| Co-Investigator(Kenkyū-buntansha) |
HAYASHI Hideharu Department of Medicine, Hamamatsu University School of Medicine, Professor, 医学部, 教授 (50135258)
TERADA Hajime Department of Medicine, Hamamatsu University School of Medicine, Research Associate, 医学部, 助手 (50252177)
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| Research Abstract |
1999 : The role of Ca influx via sarcolemmal Na/Ca exchange (NCX) in digitalis- and ischemia/reperfusion-induced injuries.
Na/Ca exchange (NCX) is a major Ca extrusion system in cardiac myocytes, but can also mediate Ca influx and can trigger SR Ca release. Under conditions such as digitalis toxicity or ischemia/reperfusion, increased [Na] i may lead to a rise in [Ca] i through NCX, causing Ca overload and triggered arrhythmias. We used an agent reported to selectively block Ca influx by NCX, KB-R7943 (KBR) and assessed twitch contractions and Ca transients in rat ventricular myocytes loaded with indo-1, and in guinea pig (GP) papillary muscles. In rat, KBR (5μM) did not decrease control steady-state twitch contractions or Ca transients. When cells were Na-loaded by perfusion of strophanthidin, the addition of KBR reduced diastolic [Ca] i and abolished spontaneous Ca oscillations which occured. In GP exposed to substrate-free hypoxic medium for 60 min, KBR reduced reoxygenation-induced
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arrhythmias both in incidence and in duration. KBR also enhanced the recovery of developed tension after reoxygenation. We conclude that Ca influx via NCX may be critical in causing myocardial Ca overload and triggered activity induced by cardiac glycoside or by reoxygenation.
2000 : Effects of intracellular acidosis on twitch contraction and Ca transients
Acidosis disturbs contractile performance by decreasing myofibrillar Ca response, but the contraction recovers at prolonged acidosis. We examined the mechanism of the contractile recovery during acidosis in isolated rat ventricular myocytes. Stable acidosis was obtained by increasing the percentage of CO2 in a bicarbonate buffer. During initial min of acidosis, the twitch cell shortening decreased, but these cells appeared subsequent contractile recovery. During the initial decline, both the diastolic [Ca] i and amplitude of Ca transient (CaT) increased, and decline of CaT prolonged. The following recovery was accompanied by a further increase in amplitude and an acceleration of decline of CaT.A blockade of SR function or selective inhibition of Ca-calmodulin kinase II (CaMKII) completely abolished the reacceleration in the decline of CaT and almost eliminated the contractile recovery. We concluded that during prolonged acidosis, the CaMKII-dependent reactivation of SR Ca uptake can increase SR Ca content and CaT amplitude. This recovery can compensate for the decreased myofibrillar Ca response, but may also cause Ca overload after returning to physiological pH.
In future projects, we plan to build a setup for simulated ischemia/reperfusion with inhibition of mitochondrial oxidative phosphorylation, then to study the effects on Ca currents, Ca transients and SR Ca contents, and also to estimate the activity of SR Ca release channel with Ca sparks which can be visualized using laser confocal microscopy. In addtion, we would like to examine the possibility of KBR and drugs protective for mitochondria (e.g. diazoxide) against ischemic/reperfused injuries. Less
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