Ischaemic preconditioning limits infarct size in the rat heart

Yellon, Derek M.; Alkhulaifi, Abdul M.; Browne, Emma E; Pugsley, W

doi:10.1093/cvr/26.10.983

Cited by 124 publications

(30 citation statements)

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“…‫,ء‬ P Ͻ 0.05, treated versus control. or ischemic preconditioning (35-50%) (Yellon et al, 1992;Lasley et al, 2007). This is also the first study that has shown cross-talk between PAR4 and adenosine receptors during myocardial ischemia and reperfusion.…”

Section: Discussionmentioning

confidence: 85%

Inhibiting Protease-Activated Receptor 4 Limits Myocardial Ischemia/Reperfusion Injury in Rat Hearts by Unmasking Adenosine Signaling

Strande

Hsu²,

Su³

et al. 2007

J Pharmacol Exp Ther

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Harnessing endogenous cardioprotectants is a novel therapeutic strategy to combat ischemia/reperfusion (I/R) injury. Thrombin causes I/R injury, whereas exogenous adenosine prevents I/R injury. We hypothesized that blocking thrombin receptor activation with a protease-activated receptor (PAR) 4 antagonist would unmask the cardioprotective effects of endogenous adenosine. The protective role of two structurally unrelated PAR4 antagonists, trans-cinnamoyl-YPGKF-amide (tc-Y-NH 2 ) and palmitoyl-SGRRYGHALR-amide (P4pal10), were evaluated in two rat models of myocardial I/R injury. P4pal10 (10 g/kg) treatment before ischemia significantly decreased infarct size (IS) by 31, 21, and 19% when given before, during, and after ischemia in the in vivo model. tc-Y-NH 2 (5 M) treatment before ischemia decreased IS by 51% in the in vitro model and increased recovery of ventricular function by 26%. To assess whether the cardioprotective effects of PAR4 blockade were due to endogenous adenosine, isolated hearts were treated with a nonselective adenosine receptor blocker, 8-sulfaphenyltheophylline (8-SPT), and tc-Y-NH 2 before ischemia. 8-SPT abolished the protective effects of tc-Y-NH 2 but did not affect IS when given alone. Adenosine-mediated survival pathways were then explored. The cardioprotective effects of tc-Y-NH 2 were abolished by inhibition of Akt (wortmannin), extracellular signal-, and K ATP channels (glibenclamide). PD98059, L-NMA, and glibenclamide alone had no effect on cardioprotection in vitro. Furthermore, inhibition of mitochondrial K ATP channels [5-hydroxydecanoic acid (5-HD)] and sarcolemmal K ATP channels (sodium (5-(2-(5-chloro-2-methoxybenzamido)ethyl)-2-methoxyphenylsulfonyl)(methylcarbamothioyl)amide; HMR 1098) abolished P4pal10-induced cardioprotection in vivo. Thrombin receptor blockade by PAR4 inhibition provides protection against injury from myocardial I/R by unmasking adenosine receptor signaling and supports the hypothesis of a coupling between thrombin receptors and adenosine receptors.

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Section: Discussionmentioning

confidence: 85%

Inhibiting Protease-Activated Receptor 4 Limits Myocardial Ischemia/Reperfusion Injury in Rat Hearts by Unmasking Adenosine Signaling

Strande

Hsu²,

Su³

et al. 2007

J Pharmacol Exp Ther

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“…Mechanistic studies have been performed in numerous models of preconditioning, including (1) preconditioned isolated rabbit, 48 rat, neonatal chicken, 49 and human 50 myocytes; (2) perfused rat, 51 rabbit, 52 or mouse hearts preconditioned in vitro; and (3) infarct sizing in vivo in small rodents. [53][54][55] Where indicated, results from these models will be included, but our discussion will concentrate on findings in large-animal hearts, because these changes are more likely to be relevant to preconditioning in the human heart.…”

Section: Mechanism(s) Of Preconditioningmentioning

confidence: 99%

Consequences of Brief Ischemia: Stunning, Preconditioning, and Their Clinical Implications

