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Derek M Yellon

Publications and source records attributed to Derek M Yellon.

18 recordsLinked to original sources
PubMed2003

Insulin therapy as an adjunct to reperfusion after acute coronary ischemia: a proposed direct myocardial cell survival effect independent of metabolic modulation.

Reperfusion therapy has become a practical and effective strategy in the salvage of ischemic myocardium. The direct enhancement of cardiac cellular tolerance against ischemic and reperfusion injury should further improve patient outcome in acute coronary syndromes (ACS). This approach has been explored for many decades, and although we await mortality-weighted randomized clinical trials, the infusion of glucose-insulin-potassium (GIK) has shown promise in protecting post-infarct myocardium. The current dogma is that this cardioprotective effect of GIK acts via the modulation of cardiac and circulating metabolites to provide the heart with an optimal metabolic milieu to resist ischemia and reperfusion injury. This concept of metabolic modulation has gained favor in coronary heart disease, and its efficacy currently is being investigated in stable angina using the new class of partial fatty acid oxidation inhibitors, including trimetazidine and ranolazine. We contend that the mitogen insulin, itself, promotes tolerance against ischemic cell death via the activation of innate cell-survival pathways in the heart. To advance this viewpoint, we will present clinical data that support a dose-dependent effect of insulin's beneficial action in the management of acute myocardial infarction. Furthermore, we present experimental data that identify cell-survival programs that are directly activated by the administration of insulin. Finally, as intravenous insulin therapy is both labor intensive and associated with metabolic perturbations, we propose that the development of pharmaco-therapeutic agents that target downstream cell-survival insulin-activated signaling molecules may be an alternate approach to promote cardioprotection during ACS.

Acute Disease↗
PubMed2003

Atorvastatin, administered at the onset of reperfusion, and independent of lipid lowering, protects the myocardium by up-regulating a pro-survival pathway.

OBJECTIVES: The purpose of this study was to determine whether atorvastatin, a 3-hydroxy-3-methylglutaryl (HMG)-co-enzyme A (CoA) reductase inhibitor, limits myocardial necrosis when administered as an adjunct to reperfusion. BACKGROUND: Statins inhibit HMG-CoA reductase to reduce the synthesis of cholesterol. However, it is proposed that statins have cardiovascular effects beyond their ability to lower cholesterol, possibly via recruitment of phosphatidyl inositol 3-kinase (PI3K) and the serine/threonine kinase, Akt. This signaling pathway has recently been linked to growth factor-mediated reperfusion salvage. METHODS: Isolated perfused mouse hearts were subjected to 35 min of global ischemia and reperfused for 30 min in the presence of incremental concentrations of atorvastatin. Infarct size was determined by triphenyltetrazolium chloride staining, and the activity of the PI3K signaling cascade was determined by Western blot analysis. RESULTS: We found that there was a profound dose-dependent reduction of infarct size with atorvastatin in the range of 25 to 100 micromol/l (optimal protection was seen at 50 micromol/l with infarct size of 16 +/- 2% vs. control, 33 +/- 2%, p < 0.01). Moreover, this protection was sensitive to inhibition with the PI3 kinase inhibitor, wortmannin, and was absent in endothelial nitric oxide synthase (eNOS) knockout mice. Western blot analysis revealed that atorvastatin resulted in rapid activation of the PI3K/Akt signaling cascade (within 5 min) and that both Akt and eNOS phosphorylation were significantly increased by 4.1-fold and 2.9-fold, respectively (p < 0.01). Moreover, phosphorylation of the PI3K substrates was abrogated by the administration of wortmannin. CONCLUSIONS: Atorvastatin attenuates lethal reperfusion-induced injury in a manner that is reliant on PI3K and Akt activity and the presence and activity of eNOS.

Animals↗
PubMed2003

B-type natriuretic peptide limits infarct size in rat isolated hearts via KATP channel opening.

B-type natriuretic peptide (BNP) has been reported to be released from the myocardium during ischemia. We hypothesized that BNP mediates cardioprotection during ischemia-reperfusion and examined whether exogenous BNP limits myocardial infarction and the potential role of ATP-sensitive potassium (K(ATP)) channel opening. Langendorff-perfused rat hearts underwent 35 min of left coronary artery occlusion and 120 min of reperfusion. The control infarct-to-risk ratio was 44.8 +/- 4.4% (means +/- SE). BNP perfused 10 min before ischemia limited infarct size in a concentration-dependent manner, with maximal protection observed at 10(-8) M (infarct-to-risk ratio: 20.1 +/- 5.2%, P < 0.01 vs. control), associated with a 2.5-fold elevation of myocardial cGMP above the control value. To examine the role of K(ATP) channel opening, glibenclamide (10(-6) M), 5-hydroxydecanoate (5-HD; 10(-4) M), or HMR-1098 (10(-5) M) was coperfused with BNP (10(-8) M). Protection afforded by BNP was abolished by glibenclamide or 5-HD but not by HMR-1098, suggesting the involvement of putative mitochondrial but not sarcolemmal K(ATP) channel opening. We conclude that natriuretic peptide/cGMP/K(ATP) channel signaling may constitute an important injury-limiting mechanism in myocardium.

