Differential Effects of Various Eicosanoids on the Production or Prevention of Arrhythmias in Cultured Neonatal Rat Cardiac Myocytes

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, PGF_2α) 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. PGF_2α 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 PGF_2α and TXA₂ (U 46619). PGE₁ exerted a dose-dependent dual effect on the contraction of the myocytes. At low concentrations (<2 μM), 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 μM), PGE₁ caused cell contractures and chaotic activity. In contrast, the lipoxygenase products [leukotriene (LT) B₄, LTC₄, LTD₄

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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, PGF_3α, 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 cycloxygenase products of AA, whereas those products of EPA are much less or not effective; PGE₁, PGI₂, ETYA and EPA have antiarrhythmic effects.