Ischaemic preconditioning in a model of global ischaemia: Infarct size limitation, but no reduction of stunning

doi:10.1016/S0022-2828(95)90590-1

Journal of Molecular and Cellular Cardiology

Volume 27, Issue 8, August 1995, Pages 1623-1632

https://doi.org/10.1016/S0022-2828(95)90590-1 Get rights and content

It is well known that ischaemic preconditioning delays infarct size during regional ischaemic insults. However, the extent of this protective effect against different ischaemia periods has not been established, and any reduction in stunning has been difficult to demonstrate with regional models. In this study we have investigated ischaemic preconditioning in a buffer-perfused isolated rabbit heart model with a global ischaemic insult, and measured both infarct volume and functional recovery. Experiments were performed with three ischaemia time periods of 15, 20 and 30 min at 37°C. Infarct volume (expressed as a percentage of left ventricular volume) was measured by tetrazolium staining after 2 hours reperfusion, and left ventricular developed pressure with an intraventricular balloon. Hearts preconditioned with 5 min ischaemia and 10 min reperfusion were compared with a control group. In this model, preconditioning resulted in a 57% reduction in infarct volume compared with control hearts (P=0.02) subjected to 20 min of global ischaemia, but the degree of this infarct delaying effect was dependent on the ischaemia time and was only 37% (P=0.02) and 11% (n.s.) with a 30 min and 15 min ischaemic challenge respectively. Recovery of post-ischaemic left ventricular developed pressure as a percentage of the pre-ischaemic value correlated very well with infarct volume in control r=−0.82 (P<0.001) and preconditioned r=−0.78 (P<0.001) groups, and the slope of the regression lines was similar for both groups. These results demonstrate that the degree of protection produced by preconditioning is not uniform but varies with the length of the ishaemic insult. By measuring both infarct volume and functional recovery we have been able to confirm that any post-ischaemic improvement in global left ventricular function produced by preconditioning is secondary to reduced infarction, and hence that preconditioning does not attenuate stunning.

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Cited by (108)

