Blockade of anaesthetic-induced preconditioning in the hyperglycaemic myocardium: The regulation of different mitogen-activated protein kinases

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Abstract

Preconditioning by volatile anaesthetics is blocked by hyperglycaemia. The regulation of mitogen-activated protein kinases during this effect has yet not been investigated.

For infarct size measurements, anaesthetized rats were subjected to 25 min coronary artery occlusion followed by 120 min reperfusion. Control animals were not further treated. One group was preconditioned by two 5-min periods of desflurane inhalation (desflurane preconditioning, Des-preconditioning, 1MAC), each followed by 10-min washout. Four groups received glucose 50% in order to achieve blood glucose concentrations between 22.2 and 33.3 mM/l. Glucose infusion started 40 min before ischaemia (early hyperglycaemia, EH) and stopped with the onset of artery occlusion with (EH+Des-preconditioning) or without (EH) preconditioning. The other two groups received glucose during ischaemia (late hyperglycaemia, LH), again with (LH+Des-preconditioning) or without (LH) preconditioning. Additional hearts were excised for Western blot of mitogen-activated protein kinases.

Infarct size was reduced from 51.7 ± 9.0% in controls to 28.8 ± 11.8% after Des-preconditioning (P< 0.01 vs Con). Hyperglycaemia alone did not affect infarct size (EH, 51.5 ± 9.0%, LH, 44.3 ± 16.9%), but EH as well as LH blocked Des-preconditioning (49.1 ± 12.3%, P< 0.01, 48.1 ± 17.6%, P< 0.05 vs Des-preconditioning). All three mitogen-activated protein kinases showed a similar time course pattern of phosphorylation in the Des-preconditioning, EH and EH+Des-preconditioning group.

Despite the lack of cardioprotection, mitogen-activated protein kinases are activated in hyperglycaemic myocardium. Therefore, it can be assumed that the hyperglycaemic induced blockade of Des-preconditioning is situated downstream or in parallel of these mitogen-activated protein kinases or involves different signal transduction pathways.

Introduction

Diabetic patients often have hyperglycaemic blood sugar levels, and hyperglycaemia is an independent risk factor for short and long-term cardiovascular mortality (Gerstein et al., 1999, Malmberg et al., 1999, Norhammar et al., 2002).

Brief episodes of ischaemia before a subsequent longer ischaemic period exert a strong myocardial protection in vivo which is called ischaemic preconditioning. Evidence from literature suggests that similar to ischaemic preconditioning also administration of volatile anaesthetics protects the heart in a preconditioning manner (for review see Weber and Schlack, 2005).

Concerning the signal transduction of preconditioning, there exist triggers, i.e., mechanisms at the beginning of the signal transduction cascade, and mediators, which finally mediate cardioprotection during the index ischaemia (Yellon and Downey, 2003).

In the last years several triggers and mediators of ischaemic- and anaesthetic-induced cardioprotection have been identified. For example, each subfamily of the mitogen-activated protein kinases (MAPK), the 42/44-kDa extracellular signal-regulated kinases (ERK 1/2), the c-Jun N-terminal kinase (JNK 1, 2 and 3), and the p38 MAPK, have been suggested to play a central role in the cardioprotection achieved by ischaemic preconditioning (Yellon and Downey, 2003, Ping and Murphy, 2000).

For anaesthetic-induced preconditioning we could show that p38 MAPK and the ERK 1/2 are involved in the cardioprotection by isoflurane and also xenon preconditioning (Weber et al., 2005a, Weber et al., 2006), whereby JNK was not influenced by xenon preconditioning of the rat heart in vivo (Weber et al., 2006).

Diabetes mellitus blocks protection by early (Kersten et al., 2000) and by late ischaemic preconditioning (Ebel et al., 2003) and there is also evidence for a clinically relevant blockade of ischaemic preconditioning in diabetic patients (Ishihara et al., 2001, Ishihara et al., 2003). Moreover, also anaesthetic-induced preconditioning was shown to be blocked by hyperglycaemia and diabetes mellitus (Tanaka et al., 2002, Kehl et al., 2002).

However, an optimal protection against ischaemia reperfusion injury may be advantageous especially for patients with increased blood sugar levels.

Therefore, detecting the underlying blockade mechanism of anaesthetic-induced preconditioning would be critically important before restoration of protection during hyperglycaemia can be achieved in clinical settings. However, so far the signal transduction step which is blocked by hyperglycaemia and its location in the signalling cascade of preconditioning remains unknown.

Therefore the present study aimed to investigate a) whether desflurane preconditioning is blocked by early (during trigger phase) and late (during mediator phase) induced hyperglycaemia and b) how MAPK phosphorylation is regulated during des-preconditioning in hyperglycaemic myocardium.

Section snippets

Materials and methods

The study was performed in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the United States National Institutes of Health. Moreover, the study was performed in accordance with the regulations of the German Animal Protection Law and was approved by the Animal Care Committee of the District of Düsseldorf, Germany. Male Wistar rats (200–250 g) were anaesthetized by intraperitoneal S-ketamine injection (150 mg/kg). S-ketamine does not interfere

Blood glucose levels

Blood glucose concentrations during the experiments are shown in Fig. 2A. The animals had under baseline conditions blood glucose concentrations of 6.7 ± 1.6 mM/l. The infusion of glucose 50% during trigger and mediator phase in the respective groups resulted in blood glucose concentrations of more than 22.2 mM/l. After stop of glucose infusion, values declined until the end of the experiment to 5.9 ± 3.1 mM/l.

Haemodynamic data

Fig. 2B–C shows the time course of heart rate (Fig. 2B) and mean aortic pressure (Fig. 2

Discussion

While hypoglycaemia mimics ischaemic preconditioning (Armstrong et al., 1994, Ebel et al., 2005), diabetes mellitus and hyperglycaemia have been shown to block cardioprotection induced by ischaemic preconditioning (Kersten et al., 2000, Kersten et al., 1998, Kristiansen et al., 2004, Ishihara et al., 2003, Ishihara et al., 2001) and anaesthetic-induced preconditioning (Tanaka et al., 2002, Kehl et al., 2002, Kehl et al., 2003) in animals and humans.

There are only three studies investigating the

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