1995 Fiscal Year Final Research Report Summary
Study on the distinct roles of ET_A and ET_B endothelin receptors in the regulation of the cardiac pacemaker potentials.
| Project/Area Number |
07670130
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
General pharmacology
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| Research Institution | National Institute of Health Sciences |
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Principal Investigator |
ONO Kageyoshi National institute of Health Sciences, Division of Chemical Pharmacology and Phytochemistry, Senior Research Scientist, 生薬部, 主任研究官 (40177259)
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| Project Period (FY) |
1995
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| Keywords | Endothelin / chronotropic effect / pacemaker / heart / sinoatrial node / electrophysiology / receptor |
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| Research Abstract |
I have discovered, in my previous studies, that endothelin-1 (ET-1) produces cardiac inhibition through ET_A endothelin receptors. In order to further analyze the ionic mechanisms for the negative chronotropic effect of ET-1, the target has been moved on to sinoatrial node cell to study electrophysiological effects of ET-1 by using the patch-clamp method. Moreover, physiological role of ET_B receptor in the regulation of heart rate has been investigated.
(1)By using selective antagonists for ET_A and ET_B receptors, it turned out that ET_A and ET_B receptors play distinct roles in regulation of heart rate ; ET_A mediates negative chronotropic response whereas ET_B mediates positive chronotropic response.
(2)Effect of ET-1 on sinoatrial (SA) node cell ; In rabbit SA node, ET-1 (1 nM-) decreased the slope of the pacemaker potential and caused a depolarizing shift of the take-off potential, in a concentration-dependent manner, which resulted in the increase in the cycle-length. This effect was blocked by BQ123 (1 muM), an ET_A receptor-selective antagonist. Analysis with using isolated SA node cell indicated that there are at least two different types of cells which behave differently against ET-1 ; one depolarized and the other hyperpolarized in response to the peptide. Whole-cell clamp analysis showed that in the former cell ET-1 decreased the If current in the presence of isoproterenol, In the latter type of cell, ET-1 strongly activated the I_<K(ACh)> channel. ET-1 strongly decreased the L-type calcium current in both types of cells. These electrophysiological actions of ET-1 on SA nodal cells can explain the strong negative chronotropic effect of the peptide.
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