Is there an effect of ischemic conditioning on myocardial contractile function following acute myocardial ischemia/reperfusion injury?
2019, Biochimica et Biophysica Acta - Molecular Basis of Disease
Citation Excerpt :
In isolated papillary muscle, atrial trabeculae, whole heart preparations and in the in vivo setting it is not possible to determine whether improved myocardial contractile function is a direct consequence of ischemic conditioning or due to improved myocardial viability associated with a reduction in I/R injury. For example, a negative correlation between infarct size and postischemic LVDP in a model of global ischemia in isolated perfused rabbit hearts, indicated that the improved LVDP was only due to a reduction in infarct size by ischemic preconditioning and not due to a direct effect on myocardial contractile function [60]. Nonetheless, evidence indicates that there may be direct effects on myocardial contractile function independent of infarct size.
Ischemic conditioning induces cardioprotection; the final infarct size following a myocardial ischemic event is reduced. However, whether ischemic conditioning has long-term beneficial effects on myocardial contractile function following such an ischemic event needs further elucidation. To date, ex vivo studies have shown that ischemic conditioning improves the contractile recovery of isolated ventricular papillary muscle or atrial trabeculae following simulated ischemia. However, in vivo animal studies and studies in patients undergoing elective cardiac surgery show conflicting results. At the subcellular level, it is known that ischemic conditioning improved energy metabolism, preserved mitochondrial respiration, ATP production, and Ca²⁺ homeostasis in isolated mitochondria from the myocardium. Ischemic conditioning also presents with post-translational modifications of proteins in the contractile machinery of the myocardium. The beneficial effects on myocardial contractile function need further elucidation. This article is part of a Special Issue entitled: The power of metabolism: Linking energy supply and demand to contractile function edited by Torsten Doenst, Michael Schwarzer and Christine Des Rosiers.
Neuropathic pain attenuates ischemia reperfusion injury through β2-adrenergic pathway
2017, Life Sciences
The relationship between neuropathic pain and myocardial infarction (MI) was uncertain because of some medication or underlying diseases. This study investigated the impact of neuropathic pain on ischemia reperfusion injury using isolated rat hearts and cardiomyocytes.
Male Sprague-Dawley rats were assigned to the control and allodynia (AL) groups, with the latter subjected to the fifth lumbar spinal-nerve ligation. First, isolated hearts underwent 25-min ischemia and 90-min reperfusion to assess hemodynamic changes and MI area. Second, isolated cardiomyocytes underwent 10-min laser illumination to assess the opening of mitochondrial permeability transition pore (mPTP) and cellular hypercontraction. Lastly, expression of pro-survival kinases was measured in another cardiomyocytes using flow cytometry. AL-treated hearts were concomitantly examined regarding the involvement of β-adrenergic pathways by esmolol (ESM), β1-blocker (100 μM, AL + ESM), and ICI118551 (ICI), β2-blocker (50 nM, AL + ICI).
All hemodynamic variables did not change significantly in between-group comparisons except at 30 min of reperfusion. MI area decreased remarkably in the AL and AL + ESM groups after 90-min reperfusion. The AL + ICI group significantly increased it as compared with the AL and AL + ESM groups. Similarly, the AL and AL + ESM groups significantly inhibited mPTP opening and cellular hypercontraction, whereas the AL + ICI group reversed these effects. Enhanced expression of pro-survival kinases was observed in the AL and AL + ESM groups, but the AL + ICI group abolished this enhancement.
Our findings suggested that neuropathic pain possessed cardioprotective effects through inhibiting mPTP opening. The underlying mechanisms were possibly regulated by β2-adrenergic activation and pro-survival kinase expression in cardiomyocytes.
Combined morphine and limb remote ischemic perconditioning provides an enhanced protection against myocardial ischemia/reperfusion injury by antiapoptosis
2016, Journal of Surgical Research
Citation Excerpt :
These results indicate that the combination of morphine and RIPer may preserve myocardial viability by inhibiting apoptotic cell death, and the antiapoptotic effects by combining the two treatments may be closely associated with the Bcl-2 and Bax expression changes in the myocytes. The infarct size is often regarded as the gold standard when evaluating the strength of different cardioprotective strategies, but the infarct size limitation does not always produce adequate mechanical functional recovery of hearts after IRI [51,52]. Actually, IRI includes various events, such as reperfusion arrhythmias, myocardial stunning, microvascular damage, myocardial hibernation, and a no-reflow phenomenon [53].
Both morphine and limb remote ischemic perconditioning (RIPer) can protect against myocardial ischemia/reperfusion injury (IRI). This experiment was designed to assess whether combined morphine and limb RIPer could provide and enhanced protection against myocardial IRI in an in vivo rat model.
