Ramos-Franco J, Lo C F, Breitwieser G E
Department of Physiology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.
Circ Res. 1993 Apr;72(4):786-94. doi: 10.1161/01.res.72.4.786.
Platelet-activating factor (PAF), a potent signaling lipid implicated as a mediator of pathological responses, has both negative chronotropic and inotropic effects on the heart, although the mechanism(s) involved is not well defined. Because activation of the muscarinic acetylcholine-activated K+ current (IK(ACh)) also produces a negative chronotropic and inotropic response in myocardium, this study examines whether PAF has effects on IK(ACh) in isolated bullfrog atrial myocytes under whole-cell voltage-clamp conditions. We find that 2 microM PAF increases the rate of GTP-gamma-S-mediated IK(ACh) activation (from 0.30 +/- 0.01 min-1 [n = 20] to 0.73 +/- 0.07 min-1 [n = 12], p < 0.005, in the absence of acetylcholine). This effect of 2 microM PAF was blocked by the PAF antagonist CV-3988 (5 microM, 0.33 +/- 0.14 min-1 [n = 12]), suggesting the presence of specific PAF receptors coupled to IK(ACh) activation. Further support for mediation by specific G protein-coupled PAF receptors derives from the inability of PAF to modulate IK(ACh) after maximal activation in the presence of GTP-gamma-S. Eicosatetraynoic acid (ETYA, an inhibitor of 5- and 12-lipoxygenases) did not prevent the PAF-mediated increase in the rate of IK(ACh) activation (10 microM ETYA, 0.28 +/- 0.03 min-1 [n = 7]; 10 microM ETYA plus 2 microM PAF, 0.58 +/- 0.13 min-1 [n = 8]; p < 0.05), suggesting that the observed PAF effect is not mediated by increases in arachidonic acid metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
血小板活化因子（PAF）是一种强效信号脂质，被认为是病理反应的介质，对心脏具有负性变时和变力作用，尽管其涉及的机制尚未明确。由于毒蕈碱型乙酰胆碱激活的钾电流（IK(ACh)）的激活在心肌中也会产生负性变时和变力反应，本研究在全细胞电压钳条件下检测了PAF对分离的牛蛙心房肌细胞中IK(ACh)的影响。我们发现，在无乙酰胆碱的情况下，2微摩尔PAF可提高GTP-γ-S介导的IK(ACh)激活速率（从0.30±0.01分钟-1 [n = 20]提高到0.73±0.07分钟-1 [n = 12]，p < 0.005）。2微摩尔PAF的这种作用被PAF拮抗剂CV-3988（5微摩尔，0.33±0.14分钟-1 [n = 12]）阻断，提示存在与IK(ACh)激活偶联的特异性PAF受体。特异性G蛋白偶联PAF受体介导作用的进一步证据来自于在存在GTP-γ-S的情况下最大激活后PAF无法调节IK(ACh)。二十碳四烯酸（ETYA，5-和12-脂氧合酶抑制剂）不能阻止PAF介导的IK(ACh)激活速率增加（10微摩尔ETYA，0.28±0.03分钟-1 [n = 7]；10微摩尔ETYA加2微摩尔PAF，0.58±0.13分钟-1 [n = 8]；p < 0.05），提示观察到的PAF效应不是由花生四烯酸代谢增加介导的。（摘要截短于25０字）
