1998 Fiscal Year Final Research Report Summary
EFFECTS OF CARDIAC DRUGS ON SODIUM-CALCIUM EXCHANGER
| Project/Area Number |
09670098
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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 | FUKUSHIMA MEDICAL UNIVERSITY |
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Principal Investigator |
KIMURA Junko FUKUSHIMA MEDICAL UNIVERSITY, 医学部, 教授 (10186322)
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| Project Period (FY) |
1997 – 1998
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| Keywords | SODIUM-CALCIUM EXCHANGE CURRENT / WHOLE-CELL PATCH CLAMP / GUINEA PIG / INHIBITORS / TRANSPORTER / CALCIUM / SODIUM / ANTIARRHYTHMIC DRUG / DIABETES / TROGLITAZONE |
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| Research Abstract |
(1) KB-R7943 is a drug we first reported to inhibit Na-Ca exchange current (iNCX) with ICィイD250ィエD2 0.3 μM for outward iNCX and with 17μM for inward iNCX when one directional iNCX flows. However, under an experimental condition where bi-directional iNCX flows. The drug inhibits both outward and inward iNCX equipotently. This result can be explained by different conformation between the binding forms for external Na and Ca.
(2) A new cardioprotective drug, JTV-519 inhibited Na-, Ca-, and inwardly rectifying K-currents in guinea pig cardiac ventricular cells. The block of Na current, was voltage- and use-dependent and was similar to quinidine rather than to lidocaine. ICィイD250ィエD2 for Na-current was 2 μM at -90 mV and 1.2 μM at -60 mV. The drug shortened the plateau of the action potential.
(3) Butanedione monoxime (BDM) inhibited iNCX in guinea pig ventricular cells. ICィイD250ィエD2 value was 2.4 mM. A similar drug, pralidoxime also inhibited iNCX, indicating that dephosphorylation of the exchanger may be a reason. We are currently investigating mutated NCX for the mechanism of the drug action.
(4) Class III antiarrhythmic drug, amiodarone inhibits iNCX. ICィイD250ィエD2 was 3 μM. Trypsin in the pipette solution diminished the inhibitory effect of amiodarone, indicating that the drug affects internal side of the exchanger.
(5) Anti-diabetic drug, troglitazone inhibited L-type Ca current in guinea pig ventricular cells. The effect was voltage-dependent. ICィイD250ィエD2 values were 0.8 μM at a holding potential of -50 mV and larger than 10 μM at -80 mV.
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