Pharmacological targets revealed by myocardial postconditioning

doi:10.1016/j.coph.2008.11.009

Current Opinion in Pharmacology

Volume 9, Issue 2, April 2009, Pages 177-188

https://doi.org/10.1016/j.coph.2008.11.009 Get rights and content

Postconditioning is an intervention in which controlled, brief, intermittent periods of ischaemia at the onset of reperfusion protect myocardium from the lethal consequences of reperfusion (‘reperfusion injury’). Postconditioning has been demonstrated in humans with acute myocardial infarction and offers the possibility of further limiting infarct size in patients undergoing reperfusion therapy. We review current research that focuses on the molecular mechanisms of postconditioning. The molecular pathways are incompletely mapped but they probably converge on suppression of mitochondrial permeability transition pore opening during early reperfusion, an event that is thought to promote cell death at reperfusion. A number of upstream signalling pathways, activated by autacoid factors, converge on this crucial target and these offer a range of realistic possibilities for pharmacological induction of a postconditioned state.

Section snippets

Reperfusion injury

Mortality in patients presenting with acute myocardial infarction (AMI) can be halved by reperfusion procedures such as percutaneous coronary intervention (PCI) and fibrinolytic therapy [1^••]. However, experimental evidence indicates that reperfusion can provoke a series of cellular events that are detrimental to myocardium [2••, 3••]. This paradoxical ‘reperfusion injury’ takes several forms and includes the irreversible injury or accelerated death of cells still viable at the end of

Postconditioning

Vinten-Johansen's group reported how postconditioning the reperfused canine heart with precisely applied periods of coronary artery re-occlusion (three 30 second periods of occlusion interspersed with 30 second periods of reperfusion) significantly reduced infarct size following 60 min left anterior descending coronary artery occlusion [5]. This protective effect was comparable to that of preconditioning with a single 5 min period of coronary occlusion applied before the 60 min occlusion. Although

Upstream targets: autacoid and receptor mechanisms

A number of autacoid ligands have been evaluated in relation to postconditioning. The general approach has been to assess the effectiveness of postconditioning in the presence of specific or subtype-selective receptor antagonists (or in receptor-deficient mice) and to assess the protective effect of exogenous autacoids or selective agonists when given immediately before reperfusion.

Activation of ERK1/2 and PI3K/Akt

Activation of anti-apoptotic growth factor-stimulated survival signals (principally the PI3K/Akt and MEK/ERK pathways) was being actively pursued as a means of limiting reperfusion injury before the formal description of postconditioning in 2003 (see [64]). Tsang et al. then provided the first demonstration that postconditioning was abrogated by inhibitors of PI3K activation and was associated with enhanced Akt phosphorylation in postconditioned hearts during early reperfusion [65].

Many

The ultimate cardioprotective target? Inhibition of mitochondrial permeability transition

In the past five years, mPTP inhibition has emerged as a potential convergence point for many cardioprotective signalling pathways and a final common effector mechanism for both preconditioning and postconditioning.

Conclusion

The resurgence of research in reperfusion injury mechanisms is largely due to the recognition of postconditioning. Although at present, the molecular mechanisms of postconditioning are unclear, a number of key elements have been identified that are pharmacologically manipulable. Arguably, the prevailing consensus on mPTP inhibition as the final target of postconditioning obviates further basic research, since an effective (and inexpensive, off-patent) inhibitor of mPTP opening is readily

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

The authors express their gratitude to the British Heart Foundation, The Wellcome Trust and Heart Research UK for their generous support.

