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STUDIES ON THE DEVELOPMENTAL AND SPECIES DIFFERENCE OF CARDIAC FUNCTION: FUNCTIONAL ROLE OF ENDOCARDIAL ENDOTHELIUM AND THE ANALYSIS OF PHYSIOLOGICAL SPECIFICITY OF MOUSE MYOCARDIA

心脏功能发育及物种差异的研究：心内膜内皮的功能作用及小鼠心肌的生理特异性分析

基本信息

批准号：
13670100
负责人：
SHIGENOBU Koki
金额：
$ 2.18万
依托单位：
Toho University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

Research results are summarized as follows:1) Since the specific nature of the mouse heart, including negative inotropic response to alpha-adrenergic stimulation, has been found to be closely related to Na+, Ca2+ exchange mechanism (NCX), the selectivity of a newly synthesized compound, SEA0400, was examined in detail. As a result, it was found that SEA0400 selectivity inhibits NCX without affecting Na+ currents, Ca2+ currents, and inwardly rectifying and delayed rectifier K+ currents.2) Ach produces positive inotropic response in mouse atria through the release of prostaglandins from endocardial endothelium. Since in mouse heart, the specific action potential configuration lacking plateau component minimizes the Ca2+ influx, the negative inotropic component through the activation of IKACh becomes small, and thus the positive inotropic response to endothelium-derived prostaglandins is considered to become marked.3) Mouse atria showed specific responses to various agents, including 4-aminopyridine, necardipine, or ryanodine, which can be explained by the specific action potential configuration and highly SR-dependent contractile mechanisms in mouse heart.4) Guinea pig hear gained the specific nature similar to mouse heat by treating with cromakalim, dimethylamiloride, and ouabain, which produces action potential shortening by activating ATP-dependent potassium channels, intracellular alkalization by inhibiting the Na+, H+ exchange, and the increase in intracellular Na+ concentration through the inhibition of Na-pump, respectively.

研究结果如下：1)由于小鼠心脏的特异性，包括对α -肾上腺素能刺激的负性肌力反应，已被发现与Na+， Ca2+交换机制（NCX）密切相关，因此对新合成的化合物SEA0400的选择性进行了详细的研究。结果发现，SEA0400选择性抑制NCX，但不影响Na+电流、Ca2+电流以及内向整流和延迟整流K+电流。2)乙酰胆碱通过心内膜内皮释放前列腺素在小鼠心房产生正性肌力反应。由于在小鼠心脏中，缺乏平台成分的特定动作电位配置使Ca2+内流最小化，通过IKACh激活的负性肌力成分变得很小，因此对内皮源性前列腺素的正性肌力反应被认为是显著的。3)小鼠心房对4-氨基吡啶、necardipine、ryanodine等多种药物均有特异性反应，这可能与小鼠心脏的特异性动作电位配置和高度依赖sr的收缩机制有关。4)豚鼠听觉通过克罗玛卡林、二甲胺和瓦巴因处理获得了类似小鼠热的特异性，分别通过激活atp依赖性钾通道产生动作电位缩短，通过抑制Na+、H+交换产生细胞内碱化，通过抑制Na-泵增加细胞内Na+浓度。