Mechanism of diastolic stiffening of the failing myocardium and its prevention by angiotensin receptor and calcium channel blockers.
Mechanism of diastolic stiffening of the failing myocardium and its prevention by angiotensin receptor and calcium channel blockers.
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DOI：
10.1097/fjc.0b013e3181ab371d
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发表时间：
2009-07
影响因子：
3
通讯作者：
Murohara T
中科院分区：
文献类型：
--
作者：
Cheng XW;Okumura K;Kuzuya M;Jin Z;Nagata K;Obata K;Inoue A;Hirashiki A;Takeshita K;Unno K;Harada K;Shi GP;Yokota M;Murohara T
目的 研究 Dahl 盐敏感 (DS) 大鼠与高血压心力衰竭相关的心脏硬度增加的机制，以及钙通道阻滞剂 [阿折地平 (AZE)] 和血管紧张素 II 1 型受体阻滞剂 [奥美沙坦 (OLM)] 联合治疗的效果。从 7 周龄开始喂养高盐饮食的 DS 大鼠在 12 至 19 周龄期间接受（或不接受）血管扩张剂肼屈嗪、OLM 加 AZE 或还原型烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶抑制剂罗布麻宁治疗。喂食低盐饮食的大鼠作为对照。 OLM加AZE治疗减弱了左心室胶原同种型表达的变化和弹性蛋白与胶原的比率的降低，并以与这些药物的降血压作用无关的方式防止DS大鼠心肌僵硬度和舒张功能障碍的增加。这种治疗还抑制弹性蛋白酶（包括组织蛋白酶 S 和 K 以及金属蛋白酶-2、-9 和 -12）的表达和激活、NADPH 氧化酶依赖性超氧化物的产生以及衰竭心肌中的炎症变化。所有这些效果都通过罗布麻宁治疗来模拟。衰竭心肌中胶原同工型表达的变化和弹性蛋白与胶原比例的降低可能是高血压心力衰竭模型中舒张期硬度增加的原因。施用血管紧张素受体和钙通道阻滞剂通过抑制由NADPH氧化酶激活诱导的弹力分解活性的增加，以独立于这些药物的降血压作用的方式阻止这些变化。
To investigate the mechanism responsible for the increased cardiac stiffness associated with hypertensive heart failure in Dahl salt-sensitive (DS) rats and the effects of treatment with the combination of a calcium channel blocker [azelnidipine (AZE)] and angiotensin II type 1 receptor blocker [olmesartan (OLM)]. DS rats fed a high-salt diet from 7 weeks of age were treated (or not) from 12 to 19 weeks of age with the vasodilator hydralazine, OLM plus AZE, or the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin. Rats fed a low-salt diet served as controls. Treatment with OLM plus AZE attenuated changes in the expression of collagen isoforms and a decrease in the ratio of elastin to collagen in the left ventricle and prevented the increase in myocardial stiffness and diastolic dysfunction in DS rats in a manner independent of the hypotensive effect of these drugs. Such treatment also inhibited the expression and activation of elastolytic proteases (including cathepsins S and K and metalloproteinases-2, -9, and -12), NADPH oxidase–dependent superoxide production, and inflammatory changes in the failing myocardium. All these effects were mimicked by treatment with apocynin. The changes in collagen isoform expression and the decrease in the elastin to collagen ratio in the failing myocardium likely account for the increase in diastolic stiffness in this model of hypertensive heart failure. Administration of angiotensin receptor and calcium channel blockers prevented these changes in a manner independent of the hypotensive effect of these drugs by inhibiting the increase in elastolytic activity induced by activation of NADPH oxidase.