References (131)

H. Kin et al.
Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine
Cardiovasc Res
(2005)
C.E. Velasco et al.
Myocardial reperfusion injury in the canine model after 40 min of ischemia: effect of intracoronary adenosine
Am Heart J
(1991)
G.J. Smits et al.
Cardioprotective effects of the novel adenosine A₁/A₂ receptor agonist AMP 579 in a porcine model of myocardial infarction
J Pharmacol Exp Ther
(1998)
R.D. Lasley et al.
The A_2A/A_2B receptor antagonist ZM-241385 blocks the cardioprotective effect of adenosine agonist pretreatment in in vivo rat myocardium
Am J Physiol Heart Circ Physiol
(2007)
D.K. Glover et al.
Cardioprotection by adenosine A_2A agonists in a canine model of myocardial stunning produced by multiple episodes of transient ischemia
Am J Physiol Heart Circ Physiol
(2007)
S.L. Kopecky et al.
A randomized, double-blinded, placebo-controlled, dose-ranging study measuring the effect of an adenosine agonist on infarct size reduction in patients undergoing primary percutaneous transluminal coronary angioplasty: the ADMIRE (AmP579 Delivery for Myocardial Infarction REduction) study
Am Heart J
(2003)
Y. Jang et al.
Postconditioning prevents reperfusion injury by activating delta-opioid receptors
Anesthesiology
(2008)
A.J. Zatta et al.
Evidence that cardioprotection by postconditioning involves preservation of myocardial opioid content and selective opioid receptor activation
Am J Physiol Heart Circ Physiol
(2008)
E.R. Gross et al.
Opioid-induced cardioprotection occurs via glycogen synthase kinase beta inhibition during reperfusion in intact rat hearts
Circ Res
(2004)
E.R. Gross et al.
Extending the cardioprotective window using a novel delta-opioid agonist fentanyl isothiocyanate via the PI3-kinase pathway
Am J Physiol Heart Circ Physiol
(2005)

S.A. Hamid et al.

Adrenomedullin limits reperfusion injury in experimental myocardial infarction

Basic Res Cardiol

(2005)

D. Schulman et al.

Urocortin protects the heart from reperfusion injury via upregulation of p42/p44 MAPK signaling pathway

Am J Physiol Heart Circ Physiol

(2002)

C.A. Efthymiou et al.

Atorvastatin and myocardial reperfusion injury: new pleiotropic effect implicating multiple prosurvival signaling

J Cardiovasc Pharmacol

(2005)

P.C. Chiari et al.

Isoflurane protects against myocardial infarction during early reperfusion by activation of phosphatidylinositol-3-kinase signal transduction: evidence for anesthetic-induced postconditioning in rabbits

Anesthesiology

(2005)

G.S. Bhamra et al.

Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening

Basic Res Cardiol

(2008)

A.D. Costa et al.

Protein kinase G transmits the cardioprotective signal from cytosol to mitochondria

Circ Res

(2005)

J.S. Kim et al.

Nitric oxide protects rat hepatocytes against reperfusion injury mediated by the mitochondrial permeability transition

Hepatology

(2004)

M.V. Cohen et al.

Acidosis, oxygen, and interference with mitochondrial permeability transition pore formation in the early minutes of reperfusion are critical to postconditioning's success

Basic Res Cardiol

(2008)

H. Yamaguchi et al.

The protein kinase PKB/Akt regulates cell survival and apoptosis by inhibiting Bax conformational change

Oncogene

(2001)

M. Crompton et al.

A heart mitochondrial Ca²⁺-dependent pore of possible relevance to re-perfusion-induced injury. Evidence that ADP facilitates pore interconversion between the closed and open states

Biochem J

(1990)

P. Ferdinandy et al.

Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning

Pharmacol Rev

(2007)

D.M. Yellon et al.

Myocardial reperfusion injury

N Engl J Med

(2007)

M.T. Dirksen et al.

Reperfusion injury in humans: a review of clinical trials on reperfusion injury inhibitory strategies

Cardiovasc Res

(2007)

C. Penna et al.

The paradigm of postconditioning to protect the heart

J Cell Mol Med

(2008)

Z.Q. Zhao et al.

Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning

Am J Physiol Heart Circ Physiol

(2003)

H.S. Na et al.

