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

PURPOSE: To study the effects of pretreatment with levosimendan (LEVO, a Ca(2+)-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 (FiO(2) ~0.3) and subjected to the following interventions: no pretreatment, LEVO pretreatment, GLIB pretreatment, or combined LEVO + GLIB pretreatment, each followed by hypoxic hypoxemia (FiO(2) ~0.1). We measured cardiac output (CO, ultrasonic flow probes), oxygen consumption (VO(2), indirect calorimetry), and gastromucosal microvascular hemoglobin oxygenation (μHbO(2), 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 VO(2) nor with markers of aggravated anaerobiosis (pH, BE, lactate). In addition, LEVO pretreatment did not further compromise gastromucosal μHbO(2) 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 VO(2), 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.