Therapeutic strategies for coronary stenosis-induced cardiac dysfunction and remodeling

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]和冠状动脉内皮型一氧化氮合酶（eNOS）激活剂（四氢生物蝶呤：BH 4）对大鼠冠状动脉狭窄诱导的缺血性左心室（LV）功能障碍和重构的影响。此外，作为一种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）的作用。在造成冠状动脉狭窄后24小时内，我们对大鼠经口给予二氮嗪（线粒体KATP通道开放剂）30或60 mg/kg/天、5-羟基癸酸酯（线粒体KATP通道抑制剂）30或60 mg/kg/天、尼可地尔（肌膜KATP开放剂）5 mg/kg/天、SMP-300（NHE抑制剂）20 mg/kg/天、BH 4 10 mg/kg/天或坎地拉坦10 mg/kg/天。4周后，超声心动图的结果，冠状动脉微球流量和冠状动脉eNOS活性的体外心肌耗氧量法进行了评估。坎地沙坦在该模型中有效地减弱LV重构。BH 4增加冠状动脉eNOS活性并减轻LV重构。虽然二氮嗪未能减轻左室功能障碍和重塑，5-羟基癸酸，而增强左室重塑。SMP-300没有改善冠状动脉eNOS功能，但减轻了LV重构。结论：在冠状动脉狭窄引起的左室功能障碍和重构中，线粒体和肌膜KATP通道开放剂似乎对减轻左室功能障碍和重构无效，这可能是由于KATP通道已经被慢性缺血开放。相比之下，NHE抑制剂可能对慢性心肌缺血引起的左室功能障碍和重塑具有治疗作用。

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.