The effects of levosimendan and glibenclamide on circulatory and metabolic variables in a canine model of acute hypoxia

Abstract

Purpose To study the effects of pretreatment with levosimendan (LEVO, a Ca²⁺-sensitizer and K ⁺_ATP channel opener) and/or the K ⁺_ATP channel antagonist glibenclamide (GLIB) on systemic hemodynamics, metabolism, and regional gastromucosal oxygenation during hypoxic hypoxemia. Methods Chronically instrumented, healthy dogs (24–32 kg, n = 6 per group, randomized cross-over design) were repeatedly sedated, mechanically ventilated (FiO₂ ~0.3) and subjected to the following interventions: no pretreatment, LEVO pretreatment, GLIB pretreatment, or combined LEVO + GLIB pretreatment, each followed by hypoxic hypoxemia (FiO₂ ~0.1). We measured cardiac output (CO, ultrasonic flow probes), oxygen consumption (VO₂, indirect calorimetry), and gastromucosal microvascular hemoglobin oxygenation (μHbO₂, spectrophotometry). Statistics: data are presented as mean ± SEM and compared by one-way ANOVA (direct drug effects within group) and two-way ANOVA (between all hypoxic conditions) both with Bonferroni corrections; p < 0.05. Results In LEVO-pretreated hypoxemia, CO was significantly higher compared to unpretreated hypoxemia. The increased CO was neither associated with an increased VO₂ nor with markers of aggravated anaerobiosis (pH, BE, lactate). In addition, LEVO pretreatment did not further compromise gastromucosal μHbO₂ in hypoxemia. After combined LEVO + GLIB pretreatment, systemic effects of GLIB were apparent, however, CO was significantly higher than during unpretreated and GLIB-pretreated hypoxemia, but equal to LEVO-pretreated hypoxemia, indicating that GLIB did not prevent the increased CO in LEVO-pretreated hypoxia. Conclusions LEVO pretreatment resulted in improved systemic circulation (CO) during hypoxemia without fueling systemic VO₂, without aggravating systemic anaerobiosis markers, and without further compromising microvascular gastromucosal oxygenation. Thus, LEVO pretreatment may be an option to support the systemic circulation during hypoxia.