Ventricular premature beat-driven intermittent restoration of coronary blood flow reduces the incidence of reperfusion-induced ventricular fibrillation in a cat model of regional ischemia

Am Heart J

(1996)

P. Staat et al.

Postconditioning the human heart

Circulation

(2005)

H. Thibault et al.

Long-term benefit of postconditioning

Circulation

(2008)

M. Donato et al.

Ischemic postconditioning reduces infarct size by activation of A₁ receptors and K_ATP channels in both normal and hypercholesterolemic rabbits

J Cardiovasc Pharmacol

(2007)

S. Philipp et al.

Postconditioning protects rabbit hearts through a protein kinase C-adenosine A_2b receptor cascade

Cardiovasc Res

(2006)

X.M. Yang et al.

Postconditioning's protection is not dependent on circulating blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylyl cyclase activation

Basic Res Cardiol

(2005)

R.R. Morrison et al.

Targeted deletion of A_2A adenosine receptors attenuates the protective effects of myocardial postconditioning

Am J Physiol Heart Circ Physiol

(2007)

B. Olafsson et al.

Reduction of reperfusion injury in the canine preparation by intracoronary adenosine: importance of the endothelium and the no-reflow phenomenon

Circulation

(1987)

G.F. Baxter et al.

Adenosine A₁ agonist at reperfusion trial (AART): results of a three-center, blinded, randomized, controlled experimental infarct study

Cardiovasc Drugs Ther

(2000)

M. Goto et al.

Adenosine infusion during early reperfusion failed to limit myocardial infarct size in a collateral deficient species

Cardiovasc Res

(1991)

J.W. Homeister et al.

Combined adenosine and lidocaine administration limits myocardial reperfusion injury

Circulation

(1990)

J.B. Louttit et al.

The time course of cardioprotection induced by GR79236, a selective adenosine A₁-receptor agonist, in myocardial ischaemia-reperfusion injury in the pig

J Cardiovasc Pharmacol

(1999)

E.D. Norton et al.

The effects of intravenous infusions of selective adenosine A₁-receptor and A₂-receptor agonists on myocardial reperfusion injury

Am Heart J

(1992)

C.J. Pitarys et al.

Reduction of myocardial reperfusion injury by intravenous adenosine administered during the early reperfusion period

Circulation

(1991)

J.D. Thornton et al.

Intravenous pretreatment with A₁-selective adenosine analogues protects the heart against infarction

Circulation

(1992)

R.S. Vander Heide et al.

Effect of adenosine therapy at reperfusion on myocardial infarct size in dogs

Cardiovasc Res

(1996)

Z.Q. Zhao et al.

A₁ receptor mediated myocardial infarct size reduction by endogenous adenosine is exerted primarily during ischaemia

Cardiovasc Res

(1994)

A. Kis et al.

Limitation of myocardial reperfusion injury by AMP579, an adenosine A₁/A_2A receptor agonist: role of A_2A receptor and ERK1/2

Cardiovasc Drugs Ther

(2003)

M.J. McVey et al.

Cardiovascular pharmacology of the adenosine A₁/A₂-receptor agonist AMP, 579: coronary hemodynamic and cardioprotective effects in the canine myocardium

J Cardiovasc Pharmacol

(1999)

Z. Xu et al.

Timing and duration of administration are crucial for anti-infarct effect of AMP 579 infused at reperfusion in rabbit heart

Heart Dis

(2003)

Z. Xu et al.

Limitation of infarct size in rabbit hearts by the novel adenosine receptor agonist AMP 579 administered at reperfusion

J Mol Cell Cardiol

(2000)

K. Forster et al.

NECA at reperfusion limits infarction and inhibits formation of the mitochondrial permeability transition pore by activating p70S6 kinase

Basic Res Cardiol

(2006)

X.M. Yang et al.

NECA and bradykinin at reperfusion reduce infarction in rabbit hearts by signaling through PI3K, ERK, and NO

J Mol Cell Cardiol

(2004)

T.H. Rork et al.

