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Objectives: Levosimendan is a calcium sensitizer that is used as positive inotropic drug in acute decompensated heart failure. An increased incidence of atrial fibrillation after levosimendan-treatment was observed in clinical and experimental studies. Due to the limited range of antiarrhythmic drugs, the aim of the present study was to assess potential antiarrhythmic effects of ranolazine in levosimendan-pretreated isolated rabbit hearts. Methods: Twelve rabbit hearts were excised and retrogradely perfused employing the Langendorff setup. Left and right atrial catheters were used to record monophasic action potentials and to obtain cycle length-dependent atrial action potential durations (aAPD₉₀) and effective refractory periods (aERP). After obtaining baseline data, 0.5 µmol/L levosimendan was infused. Subsequently, 10 µmol/L ranolazine was administered. Results: Infusion of levosimendan led to a reduction of aAPD₉₀ (–9 ms, p < 0.05) and aERP (–13 ms, p < 0.05). Additional treatment with ranolazine prolonged aAPD₉₀ (+23 ms, p < 0.01) and aERP (+30 ms, p < 0.05). Under baseline conditions, a predefined pacing protocol induced 77 episodes of atrial fibrillation. Infusion of levosimendan enhanced the vulnerability to atrial fibrillation (132 episodes, p = 0.14). Further treatment with ranolazine had a significant antiarrhythmic effect (61 episodes, p < 0.05). Conclusions: In this study, ranolazine seems to prevent atrial fibrillation in levosimendan-pretreated hearts. Underlying mechanism is a prolongation of atrial repolarization and aERP.

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Morphine had a decreasing effect on the respiratory burst of PCM only in concentrations that the human body reaches where renal clearance is reduced. In this situation the metabolites of morphine accumulate more than morphine itself and seem to have a similar effect. The weakening of phagocytosis might possibly be a direct effect of morphine and its metabolites. These investigations suggest that this phenomenon may be receptor dependent: the effect could be antagonized by naloxone, but naloxone itself caused a depression in high concentrations. In comparison the nonspecific stabilization of the membranes showed no such effect.

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