Effects on atrial repolarization of the interaction between K+ channel blockers and muscarinic receptor stimulation.
Effects on atrial repolarization of the interaction between K+ channel blockers and muscarinic receptor stimulation.
复制标题
K 通道阻滞剂和毒蕈碱受体刺激之间的相互作用对心房复极的影响。
DOI：
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发表时间：
1995
影响因子：
3.5
通讯作者：
P. Schwartz
中科院分区：
文献类型：
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作者：
A. Zaza;G. Malfatto;P. Schwartz
我们在豚鼠心房中测试了氧化震颤素（Oxo）的毒蕈碱刺激如何改变两种iK阻断剂对动作电位时程（APD）的影响：d-索他洛尔（5 μ M）和安巴西利特（1 μ M）。d-索他洛尔（+34.8 +/- 2.9%）和ambasilide（+54.2 +/- 5.5%）延长了APD。同时用0.5 μ M的Oxo进行灌流可显著缩短APD;在存在d-索他洛尔的情况下，该效应大于存在ambasilide的情况（-69 +/- 2% vs. -37.4 +/- 5%; P <0.05）。此外，ambasilide，而不是d-索他洛尔，拮抗APD缩短由Oxo。在离体兔心房和窦房肌细胞的膜片钳实验中研究了两种药物之间这种差异的基础。除了阻断iK（半数有效浓度：EC 50 = 2 μ M）外，安巴西利几乎完全抑制iKACh（10 μ M时为-86 +/-2%; EC 50 = 1.6 μ M），d-索他洛尔对iKACh的影响最小。Ambasilide 2 μ M使50% iKACh活化所需的乙酰胆碱（ACh）增加10倍，并使最大活化的iKACh减少18.8 +/-6.3%。当iKACh通过受体非依赖性机制被激活时，10 μ M的ambasilide仅将该电流降低了其对照值的18.7 +/- 1.4%。此外，ambasilide，虽然不影响电流i（f），在基础条件下，逆转其抑制乙酰胆碱。因此，1）K+通道阻滞剂对心房APD的作用可能被ACh减弱;安巴西利特的作用对ACh的敏感性低于d-索他洛尔; 2）安巴西利特（而非d-索他洛尔）抑制iKACh;这可能主要（但不完全）通过毒蕈碱受体拮抗作用发生。iKACh的抑制可能解释了尽管存在毒蕈碱刺激，但该药物对心房APD的影响持续存在。
We have tested, in guinea pig atria, how muscarinic stimulation by oxotremorine (Oxo) modifies the effects on action potential duration (APD) of two iK blockers: d-sotalol (5 microM) and ambasilide (1 microM). APD was prolonged by d-sotalol (+34.8 +/- 2.9%) and ambasilide (+54.2 +/- 5.5%). Simultaneous superfusion with Oxo 0.5 microM markedly shortened APD; this effect was larger in the presence of d-sotalol than in the presence of ambasilide (-69 +/- 2% vs. -37.4 +/- 5%; P < .05). Moreover ambasilide, but not d-sotalol, antagonized APD shortening induced by Oxo. The basis for such a difference between the two drugs was studied in patch-clamp experiments on isolated rabbit atrial and sinoatrial myocytes. Besides blocking iK (half-effective concentration: EC50 = 2 microM), ambasilide almost completely inhibited iKACh (-86 +/- 2% at 10 microM; EC50 = 1.6 microM), which was minimally affected by d-sotalol. Ambasilide 2 microM increased 10-fold the acetylcholine (ACh) required for 50% iKACh activation, and reduced maximally activated iKACh by 18.8 +/- 6.3%. When iKACh was activated through a receptor-independent mechanism, 10 microM ambasilide reduced this current by only 18.7 +/- 1.4% of its control value. Moreover, ambasilide, although not affecting the current i(f), in basal conditions, reversed its inhibition by ACh. Thus, 1) the effect of K+ channel blockers on atrial APD may be blunted by ACh; ambasilide effects are less sensitive to ACh than those of d-sotalol; 2) ambasilide, but not d-sotalol, inhibits iKACh; this probably occurs largely, although not exclusively, through muscarinic receptor antagonism. Inhibition of iKACh may account for the persistence of the effects of this drug on atrial APD despite muscarinic stimulation.