Adenosine A_2A receptor activation reduces infarct size in the isolated, perfused mouse heart by inhibiting resident cardiac mast cell degranulation

Am J Physiol Heart Circ Physiol

(2008)

A. Kuno et al.

Infarct limitation by a protein kinase G activator at reperfusion in rabbit hearts is dependent on sensitizing the heart to A_2B agonists by protein kinase C

Am J Physiol Heart Circ Physiol

(2008)

Cited by (37)

Role of transglutaminase 2 in A<inf>1</inf> adenosine receptor- and β<inf>2</inf>-adrenoceptor-mediated pharmacological pre- and post-conditioning against hypoxia-reoxygenation-induced cell death in H9c2 cells
2018, European Journal of Pharmacology
Citation Excerpt :
In this study we have shown a role for TG2 in mediating A1 adenosine receptor-induced pre-conditioning. The role of the A1 adenosine receptor in ischaemic post-conditioning is controversial (Burley and Baxter, 2009). Evidence for a role include studies showing that the infarct limiting protection of ischaemic post-conditioning was absent in A1 adenosine receptor knockout mice (Xi et al., 2008).
Pharmacologically-induced pre- and post-conditioning represent attractive therapeutic strategies to reduce ischaemia/reperfusion injury during cardiac surgery and following myocardial infarction. We have previously reported that transglutaminase 2 (TG2) activity is modulated by the A₁ adenosine receptor and β₂-adrenoceptor in H9c2 cardiomyoblasts. The primary aim of this study was to determine the role of TG2 in A₁ adenosine receptor and β₂-adrenoceptor-induced pharmacological pre- and post-conditioning in the H9c2 cells. H9c2 cells were exposed to 8 h hypoxia (1% O₂) followed by 18 h reoxygenation, after which cell viability was assessed by monitoring mitochondrial reduction of MTT, lactate dehydrogenase release and caspase-3 activation. N⁶-cyclopentyladenosine (CPA; A₁ adenosine receptor agonist), formoterol (β₂-adrenoceptor agonist) or isoprenaline (non-selective β-adrenoceptor agonist) were added before hypoxia/reoxygenation (pre-conditioning) or at the start of reoxygenation following hypoxia (post-conditioning). Pharmacological pre- and post-conditioning with CPA and isoprenaline significantly reduced hypoxia/reoxygenation-induced cell death. In contrast, formoterol did not elicit protection. Pre-treatment with pertussis toxin (G_i/o-protein inhibitor), DPCPX (A₁ adenosine receptor antagonist) or TG2 inhibitors (Z-DON and R283) attenuated the A₁ adenosine receptor-induced pharmacological pre- and post-conditioning. Similarly, pertussis toxin, ICI 118,551 (β₂-adrenoceptor antagonist) or TG2 inhibition attenuated the isoprenaline-induced cell survival. Knockdown of TG2 using small interfering RNA (siRNA) attenuated CPA and isoprenaline-induced pharmacological pre- and post-conditioning. Finally, proteomic analysis following isoprenaline treatment identified known (e.g. protein S100-A6) and novel (e.g. adenine phosphoribosyltransferase) protein substrates for TG2. These results have shown that A₁ adenosine receptor and β₂-adrenoceptor-induced protection against simulated hypoxia/reoxygenation occurs in a TG2 and G_i/o-protein dependent manner in H9c2 cardiomyoblasts.
The mitochondrial permeability transition pore in AD 2016: An update
2016, Biochimica et Biophysica Acta - Molecular Cell Research
Citation Excerpt :
Interestingly, Verma et al. [105] have reported that knock-down of SIRT4, another mitochondrial isoform which lacks deacetylase activity but has ADP-ribosyltransferase activity, has the opposite effect, i.e., it increases resistance to mPTP induction. Postconditioning and remote (and remote-post) conditioning also have the mPTP as a major end target and largely use the same signaling pathways to prevent its opening (e.g.: [55,56,69,81,106–110] (Fig. 1). The translation of the accumulated biochemical knowledge into clinical practice has now begun, and various pharmacological interventions targeting aspects of the processes leading to necrotic cell death are under consideration (see Table 1) (e.g. [81,111–127]; revs.: [31,120,128–130]).
Over the past 30 years the mitochondrial permeability transition – the permeabilization of the inner mitochondrial membrane due to the opening of a wide pore – has progressed from being considered a curious artifact induced in isolated mitochondria by Ca^2 + and phosphate to a key cell-death-inducing process in several major pathologies. Its relevance is by now universally acknowledged and a pharmacology targeting the phenomenon is being developed. The molecular nature of the pore remains to this day uncertain, but progress has recently been made with the identification of the F_OF₁ ATP synthase as the probable proteic substrate. Researchers sharing this conviction are however divided into two camps: these believing that only the ATP synthase dimers or oligomers can form the pore, presumably in the contact region between monomers, and those who consider that the ring-forming c subunits in the F_O sector actually constitute the walls of the pore. The latest development is the emergence of a new candidate: Spastic Paraplegia 7 (SPG7), a mitochondrial AAA-type membrane protease which forms a 6-stave barrel. This review summarizes recent developments of research on the pathophysiological relevance and on the molecular nature of the mitochondrial permeability transition pore. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.
