| Budget Amount *help |
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1988: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1987: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Research Abstract |
In order to elucidate the ionic mechanisms of delayed afterdepolarizations, action potential and voltage clamp studies were conducted in canine Purkinje fibers and rabbit atrioventricular node. A transient inward durrent, which was responisble for delayed afterdepolarizations, was obtained on repolarization from various test potentials to -40 - -60 mV under superfusions with 1 m acetylstrophantidin, 0.2 - 1 mM K^+, or 10 m. Ca^<2+> containing Tyrode's solutions, and inhibited by 0.1 mM Cd^<2+> (a Ca^<2+> channel blocker), 5 g/ml mexiletine (a Na^+ channel blocker), or 10 mM caffeine (a Ca^<2+> uptake blocker to sarcoplasmic reticulum). These results suggest that the transient inward current is mediated by a cyclic increase in intracellular Ca^<2+> concentration, and caused by a Ca^<2+> - induced activation of the nonspecific cation channel or a Ca^<2+> -induced activation of Na^+ -Ca^<2+> exchange system. To assess which mechanism is involved, Na^+ concentration in the Tyrode's solution was decreased to 50% of the control (replaced with either Li^+ or sucrose) since extracellular Na^+ does not affect the conductance of the nonspecific cation channel. A transient inward current induced by 0.5 mM K^+ tyrode's solution was then either decreased or inhibited by low Na^+. Next, the effect of 50 M La^<3+> Na^+ -Ca^<2+> exchange blocker) was studied on the transient inward current induced by 092 mM K^+ Tyrode in the presence of 1 mM Cd^<2+>. The transient inward current was again decreased or inhibited by La^<3+>. In conclusion, the results suggest that the transient inward current is induced by an activation of Na^+ -Ca^<2+> exchange system due to an increase in the intracellular Ca^<2+> concentration, and that a Ca^<2+> or a Na^+ channel blocker inhibits the transient inward current by suppressing the Na^+ -Ca^<2+> exchange system as these blockers reduce the intracellular Ca^<2+> or Na^+ overloading by inhibiting the transmembrane influxes of these ions, respectively.
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