Animals↗
PubMed2003

The cardioprotective and mitochondrial depolarising properties of exogenous nitric oxide in mouse heart.

OBJECTIVE: Nitric oxide (NO) is reported to be both protective and detrimental in models of myocardial ischaemia/reperfusion injury, which may be concentration dependent. Our objective was to characterise this dichotomy using the nitric oxide donor, S-nitroso N-acetyl penicillamine (SNAP) in isolated perfused mouse heart and isolated mouse cardiac mitochondria. METHODS: To determine the effect of nitric oxide concentration on myocardial viability, isolated mouse hearts were subjected to 35 min global ischaemia and 30 min reperfusion in the presence of SNAP (0.02-20 microM). To determine whether NO mediated protection was via opening of the putative mitochondrial K(ATP) channel and/or free radical synthesis, SNAP perfused hearts were also treated with the mitochondrial K(ATP) channel blocker, 5-hydroxy decanoate (5-HD) and the free-radical scavenger, N-(2-mercaptopropionyl)-glycine (MPG). This data was correlated with mitochondrial membrane potential (Delta Psi(m)), measured with the potentiometric dye, tetra-methyl rhodium methyl ester (TMRM), in isolated mitochondria,by flow cytometry. RESULTS: SNAP dose-dependently attenuated infarct size, with maximal protection observed at 2 microM (17+/-4% versus controls 32+/-3%, P<0.01). At greater concentrations however, protection was lost with infarct sizes tending towards control at 20 microM (29+/-3%). These results were paralleled by changes in Delta Psi(m) in the isolated mitochondria: Delta Psi(m) depolarisation peaking with 1 microM SNAP (26+/-4% shift in TMRM fluorescence, P<0.01); at greater concentrations, this relationship was lost. The mitochondrial K(ATP) channel blocker, 5-HD, resulted in both abrogation of SNAP infarct size reduction and concomitant loss of Delta Psi(m) depolarisation in the mitochondria. MPG however did not influence the cardioprotective properties of SNAP. CONCLUSION: We demonstrate that nitric oxide can mediate cardioprotection in a dose-dependent fashion by an effect that may be related to Delta Psi(m). Both cardioprotection and Delta Psi(m) changes are sensitive to 5-HD and the cardioprotection appears independent of free-radical synthesis.

Adenosine Triphosphate↗
PubMed2003

Bradykinin limits infarction when administered as an adjunct to reperfusion in mouse heart: the role of PI3K, Akt and eNOS.

Attenuation of reperfusion injury by growth factors has recently been linked to recruitment of phosphatidylinositol-3 kinase (PI3K) and protein kinase B (Akt), a pathway also linked to the phosphorylation of eNOS by bradykinin. We, therefore, hypothesised that bradykinin would limit infarct size when given as an adjunct to reperfusion. Using an isolated perfused mouse heart model of ischaemia/reperfusion injury, we show that 100 nmol/l bradykinin, administered upon reperfusion, attenuates infarct size (32 +/- 2% to 22 +/- 2%, P < 0.01). This protection was abrogated by concomitant administration of the PI3K inhibitor, wortmannin (100 nmol/l), whereas wortmannin alone had no impact upon infarct size (31 +/- 3% and 30 +/- 1%, respectively). In eNOS knockout hearts, bradykinin was not seen to be protective (31 +/- 2% versus 32 +/- 2%), yet knockout hearts could be rescued with the nitric oxide donor, S-nitroso-N-acetyl penicillamine (SNAP) (1 micromol/l) (17 +/- 4%, P < 0.01). Using western blot analysis, we show that bradykinin administration results in rapid, robust phosphorylation of both Akt and eNOS, greater than that seen in control hearts upon reperfusion (Akt/eNOS phosphorylation: 68 +/- 7/122 +/- 29 AU versus 32 +/- 5/47 +/- 10 AU respectively, P < 0.01). This pattern of Akt phosphorylation was mimicked in the absence of eNOS, whereas Akt phosphorylation was inhibited by wortmannin. Exogenous nitric oxide administration had no impact upon Akt phosphorylation. Therefore, we demonstrate that exogenous bradykinin, administered at reperfusion, limits infarct size with concomitant rapid phosphorylation of Akt and eNOS, and that this protection is dependent upon the presence of eNOS. These results may open new avenues for research into clinical limitation of reperfusion injury following acute myocardial infarction.

