Ischaemic preconditioning does not protect the heart in obese and lean animal models of Type 2 diabetes

Kristiansen, Steen Buus; Løfgren, Bo; Støttrup, Nicolaj Brejnholt; Khatir, Dinah Sherzad; Nielsen‐Kudsk, Jens Erik; Nielsen, Torsten T.; Bøtker, Hans Erik; Flyvbjerg, Allan

doi:10.1007/s00125-004-1514-4

Cited by 121 publications

(132 citation statements)

References 23 publications

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“…A bolus of 1,000 IU/kg heparin (Leo Pharma, Copenhagen, Denmark) was given through the femoral vein. The heart was cannulated in situ, mounted in a Langendorff apparatus and perfused retrogradely with KrebsHenseleit solution at a pressure of 80 mmHg as previously described [16,17]. All hearts were subjected to 40 min preischaemic stabilisation.…”

Section: Isolated Heart Preparationmentioning

confidence: 99%

Comparison of two sulfonylureas with high and low myocardial KATP channel affinity on myocardial infarct size and metabolism in a rat model of type 2 diabetes

et al. 2010

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Aims/hypothesis Sulfonylureas (SUs) may impair outcome in patients with acute coronary syndrome. Most experimental studies of the myocardial effects of SU treatment are performed in non-diabetic models. We compared the effect of two widely used SUs, glibenclamide (gb) and gliclazide (gc), with high and low myocardial K ATP channel affinity, respectively, at therapeutic concentrations on infarct size, left ventricular (LV) function and myocardial glycogen, lactate and alanine content before and after ischaemia/ reperfusion (I/R). Methods Non-diabetic Wistar and diabetic Goto-Kakizaki rat hearts were investigated in a Langendorff preparation. Gb (0.1 μmol/l) and gc (1.0 μmol/l) were administrated throughout the study. Infarct size was evaluated after 120 min of reperfusion. Myocardial metabolite content was measured before and after ischaemia.Results Infarct size was smaller in diabetic hearts than in non-diabetic hearts (0.33±0.03 vs 0.51±0.05, p<0.05). Gb increased infarct size (0.54±0.04 vs 0.33±0.03, p<0.05) and reduced post-ischaemic LV developed pressure (60±3 vs 76±3 mmHg, p<0.05) and coronary flow (4.9±0.5 vs 7.1±0.4 ml min -1 g -1 , p<0.05) in gb-treated diabetic rats compared with untreated diabetic rats. On comparing gb-treated diabetic rats with untreated diabetic rats, glycogen content was reduced before (9.1 ±0.6 vs 13.6 ± 1.0 nmol/mg wet weight, p<0.01) and after ischaemia (0.9±0.2 vs 1.8±0.2 nmol/mg wet weight, p<0.05), and lactate (4.8±0.4 vs 3.2±0.3 nmol/mg wet weight, p<0.01) and alanine (1.38±0.12 vs 0.96±0.09 nmol/mg wet weight, p < 0.05) contents were increased during reperfusion. Gc-treatment of diabetic and non-diabetic rats did not affect any of the measured variables. Conclusions/interpretations Gb, but not gc, exacerbates I/R injury and deteriorates LV function in diabetic hearts. These effects of gb on diabetic hearts may be due to detrimental effects on myocardial carbohydrate metabolism.

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Section: Isolated Heart Preparationmentioning

confidence: 99%

Comparison of two sulfonylureas with high and low myocardial KATP channel affinity on myocardial infarct size and metabolism in a rat model of type 2 diabetes

et al. 2010

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“…IPC fails to induce cardioprotection in many diabetes models, including Zucker fatty diabetic rats, Goto-Kakizaki lean diabetic rats, and streptozotocin-induced diabetic animals (4,8,22). Indeed, possible alterations in GSK3␤ signaling within different animal models may be the cause of altered IPC or pharmacological-induced cardioprotection, since, recently, a cardiac-specific mouse with a constitutively active GSK3␤ failed to respond to hypoxic preconditioning and pharmacological-induced cardioprotection (11).…”

