The effects of levosimendan on brain metabolism during initial recovery from global transient ischaemia/hypoxia

Abstract

BackroundNeuroprotective strategies after cardiopulmonary resuscitation are currently the focus of experimental and clinical research. Levosimendan has been proposed as a promising drug candidate because of its cardioprotective properties, improved haemodynamic effects in vivo and reduced traumatic brain injury in vitro. The effects of levosimendan on brain metabolism during and after ischaemia/hypoxia are unknown.MethodsTransient cerebral ischaemia/hypoxia was induced in 30 male Wistar rats by bilateral common carotid artery clamping for 15 min and concomitant ventilation with 6% O2 during general anaesthesia with urethane. After 10 min of global ischaemia/hypoxia, the rats were treated with an i.v. bolus of 24 μg kg-1 levosimendan followed by a continuous infusion of 0.2 μg kg-1 min-1. The changes in the energy-related metabolites lactate, the lactate/pyruvate ratio, glucose and glutamate were monitored by microdialysis. In addition, the effects on global haemodynamics, cerebral perfusion and autoregulation, oedema and expression of proinflammatory genes in the neocortex were assessed.ResultsLevosimendan reduced blood pressure during initial reperfusion (72 ± 14 vs. 109 ± 2 mmHg, p = 0.03) and delayed flow maximum by 5 minutes (p = 0.002). Whereas no effects on time course of lactate, glucose, pyruvate and glutamate concentrations in the dialysate could be observed, the lactate/pyruvate ratio during initial reperfusion (144 ± 31 vs. 77 ± 8, p = 0.017) and the glutamate release during 90 minutes of reperfusion (75 ± 19 vs. 24 ± 28 μmol·L-1) were higher in the levosimendan group. The increased expression of IL-6, IL-1ß TNFα and ICAM-1, extend of cerebral edema and cerebral autoregulation was not influenced by levosimendan.ConclusionAlthough levosimendan has neuroprotective actions in vitro and on the spinal cord in vivo and has been shown to cross the blood–brain barrier, the present results showed that levosimendan did not reduce the initial neuronal injury after transient ischaemia/hypoxia.

Effects of Levosimendan on Hemodynamics, Local Cerebral Blood Flow, Neuronal Injury, and Neuroinflammation After Asphyctic Cardiac Arrest in Rats

“…However, findings in dogs indicated that levosimendan does not substantially penetrate the bloodbrain barrier in the healthy brain (48). A recent study using a bilateral common artery clamping and hypoxic ventilation for induction of cerebral ischemia indicated that only a low brain tissue concentration of levosimendan compared to serum concentrations can be achieved (49). No effects of levosimendan treatment on time course of lactate, glucose, pyruvate, and glutamate concentrations after transient ischemia were shown.…”

Neurovascular Regulation in the Ischemic Brain

“…Two recent studies examined the influence of forebrain hypoxia ischemia on autoregulation in the cerebral circulation (64,78). Acute impairments of autoregulation were reported within 60-90 min of reperfusion, suggesting a similar early disruption of cerebral autoregulation with this model of ischemia.…”

Levosimendan limits reperfusion injury in a rat middle cerebral artery occlusion (MCAO) model

“…In fact, levosimendan has been shown to reduce cell death and inflammatory responses and improve function after transient ischemia of the spinal cord in rabbits [7,8]. While a dose-dependent protective effect in an in vitro model of traumatic brain injury could be demonstrated [9], levosimendan failed to improve brain metabolism or reduce glutamate release, inflammation and dysfunction of autoregulation in the initial phase after experimental global ischemic/hypoxic cerebral injury [10]. Its effect on focal transient ischemia has not been investigated in vivo in the brain as it has been in the heart [11].…”