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  • Title: Angiotensin II type 1 receptor blockade prevents diastolic heart failure through modulation of Ca(2+) regulatory proteins and extracellular matrix.
    Author: Sakata Y, Yamamoto K, Mano T, Nishikawa N, Yoshida J, Nakayama H, Otsu K, Suzuki K, Tada M, Hori M, Miwa T, Masuyama T.
    Journal: J Hypertens; 2003 Sep; 21(9):1737-45. PubMed ID: 12923407.
    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.
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