Therapeutic strategies for coronary stenosis-induced cardiac dysfunction and remodeling

冠状动脉狭窄引起的心功能障碍和重构的治疗策略

• 批准号: 11670696
• 负责人: MARUYAMA Yukio
• 金额: $ 1.6万
• 依托单位: Fukushima Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670696/
• 关键词: Ischemic heart disease; Mitochondria; Nitric oxide; Ion channel; 一酸化窒素; 冠動脈狭窄; 慢性虚血; ラット; リモデリング; Ca過負荷

We assessed effects of the ion channel modulator [Na-H exchanger(NHE) inhibitor and KATP channel opener/inhibitor] and coronary endothelial nitric oxide synthase(eNOS) activator(tetrahydrobiopterine : BH4)on ischemic left ventricular(LV) dysfunction and remodeling induced by coronary stenosis in rats. In addition, as a known anti-heart failure agent, the effect of angiotensin II type 1 receptor antagonist(candesartan)was also assessed. Within 24 hours after creating coronary stenosis, we administered either diazoxide(mitochondrial KATP channel opener)30 or 60 mg/kg/day, 5-hydorxydecanoate(mitochondrial KATP channel inhibitor)30 or 60 mg/kg/day, nicorandil(sarcolemmal KATP opener)5 mg/kg/day, SMP-300(NHE inhibitor)20 mg/kg/day, BH4 10 mg/kg/day, or candesratan 10 mg/kg/day orally in rats. Four weeks later, echocardiographic findings, coronary flow by microspheres, and coronary eNOS activity by in vitro myocardial oxygen consumption method were assessed. Candesartan effectively attenuated LV remodeling in this model. BH4 increased coronary eNOS activity and attenuated LV remodeling. While diazoxide failed to attenuate LV dysfunction and remodeling, 5-hydroxydecanoate rather augmented LV remodeling. SMP-300 did not improve coronary eNOS function but attenuated LV remodeling. In conclusion, in the coronary stenosis-induced LV dysfunction and remodeling, mitochondrial and sarcolemmal KATP channel openers seem to be ineffective in attenuating LV dysfunction and remodeling probably due to that KATP channels are already opened by chronic ischemia. In contrast, NHE inhibitor may have a therapeutic effect on LV dysfunction and remodeling induced by chronic myocardial ischemia.

我们评估了离子通道调节剂[Na-H交换器（NHE）抑制剂和KATP通道开放剂/抑制剂]和冠状动脉内皮一氧化氮合酶（eNOS）激活剂（四氢生物蝶呤：BH4）对大鼠冠状动脉狭窄引起的缺血性左心室（LV）功能障碍和重构的影响。此外，作为已知的抗心力衰竭药物，还评估了血管紧张素II 1型受体拮抗剂（坎地沙坦）的效果。冠状动脉狭窄后24小时内，我们给予二氮嗪（线粒体KATP通道开放剂）30或60毫克/公斤/天，5-羟基癸酸（线粒体KATP通道抑制剂）30或60毫克/公斤/天，尼可地尔（肌膜KATP通道开放剂）5毫克/公斤/天， 大鼠口服 SMP-300（NHE 抑制剂）20 mg/kg/天、BH4 10 mg/kg/天或坎地拉坦 10 mg/kg/天。 4周后，评估超声心动图结果、微球冠状动脉流量以及体外心肌耗氧量法冠状动脉eNOS活性。坎地沙坦有效减弱了该模型中的左心室重塑。 BH4 增加冠状动脉 eNOS 活性并减弱左心室重构。虽然二氮嗪未能减轻左室功能障碍和重塑，但 5-羟基癸酸酯却增强了左室重塑。 SMP-300 没有改善冠状动脉 eNOS 功能，但减弱了左心室重构。总之，在冠状动脉狭窄引起的左心室功能障碍和重塑中，线粒体和肌膜 KATP 通道开放剂似乎对减轻左心室功能障碍和重塑无效，可能是因为慢性缺血已经打开了 KATP 通道。相比之下，NHE抑制剂可能对慢性心肌缺血引起的左心室功能障碍和重构有治疗作用。