Section: Diabetes Abolish Morphine-induced Protectionmentioning

confidence: 99%

Diabetes Abolishes Morphine-Induced Cardioprotection via Multiple Pathways Upstream of Glycogen Synthase Kinase-3β

2007

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The cardioprotective effect of opioids or glycogen synthase kinase (GSK) inhibitors given at reperfusion has not been investigated in diabetes models. Therefore, nondiabetic (NDBR) or streptozotocin-induced diabetic (DBR) rat hearts were subjected to 30 min of ischemia and 2 h of reperfusion. Groups of NDBR or DBR were administered either vehicle, morphine (0.3 mg/kg), or the GSK inhibitor SB216763 (0.6 mg/kg) 5 min before reperfusion. SB216763 (but not morphine) reduced infarct size in DBRs (44 ؎ 1* and 55 ؎ 2%, respectively), while both agents reduced infarct size in NDBRs versus untreated NDBRs or DBRs (44 ؎ 3*, 42 ؎ 3*, 60 ؎ 2, and 56 ؎ 2%, respectively, *P < 0.001). Morphine-induced phospho-(P-)GSK3␤ was reduced 5 min after reperfusion in DBRs compared with NDBRs (0.83 ؎ 0.29 and 1.94 ؎ 0.12 [P < 0.05] pg/g tissue, respectively). The GSK3␤ mediators, P-Akt, P-extracellular signal-related kinase (ERK)1, and P-signal transducer and activator of transcription (STAT)3, were also significantly reduced in untreated DBR compared with NDBR rats. Morphine-induced elevations of P-Akt, P-ERK1, P-p70s6, P-janus-activated kinase-2, and P-STAT3 in NDBRs were also blunted in DBRs. H9C2 cells raised in 25 mmol/l compared with 5.56 mmol/l glucose media also demonstrated reduced morphine-induced P-GSK3␤, P-Akt, P-STAT3, and P-ERK1 after 15 min. Hence, acute GSK inhibition may provide a novel therapeutic strategy for diabetic patients during an acute myocardial infarction, whereas morphine is less effective due to signaling events that adversely affect GSK3␤. Diabetes 56:127-136, 2007

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“…Considerable evidence indicates that hypercholesterolemia abrogates both early [20] and late PC [21,22], although the effects on early PC remain controversial [23]. In addition, it appears that early and late PC are either attenuated or absent in the presence of diabetes [24][25][26]. No information is available regarding the impact of hypertension on PC.…”

Section: Cox-2 Involvement In Pcmentioning

confidence: 99%

The late phase of preconditioning and its natural clinical application—gene therapy

Bolli

Tang

et al. 2007

Heart Fail Rev

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There is little doubt that the discovery of ischemic preconditioning (PC) has been one of the fundamental milestones in the field of ischemic biology in the past 20 years. The purpose of this article is to review the pathophysiology and molecular basis of the late phase of myocardial PC. The exploitation of late PC for the development of novel gene therapy strategies aimed at inducing a permanently preconditioned cardiac phenotype (prophylactic cardioprotection) will also be discussed. Deciphering the mechanism of late PC has not only conceptual interest but also a considerable therapeutic implications, since transfer of the genes that underlie late PC would be expected to replicate the salubrious effects of this response of the heart to stress.

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Ischaemic preconditioning does not protect the heart in obese and lean animal models of Type 2 diabetes

Abstract: Aims/hypothesis.

Cited by 121 publications

References 23 publications

Comparison of two sulfonylureas with high and low myocardial KATP channel affinity on myocardial infarct size and metabolism in a rat model of type 2 diabetes

Comparison of two sulfonylureas with high and low myocardial KATP channel affinity on myocardial infarct size and metabolism in a rat model of type 2 diabetes

Diabetes Abolishes Morphine-Induced Cardioprotection via Multiple Pathways Upstream of Glycogen Synthase Kinase-3β

The late phase of preconditioning and its natural clinical application—gene therapy

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