钙离子敏化剂EMD 53998可拮抗2,3-丁二酮单肟对去垢剂处理的心肌纤维的作用。

The Ca2+ sensitizer EMD 53998 antagonizes the effect of 2,3-butanedione monoxime on skinned cardiac muscle fibres.

作者信息

Barth Z, Strauss J D, Dohet C, Ruegg J C

机构信息

Department of Physiology II, University of Heidelberg, Im Neuenheimer Feld 326, Germany.

出版信息

Eur J Pharmacol. 1996 Feb 5;296(3):285-9. doi: 10.1016/0014-2999(95)00819-5.

DOI:10.1016/0014-2999(95)00819-5

PMID:8904080

Abstract

The effects of 2,3-butanedione monoxime (BDM) and 5-[1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-6-quinolyl]-6-me thy l-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (EMD 53998) on cardiac muscle were studied in skinned muscle fibres from the right ventricle of the porcine heart. BDM decreases the Ca2+ sensitivity (pCa50 for 50% activation) and it exerts a dose-dependent inhibitory effect on force in troponin I (TnI)-depleted (unregulated) cardiac skinned muscle fibres (IC50 approximately 20 mM) thereby mimicking the effect of the TnI inhibitory peptide (cTnI 137-148, corresponding to the cardiac TnI inhibitory region) and that of inorganic phosphate (Pi). This inhibitory action can be antagonized by the calcium-sensitizing cardiotonic thiadiazinone derivative EMD 53998 that increases the IC50 to about 30 mM. In skinned fibres, BDM (10 mM) also increased the ratio of ATPase activity to isometric force (tension cost), whereas EMD 53998 (20 mu M) decreased it. We propose that BDM antagonizes EMD 53998 because both compounds affect the Pi release step of the crossbridge cycle in an antagonistic manner.

摘要

在猪心脏右心室的去表皮肌纤维中研究了2,3-丁二酮单肟（BDM）和5-[1-(3,4-二甲氧基苯甲酰基)-1,2,3,4-四氢-6-喹啉基]-6-甲基-3,6-二氢-2H-1,3,4-噻二嗪-2-酮（EMD 53998）对心肌的影响。BDM降低Ca2+敏感性（50%激活时的pCa50），并对肌钙蛋白I（TnI）缺失（无调节）的心脏去表皮肌纤维的力量产生剂量依赖性抑制作用（IC50约为20 mM），从而模拟TnI抑制肽（cTnI 137-148，对应于心脏TnI抑制区域）和无机磷酸盐（Pi）的作用。这种抑制作用可被钙敏化强心噻二嗪酮衍生物EMD 53998拮抗，后者将IC50提高到约30 mM。在去表皮纤维中，BDM（10 mM）还增加了ATP酶活性与等长力的比值（张力成本），而EMD 53998（20 μM）则降低了该比值。我们提出BDM拮抗EMD 53998，因为这两种化合物以拮抗方式影响横桥循环的Pi释放步骤。