Influence of a Na+-H+ exchange inhibitor ethylisopropylamiloride, a Na+-Ca2+ exchange inhibitor KB-R7943 and their combination on the increases in contractility and Ca2+ transient induced by angiotensin II in isolated adult rabbit ventricular myocytes
Influence of a Na+-H+ exchange inhibitor ethylisopropylamiloride, a Na+-Ca2+ exchange inhibitor KB-R7943 and their combination on the increases in contractility and Ca2+ transient induced by angiotensin II in isolated adult rabbit ventricular myocytes
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DOI：
10.1007/s002109900123
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发表时间：
1999-11-01
影响因子：
3.6
通讯作者：
Endoh, M
中科院分区：
文献类型：
--
作者：
Fujita, S;Endoh, M
在兔心室肌细胞中，加载indo-1/AM，血管紧张素II（0.1 nM-0.1 µM）产生正性肌力作用，Ca 2+瞬变幅度显著增加。对于给定的细胞缩短的增加，由血管紧张素II诱导的Ca 2+瞬变的增加小于由细胞外Ca 2+浓度（[Ca 2 +]o）或异丙肾上腺素升高诱导的增加，这表明细胞内Ca 2+离子动员的增加和肌原纤维对Ca 2+离子的敏感性都有助于血管紧张素II的正性肌力作用。AT 1受体拮抗剂losartan可抑制血管紧张素II对细胞内钙瞬变和细胞缩短的作用。Na+-H+交换抑制剂EIPA [5-（N-乙基-N-异丙基）阿米洛利]在1和3 µM时不影响Ca 2+瞬变和细胞缩短，但它以浓度依赖性方式抑制血管紧张素II诱导的反应比[Ca 2 +]o升高的反应更有效，表明EIPA对血管紧张素II的作用产生选择性抑制作用。10 µM EIPA可消除血管紧张素II的正性变力作用，但对[Ca 2 +] o升高的变力反应无显著抑制，这一观察结果支持高浓度EIPA对血管紧张素II反应的选择性作用。一种新型的选择性Na+-Ca 2+交换（反向模式）抑制剂KB-R7943，2-[2-[4-（-硝基苄氧基）苯基]乙基]异噻唑烷甲磺酸盐，在0.3和1 μM时，也能比对[Ca 2 +]o升高的反应更有效地抑制对血管紧张素II的反应;然而，在相同的浓度范围内，它能显著抑制Ca 2+瞬变和细胞缩短的幅度。EIPA（3 μM）和KB-R7943（0.3 μM）的组合（每一种都部分减弱血管紧张素-II诱导的反应）消除了血管紧张素-II诱导的正性肌力作用和Ca 2+瞬变增加，对[Ca 2 +]o升高的反应的抑制作用小得多。因此，这些离子交换抑制剂对各自的目标发挥选择性作用。这些选择性抑制剂的作用结果表明，血管紧张素Ⅱ激活AT_（11）受体引起的心肌细胞[Ca ~（2+）] i增加和肌丝Ca ~（2+）增敏作用可能与Na ~+-H ~+交换器的激活和随后Na ~+-Ca ~（2+）交换器活性的调节有关。
In rabbit, ventricular myocytes loaded with indo-1/AM, angiotensin II (0.1 nM–0.1 µM) exerted a positive inotropic effect with a significant increase in the amplitude of Ca2+transients. For a given increase in cell shortening, the increase in Ca2+transients induced by angiotensin II was less than that induced by elevation of extracellular Ca2+concentration ([Ca2+]o) or isoprenaline, an indication that both the increase in mobilization of intracellular Ca2+ions and myofibrillar sensitivity to Ca2+ions contribute to the positive inotropic effect of angiotensin II. The effects of angiotensin II on Ca2+transients and cell shortening were inhibited by the AT1receptor antagonist losartan. A Na+-H+exchange inhibitor EIPA [5-(N-ethyl-N-isopropyl)amiloride] at 1 and 3 µM did not affect the Ca2+transients and cell shortening, but it inhibited the angiotensin-II-induced responses in a concentration-dependent manner more effectively than the responses to elevation of [Ca2+]o, indicating that EIPA elicited a selective inhibitory action on the effects of angiotensin II. The observation that EIPA at 10 µM abolished the positive inotropic effect of angiotensin II without a significant depression of the inotropic response to elevation of [Ca2+]osupports the selective action of EIPA at the high concentration on the response to angiotensin II. A novel selective Na+-Ca2+exchange (reverse mode) inhibitor KB-R7943, 2-[2-[4-(-nitrobenzyloxy)phenyl]ethyl] isothiourea methanesulphonate, at 0.3 and 1 µM inhibited also the responses to angiotensin II more effectively than the response to elevation of [Ca2+]o; however, over the same concentration range it suppressed significantly the amplitude of Ca2+transients and cell shortening. Combination of EIPA (3 µM) and KB-R7943 (0.3 µM), each of which attenuated partially the angiotensin-II-induced responses, abolished the positive inotropic effect and the increase in Ca2+transients induced by angiotensin II with much less depressant effect on the responses to elevation of [Ca2+]o. Thus, these ion exchange inhibitors exerted selective actions on the respective targets. The results with these selective inhibitors indicate that the activation of Na+-H+exchanger and subsequent modulation of the activity of Na+-Ca2+exchanger may be responsible for the increase in [Ca2+]iand the myofilament Ca2+sensitization induced by stimulation of AT1receptors by angiotensin II in rabbit ventricular myocytes.