Iwase, Mitsunori ; Yamada, Yoshiji ; Nakashima, Nobuo ; Yokota, Mitsuhiro. / AT1 receptor blockade reduces cardiac calcineurin activity in hypertensive rats. In: Hypertension. 2002 ; Vol. 40, No. 2. pp. 168-174.
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Nagata, K, Somura, F, Obata, K, Odashima, M, Izawa, H, Ichihara, S, Nagasaka, T, Iwase, M, Yamada, Y, Nakashima, N & Yokota, M 2002, 'AT1 receptor blockade reduces cardiac calcineurin activity in hypertensive rats', Hypertension, vol. 40, no. 2, pp. 168-174. https://doi.org/10.1161/01.HYP.0000026668.50222.1E

AT1 receptor blockade reduces cardiac calcineurin activity in hypertensive rats. / Nagata, Kohzo; Somura, Fuji; Obata, Koji; Odashima, Mari; Izawa, Hideo; Ichihara, Sahoko; Nagasaka, Tetsuro; Iwase, Mitsunori; Yamada, Yoshiji; Nakashima, Nobuo; Yokota, Mitsuhiro.

In: Hypertension, Vol. 40, No. 2, 14.08.2002, p. 168-174.

Research output: Contribution to journalArticle

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T1 - AT1 receptor blockade reduces cardiac calcineurin activity in hypertensive rats

AU - Nagata, Kohzo

AU - Somura, Fuji

AU - Obata, Koji

AU - Odashima, Mari

AU - Izawa, Hideo

AU - Ichihara, Sahoko

AU - Nagasaka, Tetsuro

AU - Iwase, Mitsunori

AU - Yamada, Yoshiji

AU - Nakashima, Nobuo

AU - Yokota, Mitsuhiro

PY - 2002/8/14

Y1 - 2002/8/14

N2 - 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)-β1 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-β1 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-β1 in AT1 receptor-mediated angiotensin II signaling in vivo.

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