Pharmacological postconditioning against myocardial infarction with a slow-releasing hydrogen sulfide donor, GYY4137
2016, Pharmacological Research
Citation Excerpt :
Other kinases have been described as part of the RISK pathway including extracellular regulated kinase (ERK1/2; p42/p44 mitogen activated protein kinase) and glycogen synthase-3β (GSK-3β). Although IPost-C is of limited clinical applicability, a number of pharmacological approaches that mimic IPost-C have been described, including the administration of autacoids and other mediators thought to activate the kinases of the RISK cascade [5]. Hydrogen sulfide (H2S) has attracted considerable interest as a cardiovascular autacoid.
Exogenous hydrogen sulfide (H₂S) protects against myocardial ischemia/reperfusion injury but the mechanism of action is unclear. The present study investigated the effect of GYY4137, a slow-releasing H₂S donor, on myocardial infarction given specifically at reperfusion and the signalling pathway involved. Thiobutabarbital-anesthetised rats were subjected to 30 min of left coronary artery occlusion and 2 h reperfusion. Infarct size was assessed by tetrazolium staining. In the first study, animals randomly received either no treatment or GYY4137 (26.6, 133 or 266 μmol kg^⿿1) by intravenous injection 10 min before reperfusion. In a second series, involvement of PI3K and NO signalling were interrogated by concomitant administration of LY294002 or L-NAME respectively and the effects on the phosphorylation of Akt, eNOS, GSK-3β and ERK1/2 during early reperfusion were assessed by immunoblotting. GYY4137 266 μmol kg^⿿1 significantly limited infarct size by 47% compared to control hearts (P < 0.01). In GYY4137-treated hearts, phosphorylation of Akt, eNOS and GSK-3β was increased 2.8, 2.2 and 2.2 fold respectively at early reperfusion. Co-administration of L-NAME and GYY4137 attenuated the cardioprotection afforded by GYY4137, associated with attenuated phosphorylation of eNOS. LY294002 totally abrogated the infarct-limiting effect of GYY4137 and inhibited Akt, eNOS and GSK-3β phosphorylation. These data are the first to demonstrate that GYY4137 protects the heart against lethal reperfusion injury through activation of PI3K/Akt signalling, with partial dependency on NO signalling and inhibition of GSK-3β during early reperfusion. H₂S-based therapeutic approaches may have value as adjuncts to reperfusion in the treatment of acute myocardial infarction.
Intracoronary followed by intravenous administration of the short-acting β-blocker landiolol prevents myocardial injury in the face of elective percutaneous coronary intervention
2013, International Journal of Cardiology
Citation Excerpt :
Embolization of the atheromatous material in the distal vasculature and the intense arteriole vasospasm caused by microembolization of platelet-rich thrombi that release vasoactive agents, resulting in microvascular obstructions, are likely mechanisms of PCI-induced myocardial injury [5]. The current prophylactic management strategies used to minimize the PCI-induced myocardial injury include distal protection devices [6,7] and the intracoronary administration of vasodilators such as adenosine and nicorandil [8–10]. Although these therapies may be effective in preventing microembolization and reopening the occluded micro vessels, alternative strategies are required to prevent the ischemia and reperfusion injury that occur during the occlusion of the micro vessels and subsequent reperfusion.
Myocardial injury during elective percutaneous coronary intervention (PCI) is associated with higher subsequent cardiac events and mortality. β-Blockers have been used to reduce myocardial injury during ischemia and reperfusion. We investigated whether intracoronary followed by intravenous administration of the short-acting β-blocker landiolol prevents myocardial injury in the face of elective PCI.
Patients undergoing elective PCI (n = 70) were randomly assigned to the landiolol (n = 35) or control (n = 35) group. Landiolol or saline was administered into target vessels through a balloon catheter for 1 min before and after first balloon inflation followed by continuous intravenous administration for 6 h after PCI. The incidence of myocardial injury defined by cardiac troponin-I (cTnI) ≧ 0.05 ng/ml was 79% of the patients in the control group compared to 56% in the landiolol group (p = 0.04). The cTnI level at 24 h after PCI tended to be lower in the landiolol group (0.57 ± 1.14 versus 1.27 ± 2.48 ng/ml; p = 0.07), while the CK-MB level was not significantly different between the landiolol and control groups. The incidence of peri-procedural myocardial infarction defined by cTnI ≧ 0.12 ng/ml was significantly (p = 0.02) lower in the landiolol group (41%) compared to the control group (70%). There was no incidence of coronary spasm, hypotension, bradycardia or heart failure during and after PCI in the two groups.