One hundred male Sprague–Dawley rats were randomly allocated to six groups: sham, ischemia/reperfusion (IR), ischemic preconditioning, RIPer, morphine (M), and combined morphine and remote ischemic perconditioning (M + RIPer). Ventricular arrhythmias that occurred during ischemia and early reperfusion were scored, and serum creatine kinase isoenzyme and cardiac troponin I levels were assayed. The infarct size was determined by Evans blue and triphenyl tetrazolium chloride staining. The apoptosis in the myocardial ischemic core, ischemic border, and nonischemic areas was assessed through real-time polymerase chain reaction for Bax and Bcl-2 and with the transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay.
The infarct size, serum cardiac troponin I level, incidence, and score of the arrhythmias during the initial reperfusion were significantly reduced in the M + RIPer group compared with the IR group but did not differ significantly between the ischemic preconditioning and M + RIPer groups. Transferase-mediated deoxyuridine triphosphate-biotin nick end labeling–positive cells were significantly decreased, and the Bcl-2/Bax ratio was significantly increased in the M + RIPer group compared with the IR group.
This experiment demonstrates that combined morphine and limb RIPer provides an enhanced protection against myocardial IRI by the Bcl-2-linked apoptotic signaling pathway.
Pre-treatment with glucagon-like peptide-1 protects against ischemic left ventricular dysfunction and stunning without a detected difference in myocardial substrate utilization
2015, JACC: Cardiovascular Interventions
Citation Excerpt :
Studies have suggested that GLP-1 may activate the same prosurvival kinase pathways recruited by ischemic conditioning phenomena, which in turn mediate their cardioprotective effects via the maintenance of mitochondrial membrane integrity (4–6). However, our data indicate that pre-treatment with GLP-1 protects against both ischemic LV contractile dysfunction and stunning, neither of which are believed to be attenuated by ischemic pre-conditioning when infarct size has been accounted for (30–32). This may therefore argue against the hypothesis that GLP-1 exerts its favorable cardiovascular effects solely as a pre-conditioning mimetic.
This study sought to determine whether pre-treatment with intravenous glucagon-like peptide-1 (GLP-1)(7-36) amide could alter myocardial glucose use and protect the heart against ischemic left ventricular (LV) dysfunction during percutaneous coronary intervention.
GLP-1 has been shown to have favorable cardioprotective effects, but its mechanisms of action remain unclear.
Twenty patients with preserved LV function and single-vessel left anterior descending coronary artery disease undergoing elective percutaneous coronary intervention were studied. A conductance catheter was placed into the LV, and pressure-volume loops were recorded at baseline, during 1-min low-pressure balloon occlusion (BO), and at 30-min recovery. Patients were randomized to receive an infusion of either GLP-1(7-36) amide at 1.2 pmol/kg/min or saline immediately after baseline measurements. Simultaneous coronary artery and coronary sinus blood sampling was performed at baseline and after BO to assess transmyocardial glucose concentration gradients.
BO caused both ischemic LV dysfunction and stunning in the control group but not in the GLP-1 group. Compared with control subjects, the GLP-1 group had a smaller reduction in LV performance during BO (delta dP/dT_max, –4.3 vs. –19.0%, p = 0.02; delta stroke volume, –7.8 vs. –26.4%, p = 0.05), and improved LV performance at 30-min recovery. There was no difference in transmyocardial glucose concentration gradients between the 2 groups.
Pre-treatment with GLP-1(7-36) amide protects the heart against ischemic LV dysfunction and improves the recovery of function during reperfusion. This occurs without a detected change in myocardial glucose extraction and may indicate a mechanism of action independent of an effect on cardiac substrate use. (Effect of Glucgon-Like-Peptide-1 [GLP-1] on Left Ventricular Function During Percutaneous Coronary Intervention [PCI]; ISRCTN77442023)
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View full text

Ischaemic preconditioning in a model of global ischaemia: Infarct size limitation, but no reduction of stunning

J Mol Cell Cardiol

Am Heart J

Lancet

Depletion of norepinepherine by chronic surgical sympathectomy does not block protection from ischaemic preconditioning

Circulation

Ischemic preconditioning attenuates acidosis in isolated rat heart

Am J Physiol

Ischaemic preconditioning of the myocardium: a new paradigm for clinical cardioprotection

Br J Clin Pharmac

“Normothermic range” temperature affects myocardial infarct size

Cardiovasc Res

Preconditioning causes improved wall motion as well as smaller infarcts after transient coronary occlusion in rabbits

Circulation

Bradykinin limits myocardial infarction in rabbits by protein kinase C activation and not by nitric oxide synthesis

Circulation

Muscarinic receptor stimulation by carbachol improves functional recovery in isolated, blood perfused rabbit heart

Cardiovasc Res

Ischaemic preconditioning does not attenuate post-ischaemic reperfusion dysfunction but has an infarct-limiting effect

Eur Heart J

Ischaemic and hypoxic preconditioning enhance postischaemic recovery of function in the rat heart

Cardiovasc Res