Beneficial effects of levosimendan on cerebral vasospasm induced by subarachnoid haemorrhage: an experimental study.
ABSTRACT The aim of this study was to investigate the ability of levosimendan to prevent cerebral vasospasm in a rabbit model of subarachnoid haemorrhage (SAH).
Eighteen New Zealand white rabbits were allocated into three groups randomly. SAH was induced by injecting autologous blood into the cisterna magna. (Group 1 = control:sham surgery group, Group 2 = SAH alone group, Group 3 = SAH plus levosimendan group). Histopathological examination was performed on day 3 as described. Intravenous levosimendan dose (initially 12 microg kg(-1) infusion, continuously for at least 10 minutes and then continued with a dose of 0.2 microg kg(-1) min(-1)) treatment was started after the induction of SAH. Three days later, the animals were sacrificed.
In pathological investigation; there was statistically significant difference in luminal area and muscular wall thickness of the basilar artery between all groups (p < 0.005). Malondialdehyde level was also found significantly low in the levosimendan group compared with the SAH group.
Intravenous levosimendan treatment was found effective by increasing the pathological luminal area and reducing muscular wall thickness measurements. This is the first study to show that intravenous administration of levosimendan is effective in preventing cerebral vasospasm induced by SAH in rabbits.
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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. 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 % O2 during general anaesthesia with urethane. After 10 min of global ischaemia/hypoxia, the rats were treated with an i.v. bolus of 24 mug kg-1 levosimendan followed by a continuous infusion of 0.2 mug 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 [PLUS-MINUS SIGN] 14 vs. 109 [PLUS-MINUS SIGN] 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 [PLUS-MINUS SIGN] 31 vs. 77 [PLUS-MINUS SIGN] 8, p = 0.017) and the glutamate release during 90 minutes of reperfusion (75 [PLUS-MINUS SIGN] 19 vs. 24 [PLUS-MINUS SIGN] 28 mumol[MIDDLE DOT]L-1) were higher in the levosimendan group. The increased expression of IL-6, IL-1ss TNFalpha 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.BMC Neurology 08/2012; 12(1):81. · 2.56 Impact Factor
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ABSTRACT: The aim of the present study was to evaluate the effects of phosphodiesterase type 5 (PDE5) inhibitory drugs, Tadalafil and Sildenafil, on inducible NOS (iNOS), endothelial NOS (eNOS) and p53 genes expressions and apoptosis in ischemia/reperfusion (I/R) induced oxidative injury in rat renal tissue. Eighty Sprague-Dawley rats (300-350 g) were divided into four groups. In ischemia/reperfusion group, rats were subjected to renal ischemia by clamping the left pedicle for 60 min, and then reperfused for 90 min. On the other hand, in other two groups the rats were individually pretreated with Tadalafil and Sildenafil 1 h before the induction of ischemia. Malondialdehyde (MDA) is determined in renal tissue homogenates by high-performance liquid chromatography, the number of apoptotic cell were calculated by TUNEL method and p53 and eNOS expression were detected with immunohistochemistry. On the other hand, myeloperoxidase (MPO) levels were measured by spectrophotometric method and the mRNA level of iNOS in renal tissue was determined by Real-time PCR (RT-PCR). Our results indicate that MDA and MPO levels were increased in the I/R group than those in the control group. Both Tadalafil and Sildenafil treatment decreased the MDA levels in ischemia/reperfusion group, whereas this effect was more potent with Sildenafil. RT-PCR results showed that, iNOS gen expression increased in the I/R group, but decreased in the PDE5 inhibitory drugs treated group. Apoptotic cells, eNOS levels and p53 positive cells were also decreased in PDE5 inhibitory drugs treated group. We suggest that Tadalafil and Sildenafil have beneficial effects against I/R related renal tissue injury and this protective effect is clearer for Sildenafil than Tadalafil.Molecular Biology Reports 06/2012; 39(10):9775-82. · 2.51 Impact Factor
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ABSTRACT: Neuroprotective strategies in ischemic stroke are an important challenge in clinical and experimental research as an adjunct to reperfusion therapy that may reduce neurologic injury and improve outcome. The neuroprotective properties of levosimendan in traumatic brain injury in vitro, transient global brain ischemia and focal spinal cord ischemia suggest the potential for similar effects in transient brain ischemia. Transient brain ischemia was induced for 60 min by intraluminal occlusion of the middle cerebral artery in 40 male Wistar rats under general anesthesia with s-ketamine and xylazine and with continuous monitoring of their blood pressure and cerebral perfusion. Five minutes before inducing reperfusion, a levosimendan bolus (24 mug kg -1) was administered over a 20 minute period. Infarct size, brain swelling, neurological function and the expression of inflammatory markers were quantified 24 hours after reperfusion. Although levosimendan limited the infarct size and brain swelling by 40% and 53%, respectively, no effect on neurological outcome or mortality could be demonstrated. Upregulation of tumor necrosis factor alpha and intercellular adhesion molecule 1 was significantly impeded. Cerebral blood flow during reperfusion was significantly reduced as a consequence of sustained autoregulation. Levosimendan demonstrated significant neuroprotective properties in a rat model of transient brain ischemia by reducing reperfusion injury.BMC Neurology 08/2013; 13(1):106. · 2.56 Impact Factor