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.

Fig. 1

Gastric mucosal microcirculatory hemoglobin oxygenation (μHbO₂). Gastromucosal μHbO₂ during normoxia (FiO₂ ~0.3, thin outlined bars) and the two hypoxia episodes (FiO₂ ~ 0.1, bold outlined bars) of the two experimental groups I (left bar per condition) and II (right bar per condition). Levosimendan was not given in group I, thus condition LEVO in group I is not determined (n.d.). Filling patterns: gray no pretreatment, downward stripes levosimendan (LEVO) pretreatment, upward stripes glibenclamide (GLIB) pretreatment, hatches levosimendan + glibenclamide pretreatment. Recovery-30 and recovery-60 are measurement points at 30 and 60 min of normoxic recovery. Mean ± SEM for n = 6 per group. ^aNo difference between hypoxia episodes, ^bsignificant difference within one group’s hypoxia episodes, ^csignificant difference between the two groups’ hypoxia episodes, * significant drug effects of LEVO and ^$ GLIB

Fig. 2

Cardiac output. Cardiac output during normoxia (FiO₂ ~0.3, thin outlined bars) and the two hypoxia episodes (FiO₂ ~0.1, bold outlined bars) of the two experimental groups I (left bar per condition) and II (right bar per condition). Levosimendan was not given in group I, thus condition LEVO in group I is not determined (n.d.). Filling patterns: gray no pretreatment, downward stripes levosimendan (LEVO) pretreatment, upward stripes glibenclamide (GLIB) pretreatment, hatches levosimendan + glibenclamide pretreatment. Recovery-30 and recovery-60 are measurement points at 30 and 60 min of normoxic recovery. Mean ± SEM for n = 6 per group. ^aNo difference between hypoxia episodes, ^bsignificant difference within one group’s hypoxia episodes, ^csignificant difference between the two groups’ hypoxia episodes, *significant drug effects of LEVO and ^$GLIB

Fig. 3

Pressure-curve-derived contractility, +dP/dt _max. Resulting +dP/dt _max during normoxia (FiO₂ ~0.3, thin outlined bars) and the two hypoxia episodes (FiO₂ ~0.1, bold outlined bars) of the two experimental groups I (left bar per condition) and II (right bar per condition). Levosimendan was not given in group I, thus condition LEVO in group I is not determined (n.d.). Filling patterns: gray no pretreatment, downward stripes levosimendan (LEVO) pretreatment, upward stripes glibenclamide (GLIB) pretreatment, hatches levosimendan + glibenclamide pretreatment. Recovery-30 and recovery-60 are measurement points at 30 and 60 min of normoxic recovery. Mean ± SEM for n = 6 per group. ^aNo difference between hypoxia episodes, ^bsignificant difference within one group’s hypoxia episodes, ^csignificant difference between the two groups’ hypoxia episodes, *significant drug effects of LEVO and ^$GLIB