Li Y, Kang J X, Leaf A
Department of Medicine, Massachusetts General Hospital, Charlestown 02129, USA.
Prostaglandins. 1997 Aug;54(2):511-30. doi: 10.1016/s0090-6980(97)00122-6.
To identify the arrhythmogenic and the antiarrhythmic eicosanoids, cultured, spontaneously beating, neonatal rat cardiac myocytes were used to examine the effects of various eicosanoids added to the medium superfusing the cells at different concentrations on the contraction of the myocytes. Superfusion of the myocytes with the prostaglandins (PGD2, PGE2, PGF2 alpha) or the thromboxane (TXA2)-mimetic, U 46619, induced reversible tacharrhythmias characterized by an increased beating rate, chaotic activity and contractures. These effects are concentration-dependent. PGF2 alpha and U 46619 were much more potent than PGD2 or PGE2 in the production of tachyarrhythmias. Prostacyclin (PGI2) induced a marked reduction in the contraction rate of the cells with a slight increase in the amplitude of the contractions and showed a protective effect against the arrhythmias induced by PGF2 alpha and TXA2 (U 46619). PGE1 exerted a dose-dependent dual effect on the contraction of the myocytes. At low concentrations (< 2 microM), PGE1 reduced the contraction rate of the cells with an increase in the amplitude of the contractions and effectively terminated the tachyarrhythmias induced by arrhythmogenic agents, such as isoproterenol, ouabain and U 46619. At higher concentrations (> 5 microM), PGE1 caused cell contractures and chaotic activity. In contrast, the lipoxygenase products [leukotriene (LT) B4, LTC4, LTD4 & LTE4] of arachidonic acid (AA) had no significant effect on the myocyte contractions. The eicosanoids derived from eicosapentaenoic acid (EPA), including both the cyclooxygenase products (PGD3, PGE3, PGF3 alpha, TXB3) showed lesser effects on the contraction of the myocytes. The lipoxygenase products (LTB5, LTC5, LTD5 & LTE5), as with the AA metabolites showed little effect on the contraction of cardiac myocytes. The arrhythmias induced by the arrhythmogenic prostaglandins and thromboxane A2 could be suppressed by the nonmetabolizable AA analog eicosatetraynoic acid (ETYA) or free AA and EPA, indicating a distinction in the effect on cardiac arrhythmia between the precursor fatty acids (AA & EPA) themselves and their metabolites. In conclusion, the major arrhythmogenic eicosanoids are the cyclooxygenase products of AA, whereas those products of EPA are much less or not effective; PGE1, PGI2, ETYA and EPA have antiarrhythmic effects.
为了鉴别致心律失常和抗心律失常的类二十烷酸，采用培养的、自发搏动的新生大鼠心肌细胞，以检测添加到灌注细胞的培养基中不同浓度的各种类二十烷酸对心肌细胞收缩的影响。用前列腺素（PGD2、PGE2、PGF2α）或血栓素（TXA2）类似物U 46619灌注心肌细胞，可诱发可逆性快速心律失常，其特征为心率加快、活动紊乱和挛缩。这些效应呈浓度依赖性。PGF2α和U 46619在诱发快速心律失常方面比PGD2或PGE2更有效。前列环素（PGI2）可使细胞收缩率显著降低，收缩幅度略有增加，并对PGF2α和TXA2（U 46619）诱发的心律失常具有保护作用。PGE1对心肌细胞的收缩产生剂量依赖性的双重作用。在低浓度（<2μM）时，PGE1可降低细胞收缩率，同时增加收缩幅度，并有效终止由致心律失常药物如异丙肾上腺素、哇巴因和U 46619诱发的快速心律失常。在高浓度（>5μM）时，PGE1可导致细胞挛缩和活动紊乱。相比之下，花生四烯酸（AA）的脂氧合酶产物[白三烯（LT）B4、LTC4、LTD4和LTE4]对心肌细胞收缩无显著影响。二十碳五烯酸（EPA）衍生的类二十烷酸，包括环氧化酶产物（PGD3、PGE3、PGF3α、TXB3）对心肌细胞收缩的影响较小。脂氧合酶产物（LTB5、LTC5、LTD5和LTE5），与AA代谢产物一样，对心肌细胞收缩几乎没有影响。由致心律失常的前列腺素和血栓素A2诱发的心律失常可被不可代谢的AA类似物二十碳四烯酸（ETYA）或游离AA和EPA抑制，这表明前体脂肪酸（AA和EPA）本身及其代谢产物对心脏心律失常的影响存在差异。总之，主要的致心律失常类二十烷酸是AA的环氧化酶产物，而EPA的那些产物作用小得多或无效；PGE1、PGI2、ETYA和EPA具有抗心律失常作用。
