新型“细胞内钙抑制剂”2-氨基异喹啉-1,3（2H，4H）-二酮的血管舒张作用模式

The mode of vasorelaxant action of 2-aminoisoquinoline, 1.3 (2H.4H)-dione, a novel 'intracellular calcium inhibitor'.

作者信息

Hester R K, Satake N, Shibata S, Ueda S, Yamahara J

出版信息

Br J Pharmacol. 1986 Feb;87(2):387-93. doi: 10.1111/j.1476-5381.1986.tb10828.x.

DOI:10.1111/j.1476-5381.1986.tb10828.x

PMID:3082401

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1916548/

Abstract

In rabbit aorta, pretreatment with 2-aminoisoquinoline, 1.3 (2H.4H)-dione (AQ, 10(-5) M and 10(-4) M) shifted the concentration-response relationship to noradrenaline (NA, 10(-9) M to 10(-4) M) in a parallel manner whereas the agent (10(-4) M) failed to affect the response to potassium and only slightly depressed Ca2+-induced contractions in a Ca2+-free medium in the presence of K+ (40 mM). Ca2+-entry blockers such as nifedipine and diltiazem (10(-6) M and 10(-5) M) had very weak or no apparent effects on the response to NA but markedly attenuated or abolished the K+- and Ca2+-induced contractions. Following incubation of tissues for 15 min in a Ca2+-free medium with low EGTA (0.01 mM) and methoxyverapamil (D600, 10(-5) M), NA (3 X 10(-7) M) caused a phasic (transient) contraction and the subsequent application of Ca2+ (2mM) resulted in a tonic contraction. This NA-induced, Ca2+-dependent, D600-insensitive contraction was inhibited by AQ (10(-5) M and 10(-4) M) in a concentration-dependent manner. This suggests that the inhibitory action of AQ may be related to Ca2+ entry through specific receptor activated pathways. Following incubation of tissues for 30 min in a Ca2+-free medium with high EGTA (2.0 mM), NA (10(-5) M) caused a contraction of rabbit aorta which is dependent upon release of intracellular Ca2+, but the response was 50% to 60% less than that in a normal medium. This contraction was inhibited by AQ (10(-5) M and 10(-4) M) and nitroglycerin (10(-5) M) but not by nifedipine or diltiazem. The inhibitory action of combined treatment with AQ and nitroglycerin (10-5 M) on the response to NA was not different from that of either agent alone. 5 These results suggest that AQ may have inhibitory actions on the release of intracellular Ca2+ and also on Ca2+-entry through D600-insensitive, receptor-activated Ca2+ pathways in rabbit aorta.

摘要

在兔主动脉中，用2-氨基异喹啉-1,3(2H,4H)-二酮（AQ，10⁻⁵ M和10⁻⁴ M）预处理可使去甲肾上腺素（NA，10⁻⁹ M至10⁻⁴ M）的浓度-反应关系呈平行移动，而该药物（10⁻⁴ M）对钾离子反应无影响，且在存在钾离子（40 mM）的无钙培养基中仅轻微抑制钙离子诱导的收缩。钙离子通道阻滞剂如硝苯地平和地尔硫䓬（10⁻⁶ M和10⁻⁵ M）对NA反应的影响非常微弱或无明显作用，但显著减弱或消除了钾离子和钙离子诱导的收缩。在含低EGTA（0.01 mM）和甲氧基维拉帕米（D600，10⁻⁵ M）的无钙培养基中孵育组织15分钟后，NA（3×10⁻⁷ M）引起阶段性（短暂性）收缩，随后施加钙离子（2 mM）导致强直性收缩。这种NA诱导的、钙离子依赖性的、对D600不敏感的收缩被AQ（10⁻⁵ M和10⁻⁴ M）以浓度依赖性方式抑制。这表明AQ的抑制作用可能与通过特定受体激活途径的钙离子内流有关。在含高EGTA（2.0 mM）的无钙培养基中孵育组织30分钟后，NA（10⁻⁵ M）引起兔主动脉收缩，该收缩依赖于细胞内钙离子的释放，但反应比在正常培养基中少50%至60%。这种收缩被AQ（10⁻⁵ M和10⁻⁴ M）和硝酸甘油（10⁻⁵ M）抑制，但不被硝苯地平或地尔硫䓬抑制。AQ与硝酸甘油（10⁻⁵ M）联合处理对NA反应的抑制作用与单独使用任何一种药物的作用无差异。这些结果表明，AQ可能对兔主动脉中细胞内钙离子的释放以及通过对D600不敏感的受体激活钙离子途径的钙离子内流具有抑制作用。