Brief intracoronary followed by continuous intravenous administration of landiolol is safe and effective for myocardial protection in the face of elective PCI.
U50,488H postconditioning reduces apoptosis after myocardial ischemia and reperfusion
2011, Life Sciences
Evidence has indicated U50,488H, a selective κ-opioid receptor (κ-OR) agonist, administered before ischemia attenuates apoptosis and infarction during ischemia and reperfusion (I/R). However, it remains unclear whether U50,488H postconditioning reduces apoptosis during I/R. This study was designed, therefore, to test the hypothesis that U50,488H administered at the onset of reperfusion inhibits cardiomyocyte apoptosis and to investigate the underlying mechanisms.
Male Sprague–Dawley rats were subjected to myocardial ischemia and reperfusion(MI/R) and were randomized to receive either vehicle, U50,488H, U50,488H plus Nor-BNI, a selective κ-OR antagonist, U50,488H plus wortmannin, a specific inhibitor of phosphoinositide 3′-kinase (PI3K), or U50,488H plus L-NAME, a nitric oxide synthase inhibitor (NOS inhibitor), immediately prior to reperfusion. In vitro study was performed on cultured neonatal cardiomyocytes subjected to simulated ischemia/reperfusion.
Treatment with U50,488H resulted in increases in Akt and endothelial nitric oxide synthase (eNOS) phosphorylation with secondary NO production both in vivo and in vitro and these effect were completely blocked by wortmannin and specific Akt inhibitor(AI). L-NAME treatment had no effect on Akt and eNOS phosphorylation; but, significantly reduced NO production. Moreover, treatment with U50,488H markedly reduced myocardial apoptotic death. Treatment with wortmannin and specific Akt inhibitor abolished the anti-apoptotic effect of U50,488H. L-NAME also significantly attenuated the anti-apoptotic effect of U50,488H.
These results demonstrate that U50,488H administered immediately prior to reperfusion increases Akt phosphorylation through a PI3-kinase-dependent mechanism and reduces postischemic myocardial apoptosis. Phosphorylation of eNOS with secondary NO production contribute significantly to the anti-apoptotic effect of U50,488H postconditioning.
Deterioration of myocardial injury due to dexmedetomidine administration after myocardial ischaemia
2010, Resuscitation
Citation Excerpt :
The direct effect of α-2 adrenoceptor stimulants on ischaemic cardiac muscle and the involvement of intracellular changes after ischaemia have not yet been clarified. The receptors for adenosine,12 opioids,13 bradykinin B214 and natriuretic peptide15 are reportedly involved in pharmacological postconditioning,16 but the relationship between dexmedetomidine and these receptors remains unknown. We do not know whether α-2 adrenoceptor stimulants have a cardioprotective effect or the opposite effect.
Dexmedetomidine is a highly selective α-2 adrenergic agonist used perioperatively. Dexmedetomidine's cardioprotective effect after myocardial ischaemia remains unknown. In this study, we administered dexmedetomidine after ischaemia to investigate its ability to protect the cardiac muscle from ischaemia-reperfusion injury in isolated rat hearts.
After a 30-min stop of perfusion, isolated rat hearts underwent reperfusion for 120 min. At the initiation of reperfusion, dexmedetomidine was administered for 25 min at concentrations of 0 nM (control group), 1 nM (Dex 1 group), and 10 nM (Dex 10 group). Yohimbine (an α-2 adrenergic antagonist) was administered in the manner as above in another group of isolated rat hearts at a concentration of 1 μM without dexmedetomidine (Yoh group) and at 1 μM with 10 nM dexmedetomidine (Yoh + Dex 10 group). The area of infarction was measured using 2,3,5-triphenyltetrazolium staining.
Dexmedetomidine administration did not influence haemodynamics or the coronary flow (CF), but did increase the myocardial infarct size. Neither concentration of dexmedetomidine affected the infarct size as the Dex 1 and Dex 10 groups had almost the same infarct size. The infarct size was 40.5 ± 2.9% in the control group, 60.9 ± 5.3% in the Dex 1 group, and 60.9 ± 2.8% in the Dex 10 group. The infarct size was reduced in the yohimbine groups. The infarct size was 39.2 ± 3.3% in the Yoh + Dex 10 group and 45.0 ± 3.2% in the Yoh group.
Dexmedetomidine administration does not influence haemodynamics or CF, but does increase the cardiac infarct size. α-2 Adrenergic stimulation may induce this mechanism.

