Angiotensin II type 1 receptor blockade prevents diastolic heart failure through modulation of Ca(2+) regulatory proteins and extracellular matrix.

Abstract

BACKGROUND:

Angiotensin II type 1 receptor (AT(1)R) blockade attenuates left ventricular relaxation abnormality and myocardial stiffening in a model of hypertensive diastolic heart failure, but the mechanisms remain unclear.

OBJECTIVE:

To test the hypothesis that such benefits are provided by modulation of the quantitative or qualitative changes, or both, in Ca2+ regulatory proteins and extracellular matrix.

DESIGN AND METHODS:

Dahl salt-sensitive rats fed a diet containing 8% sodium chloride from 7 weeks of age present pulmonary congestion as a result of diastolic dysfunction with preserved systolic function, around 20 weeks of age. In this study, animals of this model were divided into groups that received (n = 7) or did not receive (n = 6) a subdepressor dose of an AT(1)R antagonist (candesartan cilexetil) from 8 weeks of age.

RESULTS:

Long-term AT(1)R blockade prevented the development of diastolic heart failure through attenuation of left ventricular relaxation abnormality and myocardial stiffening without a reduction in blood pressure. Left ventricular relaxation abnormality was not associated with any change in the ratio of abundance of phospholamban to that of sarcoplasmic reticulum Ca2+-ATPase 2a protein, but was accompanied by a decrease in Ser16-phosphorylated phospholamban. The AT(1)R blockade inhibited this decrease. Attenuation in myocardial stiffening was associated with reduced tissue collagen content, attenuated collagen cross-linking, and suppressed gene expression of collagen type I rather than type III.

CONCLUSIONS:

AT(1)R blockade prevented abnormal relaxation at least partly through functional alterations in Ca2+-handling proteins in a hypertensive model of diastolic heart failure. It attenuated myocardial stiffening through preventing a shift in the phenotype of collagen synthesized and the accumulation of cross-linked collagen. These beneficial effects of AT(1)R blockade in diastolic heart failure are achieved without a reduction in blood pressure.

• Authors: Yasushi Sakata, Kazuhiro Yamamoto, Toshiaki Mano, Nagahiro Nishikawa, Junichi Yoshida, Hiroyuki Nakayama, Kinya Otsu, Keiichiro Suzuki, Michihiko Tada, Masatsugu Hori, Takeshi Miwa, Tohru Masuyama
• Journal: Journal of hypertension (J Hypertens) Vol. 21 Issue 9 Pg. 1737-45 (Sep 2003) ISSN: 0263-6352 [Print] Netherlands
• PMID: 12923407 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin Receptor Antagonists
• Antihypertensive Agents
• Benzimidazoles
• Biphenyl Compounds
• Calcium-Binding Proteins
• Cross-Linking Reagents
• Receptor, Angiotensin, Type 1
• Tetrazoles
• phospholamban
• Collagen
• Cyclic AMP
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Calcium-Transporting ATPases
• candesartan cilexetil
• Calcium

Topics

• Angiotensin Receptor Antagonists
• Animals
• Antihypertensive Agents (pharmacology)
• Benzimidazoles (pharmacology)
• Biphenyl Compounds (pharmacology)
• Calcium (metabolism)
• Calcium-Binding Proteins (metabolism)
• Calcium-Transporting ATPases (metabolism)
• Collagen (genetics, metabolism)
• Cross-Linking Reagents (metabolism)
• Cyclic AMP (metabolism)
• Diastole (drug effects, physiology)
• Extracellular Matrix (metabolism)
• Gene Expression
• Heart Failure (metabolism, prevention & control)
• Hypertension (drug therapy, metabolism)
• Hypertrophy, Left Ventricular (metabolism, prevention & control)
• Male
• Phosphorylation
• Rats
• Rats, Inbred Dahl
• Receptor, Angiotensin, Type 1
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Tetrazoles