Therapeutic strategies for coronary stenosis-induced cardiac dysfunction and remodeling

2000 Fiscal Year Final Research Report Summary

• Project/Area Number: 11670696
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Fukushima Medical University
• Principal Investigator: MARUYAMA Yukio Fukushima Medical University, First Department of Internal Medicine, Professor, 医学部, 教授 (90004712)
• Co-Investigator(Kenkyū-buntansha): MAEHARA Kazuhira Fukushima Medical University, First Department of Internal Medicine, Associate professor, 医学部, 助教授 (90181817) ; YAOITA Hiroyuki Fukushima Medical University, First Department of Internal Medicine, Instructor, 医学部, 助手 (50264544)
• Project Period (FY): 1999 – 2000
• Keywords: Ischemic heart disease / Mitochondria / Nitric oxide / Ion channel

Research Abstract

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.