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Effect of bradykinin on excitation-contraction coupling in excised human atrial muscles

缓激肽对离体心房肌兴奋-收缩耦合的影响

基本信息

批准号：
11670717
负责人：
IMANISHI Sunao
金额：
$ 2.18万
依托单位：
Kanazawa Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

The myocardium has a local kallikrein-kinin system including bradykinin(BK)-B_2 receptors, and the level of BK is further increased by angiotensin-converting enzyme (ACE) inhibitor. It is known that ACE-inhibitor may provide cardioprotection by inhibiting the degradation of BK and/or by potentiating the pharmacological actions of BK. However, direct effect of BK on myocardial cells is as yet equivocal. As a pilot study, we have investigated the direct actions of BK (10^<-7>〜10^<-5> M) on action potentials, whole-eell membrane currents, and contraction in cardiac muscles and enzymatically-isolated single cells of guinea-pig atria and ventricle, using conventional microelectrode technique, patch clamp method and strain gauge.BK was, under physiologically-normal condition, shown to produce minimal or no changes in action potentials and membrane currents of guinea-pig ventricular myocytes. However, BK markedly shortened action potential duration prolonged by pretreatment with forskol in in … More both atrial and ventricular myocytes. These effects of BK were more pronounced in atrial myocytes as compared with ventricular ones, suggesting that atrial cell has higher density of BK-B_2 receptor than ventricular cell.It is assumed that BK exerts its more potent inhibitory action when the protein kinase A )PKA) is fully activated by an application of forskolin or β-receptor stimulation, but BK may have little or no effect under condition without PKA activation )"accentuated antagonism"). The mode of action of BK appears to be quite similar to that of acetylcholine. It is quite plausible that BK may reduce L-type Ca current )ICa) in cells where it has already been raised by forskoline or β-stimulants, though it does not affect the basal level of ICa in unstimulated cells. On the other hand, in regard to the effect of BK on the contraction in ventricular papillary muscle, we could not obtain the specified effects of BK in our experiments. Individual inotropic responses to BK application were quite variable, and BK showed dual action from time to time. At present, we have no explanation of the findings.Further studies into these problems are needed because the possible mechanisms underlying various BK's actions remain to be determined. Less

心肌局部存在包括缓激肽（BK）-B_2受体在内的激肽释放酶-激肽系统，血管紧张素转换酶（ACE）抑制剂可使BK水平进一步升高。ACE抑制剂可通过抑制BK的降解和/或增强BK的药理作用来提供心肌保护作用，但BK对心肌细胞的直接作用尚不明确。作为初步研究，我们<-7><-5>用常规微电极技术、膜片钳技术和应变片技术，观察了BK（10 μ M ~ 10 μ M）对豚鼠心室肌和心房肌单细胞动作电位、全细胞膜电流和收缩的直接作用。然而，BK可明显缩短Forskol预处理延长的动作电位时程。 ...更多信息心房和心室肌细胞。BK的这种抑制作用在心房肌细胞比心室肌细胞更明显，提示心房肌细胞BK-B_2受体密度高于心室肌细胞，推测BK在蛋白激酶A（PKA）被Forskolin或β-受体刺激完全激活时发挥更强的抑制作用。但BK在没有PKA活化的条件下可能几乎没有或没有作用（“增强的拮抗作用”）。BK的作用方式似乎与乙酰胆碱非常相似。BK可能会降低已经被毛喉素或β兴奋剂升高的细胞中的L型Ca电流（伊卡），这是非常合理的，尽管它不会影响未刺激细胞中伊卡的基础水平。另一方面，关于BK对心室乳头肌收缩的影响，我们在实验中未能获得BK的特定作用。个体对BK应用的变力性反应差异很大，BK不时表现出双重作用。目前，我们还没有对这些发现的解释，这些问题还需要进一步的研究，因为BK的各种作用的可能机制还有待确定。少