View all citing articles on Scopus

View full text

Pharmacological targets revealed by myocardial postconditioning

Section snippets

Reperfusion injury

Postconditioning

Upstream targets: autacoid and receptor mechanisms

Activation of ERK1/2 and PI3K/Akt

The ultimate cardioprotective target? Inhibition of mitochondrial permeability transition

Conclusion

References and recommended reading

Acknowledgements

Cardiovasc Res

Am Heart J

J Pharmacol Exp Ther

Am J Physiol Heart Circ Physiol

Am J Physiol Heart Circ Physiol

Am Heart J

Anesthesiology

Am J Physiol Heart Circ Physiol

Circ Res

Am J Physiol Heart Circ Physiol

Basic Res Cardiol

Am J Physiol Heart Circ Physiol

J Cardiovasc Pharmacol

Anesthesiology

Basic Res Cardiol

Circ Res

Hepatology

Basic Res Cardiol

Oncogene

Biochem J

Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning

Pharmacol Rev

Myocardial reperfusion injury

N Engl J Med

Reperfusion injury in humans: a review of clinical trials on reperfusion injury inhibitory strategies

Cardiovasc Res

The paradigm of postconditioning to protect the heart

J Cell Mol Med

Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning

Am J Physiol Heart Circ Physiol

Ventricular premature beat-driven intermittent restoration of coronary blood flow reduces the incidence of reperfusion-induced ventricular fibrillation in a cat model of regional ischemia

