Sakata Yasushi, Yamamoto Kazuhiro, Mano Toshiaki, Nishikawa Nagahiro, Yoshida Junichi, Nakayama Hiroyuki, Otsu Kinya, Suzuki Keiichiro, Tada Michihiko, Hori Masatsugu, Miwa Takeshi, Masuyama Tohru
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Japan.
J Hypertens. 2003 Sep;21(9):1737-45. doi: 10.1097/00004872-200309000-00024.
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.
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.
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.
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.
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.
在高血压舒张性心力衰竭模型中，血管紧张素II 1型受体（AT(1)R）阻断可减轻左心室舒张异常和心肌僵硬度，但其机制尚不清楚。
检验以下假设，即这些益处是通过调节钙调节蛋白和细胞外基质的定量或定性变化，或两者的变化来实现的。
从7周龄开始喂食含8%氯化钠饮食的 Dahl 盐敏感大鼠，在20周龄左右会因舒张功能障碍且收缩功能保留而出现肺充血。在本研究中，将该模型的动物分为两组，从8周龄开始，一组接受（n = 7）或不接受（n = 6）亚降压剂量的AT(1)R拮抗剂（坎地沙坦酯）。
长期AT(1)R阻断可通过减轻左心室舒张异常和心肌僵硬度来预防舒张性心力衰竭的发生，而不会降低血压。左心室舒张异常与受磷蛋白与肌浆网Ca2+-ATP酶2a蛋白丰度比的任何变化均无关，但伴有Ser16磷酸化受磷蛋白的减少。AT(1)R阻断可抑制这种减少。心肌僵硬度的减轻与组织胶原蛋白含量降低、胶原蛋白交联减弱以及I型而非III型胶原蛋白基因表达受抑制有关。
在舒张性心力衰竭高血压模型中，AT(1)R阻断至少部分通过钙处理蛋白的功能改变预防了舒张异常。它通过防止合成的胶原蛋白表型转变和交联胶原蛋白的积累减轻了心肌僵硬度。AT(1)R阻断在舒张性心力衰竭中的这些有益作用是在不降低血压的情况下实现的。
