Therapeutic strategies for coronary stenosis-induced cardiac dysfunction and remodeling

我们观察了离子通道调节剂[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：BH4)对冠脉狭窄所致大鼠缺血性左心功能障碍和重构的影响。此外，作为一种已知的抗心衰药物，血管紧张素II 1型受体拮抗剂坎地沙坦的效果也得到了评估。在造成冠状动脉狭窄后的24小时内，给予二氮嗪(线粒体KATP通道开放剂)30或60 mg/kg/d，5-羟基癸酸酯(线粒体KATP通道抑制剂)30或60 mg/kg/d，尼可地尔(肌膜KATP开放剂)5 mg/kg/d，SMP-300(NHE抑制剂)20 mg/kg/d，BH4 10 mg/kg/d，或坎地拉坦10 mg/kg/d。4周后，超声心动图、微球冠脉流量、体外心肌耗氧量法检测冠脉eNOS活性。坎地沙坦有效地抑制了该模型的左室重构。BH4可增加冠脉eNOS活性，减轻左室重构。二氮嗪不能减轻左心室功能障碍和重塑，而5-羟基癸酸却能增强左心室重塑。SMP-300不能改善冠脉内皮型一氧化氮合酶功能，但可减轻左室重构。综上所述，在冠状动脉狭窄所致的LV功能障碍和重构中，线粒体和肌膜KATP通道开放剂似乎不能有效地减轻LV功能障碍和重构，这可能是因为慢性缺血已经开放了KATP通道。相反，NHE抑制剂可能对慢性心肌缺血所致的左心功能不全和重构有治疗作用。

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.