2001

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Abstract-In experimental studies in the dog, total proximal coronary artery occlusions of up to 15 minutes result in reversible injury, meaning that the myocytes survive this insult. The 15 minutes of ischemia, however, induce numerous changes in the myocardium, including certain monuments to the brief episode of ischemia that may persist for days. One of these monuments is stunned myocardium, which represents "prolonged postischemic contractile dysfunction of myocardium salvaged by reperfusion." The mechanism of stunning involves generation of oxygen radicals as well as alteration in calcium homeostasis and possibly alteration in contractile protein structure. Stunning has been observed in several clinical scenarios, including after percutaneous transluminal coronary angioplasty, unstable angina, stressinduced ischemia, after thrombolysis, and after cardiopulmonary bypass. Oxygen radical scavengers and calcium channel blockers have been shown to enhance function of stunned myocardium in experimental studies, and in a few clinical studies, calcium channel blockers have been shown to ameliorate stunning. Although brief periods of ischemia can contribute to prolonged left ventricular dysfunction and even heart failure, they paradoxically play a cardioprotective role. Episodes of ischemia as short as 5 minutes, followed by reperfusion, protect the heart from a subsequent longer coronary artery occlusion by markedly reducing the amount of necrosis that results from the test episode of ischemia. This phenomenon, called ischemic preconditioning, has been observed in virtually every species in which it has been studied and is a powerful cardioprotective effect. The mechanism of ischemic preconditioning involves both triggers and mediators and involves complex second messenger pathways that appear to involve such components as adenosine, adenosine receptors, the epsilon isoform of protein kinase C, the ATP-dependent potassium channels, as well as others, including a paradoxical protective role of oxygen radicals. Both an early and a late phase of preconditioning have been described, and the mechanisms underlying their induction are under investigation. That preconditioning may occur in humans is suggested by the observations that repetitive balloon inflations in the coronary artery are associated with progressively less chest pain, ST-segment elevation, lactate production, the protective effects of preinfarction angina, the anginal "warm-up phenomenon," and studies performed on human cardiac biopsies that show metabolic properties suggesting preconditioning. Development of pharmacological agents that stimulate second messenger pathways thought to be involved in preconditioning, but without causing ischemia, could result in novel approaches to treating ischemia. Hence, on one hand, brief episodes of ischemia can have a negative effect on the heart: stunning; and on the other hand, they have a protective effect: preconditioning. The future challenge is how to minimize the stunning phenomenon and maximize the preconditioni...

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“…Finally, although several studies have shown that ischaemic preconditioning markedly limits myocardial infarct size in the rat (Liu & Downey, 1992;Yellon, et al, 1992;Li & Kloner, 1993;Richard et al, 1993;1994b) the mechanisms of the beneficial effect of preconditioning in this species are not fully understood. Thus, we also designed experiments to assess whether acetylcholine contributes to the beneficial effect of preconditioning in rats.…”

Section: Introductionmentioning

confidence: 99%

Myocardial and coronary endothelial protective effects of acetylcholine after myocardial ischaemia and reperfusion in rats: role of nitric oxide

Richard

Blanc

Kaeffer

et al. 1995

British J Pharmacology

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1 Recent experiments suggest that acetylcholine (ACh) may exert myocardial protective effects during ischaemia (I) and reperfusion (R). The present study was designed (i) to assess whether ACh limits infarct size and protects coronary endothelial cells in a rat model of I and R, (ii) to evaluate the role of ATP-sensitive potassium (KATP) channels and nitric oxide (NO) in the beneficial effect of ACh (iii) to evaluate whether the protective effect of ACh also extends to coronary endothelial cells and (iv) to assess whether ACh contributes to the beneficial effect of preconditioning. 2 Anaesthetized rats were subjected to 20 min I (left coronary artery occlusion) and 2 h of R. Infarct size was assessed by triphenyltetrazolium (TTC) staining and expressed as a % of the area at risk (India ink injection). Vascular studies were performed on 1.5-2 mm coronary segments (internal diameter 250-300 pm) removed distal to the site of occlusion and mounted in wire myographs. 3 ACh limited infarct size (from 59+3 to 26+5%, P<0.01), and this was prevented by atropine (46+7%; P<0.05 vs ACh), but not by the inhibitor of KATP channels, glibenclamide (29±8%). The inhibitor of NO synthesis N0-nitro L-arginine did not affect infarct size (54+5%) but abolished the beneficial effect of ACh (59 8%; P<0.05 vs ACh), whereas the NO donor 3-morpholinosydnonimine-N-ethylcarbamide (SIN-I limited infarct size to the same extent as ACh (28 ± 6%). Preconditioning also limited infarct size (5 2%, P< 0.01 vs control), and this was not affected by atropine (6 ± 2%). I and R induced a significant decrease in the endothelium-dependent relaxations of isolated coronary arteries to ACh (maximal response: sham: 58+4; I/R: 25±5%; P<0.01) and this dysfunction was prevented by prior in vivo treatment with ACh (55+7%; P<0.01 vs I/R) or (SIN-1 50+5%; P<0.05 vs I/R). 4 Thus, in the rat model, ACh is able to stimulate potent endogenous protective mechanisms during I and R, which are evident both at the level of myocardial and coronary endothelial cells, and appear entirely mediated through the production of NO. Pharmacological stimulation of this endogenous protective mechanism may constitute a new approach in the treatment of acute myocaridal ischaemia.

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Ischaemic preconditioning limits infarct size in the rat heart

Cited by 124 publications

References 0 publications

Inhibiting Protease-Activated Receptor 4 Limits Myocardial Ischemia/Reperfusion Injury in Rat Hearts by Unmasking Adenosine Signaling

Inhibiting Protease-Activated Receptor 4 Limits Myocardial Ischemia/Reperfusion Injury in Rat Hearts by Unmasking Adenosine Signaling

Consequences of Brief Ischemia: Stunning, Preconditioning, and Their Clinical Implications

Myocardial and coronary endothelial protective effects of acetylcholine after myocardial ischaemia and reperfusion in rats: role of nitric oxide

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