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

Backround: Neuroprotective 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. Methods: Transient cerebral ischaemia/hypoxia was induced in 30 male Wistar rats by bilateral common carotid artery clamping for 15 min and concomitant ventilation with 6% O-2 during general anaesthesia with urethane. After 10 min of global ischaemia/hypoxia, the rats were treated with an i.v. bolus of 24 mu g kg(-1) levosimendan followed by a continuous infusion of 0.2 mu g 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. Results: Levosimendan 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 mu mol.L-1) were higher in the levosimendan group. The increased expression of IL-6, IL-1 beta TNFa and ICAM-1, extend of cerebral edema and cerebral autoregulation was not influenced by levosimendan. Conclusion: Although 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.