Am Heart J

Postconditioning the human heart

Circulation

Long-term benefit of postconditioning

Circulation

Ischemic postconditioning reduces infarct size by activation of A1 receptors and KATP channels in both normal and hypercholesterolemic rabbits

J Cardiovasc Pharmacol

Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade

Cardiovasc Res

Postconditioning's protection is not dependent on circulating blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylyl cyclase activation

Basic Res Cardiol

Targeted deletion of A2A adenosine receptors attenuates the protective effects of myocardial postconditioning

Am J Physiol Heart Circ Physiol

Reduction of reperfusion injury in the canine preparation by intracoronary adenosine: importance of the endothelium and the no-reflow phenomenon

Circulation

Adenosine A1 agonist at reperfusion trial (AART): results of a three-center, blinded, randomized, controlled experimental infarct study

Cardiovasc Drugs Ther

Adenosine infusion during early reperfusion failed to limit myocardial infarct size in a collateral deficient species

Cardiovasc Res

Combined adenosine and lidocaine administration limits myocardial reperfusion injury

Circulation

The time course of cardioprotection induced by GR79236, a selective adenosine A1-receptor agonist, in myocardial ischaemia-reperfusion injury in the pig

J Cardiovasc Pharmacol

The effects of intravenous infusions of selective adenosine A1-receptor and A2-receptor agonists on myocardial reperfusion injury

Am Heart J

Reduction of myocardial reperfusion injury by intravenous adenosine administered during the early reperfusion period

Circulation

Intravenous pretreatment with A1-selective adenosine analogues protects the heart against infarction

Circulation

Effect of adenosine therapy at reperfusion on myocardial infarct size in dogs

Cardiovasc Res

A1 receptor mediated myocardial infarct size reduction by endogenous adenosine is exerted primarily during ischaemia

Cardiovasc Res

Limitation of myocardial reperfusion injury by AMP579, an adenosine A1/A2A receptor agonist: role of A2A receptor and ERK1/2

Cardiovasc Drugs Ther

Cardiovascular pharmacology of the adenosine A1/A2-receptor agonist AMP, 579: coronary hemodynamic and cardioprotective effects in the canine myocardium

J Cardiovasc Pharmacol

Timing and duration of administration are crucial for anti-infarct effect of AMP 579 infused at reperfusion in rabbit heart

Heart Dis

Ischemic postconditioning reduces infarct size by activation of A₁ receptors and K_ATP channels in both normal and hypercholesterolemic rabbits

Postconditioning protects rabbit hearts through a protein kinase C-adenosine A_2b receptor cascade

Targeted deletion of A_2A adenosine receptors attenuates the protective effects of myocardial postconditioning

Adenosine A₁ agonist at reperfusion trial (AART): results of a three-center, blinded, randomized, controlled experimental infarct study

The time course of cardioprotection induced by GR79236, a selective adenosine A₁-receptor agonist, in myocardial ischaemia-reperfusion injury in the pig

The effects of intravenous infusions of selective adenosine A₁-receptor and A₂-receptor agonists on myocardial reperfusion injury

Intravenous pretreatment with A₁-selective adenosine analogues protects the heart against infarction

A₁ receptor mediated myocardial infarct size reduction by endogenous adenosine is exerted primarily during ischaemia

Limitation of myocardial reperfusion injury by AMP579, an adenosine A₁/A_2A receptor agonist: role of A_2A receptor and ERK1/2

Cardiovascular pharmacology of the adenosine A₁/A₂-receptor agonist AMP, 579: coronary hemodynamic and cardioprotective effects in the canine myocardium

Adenosine A_2A receptor activation reduces infarct size in the isolated, perfused mouse heart by inhibiting resident cardiac mast cell degranulation

Infarct limitation by a protein kinase G activator at reperfusion in rabbit hearts is dependent on sensitizing the heart to A_2B agonists by protein kinase C