| Project/Area Number |
13670080
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | CHIBA UNIVERSITY |
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Principal Investigator |
NAKAYA Haruaki CHIBA UNIVERSITY, GRADUATE SCHOOL OF MEDICINE, PROFESSOR, 大学院・医学研究院, 教授 (60113594)
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| Co-Investigator(Kenkyū-buntansha) |
SATO Toshiaki CHIBA UNIVERSITY, GRADUATE SCHOOL OF MEDICINE, ASSOCIATE PROFESSOR, 大学院・医学研究院, 助教授 (60244159)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2002: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 2001: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | ATP-sensitive K^+ channel / sarcolemma / mitochondria / ischemia・reperfusion / ischemic preconditioning / Kir6.1 / Kir6.2 / knockout mouse / 活動電位 |
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| Research Abstract |
In order to clarify the pathophysiological roles of sarcolemmal ATP-sensitive K^+ (sarcK_<ATP>) channel in cardiac and vascular smooth muscle cells, we conducted functional experiments using Kir6.2-deficient (Kir6.2^<-/->) and Kir6.1-deficient (Kir6.1^<-/->) mice.
In ventricular cells of Kir6.2^<-/-> mice sarcK_<ATP> channel function was negated but the mitochondrial K_<ATP> (mitoK_<ATP>) channel function, evaluated by diazoxide-induced flavoprotein oxidation, was preserved. For ischemic preconditioning (IPC) experiments coronary artery was occluded for three periods of 3 min, each followed by 5 min reperfusion, before the long-term ischemia (45 min) in anesthetized mice. IPC reduced the infarct size in wild-type (WT) mice but not in Kir6.2^<-/-> mice. The recovery of the left ventricular contractile function after global ischemia/reperfusion was worse in Langendorff-perfused hearts of Kir6.2^<-/-> mice than in WT hearts. These findings indicate that sarcK_<ATP> channel is important for the establishment of ischemic preconditioning and the recovery of mechanical function after ischemia/reperfusion.
We also evaluated sarcK_<ATP> channel function in cardiac and vascular smooth muscle cells of Kir6.1^<-/-> mice. Although both sarcK_<ATP> and mitoK_<ATP> channel function were preserved in cardiac cells of Kir6.1^<-/-> mice, functional responses of sarcK_<ATP> channels to K^+ channel openers were impaired in vascular smooth muscle cells of Kir6.1^<-/-> mice. Of particular interest are the findings that Kir6.2^<-/-> mice showed a high rate of sudden cardiac death associated with spontaneous ST elevation followed by atrioventricular block on ECG. These results suggest that Kir6.1 is critical in the regulation of vascular tone, especially in the coronary arteries, and the dysfunction of the K_<ATP> channel causes Prinzmetal angina.
Thus, either Kir6.2 or Kir6.1 is absolutely important for the function of sarcK_<ATP> channels in the cardiovascular system.
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