Androstadienes↗
PubMed2003

Second window of protection following myocardial preconditioning: an essential role for PI3 kinase and p70S6 kinase.

Ischaemic preconditioning (IPC) protects the heart against myocardial infarction acutely as well as several hours later (e.g. 24-48 h). The mechanism of the profound cardioprotection is not completely explored. We hypothesized that PI3K/PDK1/Akt/mTOR/p70S6K-mediated pro-survival pathway is involved in delayed cardioprotection induced by IPC. Under Hypnorm-Diazepam anaesthesia, male New Zealand White rabbits were either sham-operated (SC) or preconditioned by four cycles of 5-min ischaemia and 10-min reperfusion on day 1. Twenty-four hours after recovery, the animals were anaesthetized with sodium pentobarbitone and subjected to 30-min ischaemia followed by 180-min reperfusion. Wortmannin (0.6 mg/kg, i.v.), an irreversible PI3 kinase (PI3K) inhibitor, rapamycin (0.25 mg/kg, i.v.), which prevents the phosphorylation of p70S6 kinase (p70S6K), or DMSO (control vehicle) was given 15 min prior to IPC. IPC significantly reduced infarct size compared to the control group (SC) (31.9 +/- 5.8% (n = 7) vs. 54.9 +/- 2.9% (n = 6), P < 0.05). Wortmannin and rapamycin alone had no effect on infarct size (56.3 +/- 1.6% (n = 6) and 54.7 +/- 3.8% (n = 6), respectively). However, when wortmannin or rapamycin were given prior to IPC the protection was completely abolished (49.9 +/- 2.8% (n = 6), 45.1 +/- 4.6% (n = 7), P < 0.05 vs. IPC). Western blot analysis showed that wortmannin, at a dose of 0.6 mg/kg, and rapamycin, at a dose of 0.25 mg/kg, were sufficient to prevent phosphorylation of Akt and p70S6K, respectively, when the inhibitors were given prior to IPC. We conclude that PI3K/PDK1/Akt/mTOR/p70S6K-signalling pathway plays an essential role in the development of the cardioprotection against infarction in rabbits.

Androstadienes↗
PubMed2003

Role of nuclear factor-kappa B activation in acute ischaemia-reperfusion injury in myocardium.

(1) Our aims were to characterize activation of the transcription factor, nuclear factor kappa-B(NF-kappaB), during myocardial ischaemia-reperfusion and to assess its functional role in the evolution of acute ischaemia-reperfusion injury in intact myocardium in vivo. (2) Under pentobarbitone anaesthesia, rabbits underwent sham operation, 30 min left coronary artery occlusion followed by 0, 10 or 180 min reperfusion. Saline or NF-kappaB inhibitor diethyldithiocarbamic acid (DDTC, 50, 100 or 200 mg kg(-1)) was given intravenously 5 min prior to reperfusion. (3) Electromobility shift assay revealed that 30 min ischaemia alone did not activate NF-kappaB compared to time-matched sham-operated controls (85+/-13% vs 100+/-28%, respectively). However, ischaemia plus 10 min reperfusion markedly increased activation of NF-kappaB (295+/-77%). DDTC 50 mg kg(-1) did not inhibit NF-kappaB activation (278+/-67%) but at the higher doses complete inhibition was observed (54+/-20%, 31+/-16%, respectively). (4) Infarct to risk ratio was determined by triphenyltetrazolium chloride staining after 30 min ischaemia and 180 min reperfusion. DDTC 50 or 100 mg kg(-1) significantly reduced infarct size compared to the saline-treated control group (34.9+/-5.2%, 37.1+/-5.9%, vs 51.3+/-3.6%, P<0.05, respectively), whereas there was no protection with 200 mg kg(-1) (45.6+/-5.3%). (5) We conclude that ischaemia alone does not activate NF-kappaB, but post-ischaemic reperfusion robustly activates NF-kappaB in the myocardium. DDTC limited irreversible injury at low doses, but this effect appears to be dissociated from inhibition of NF-kappaB. Thus, activation of NF-kappaB during reperfusion does not appear to play a role in the evolution of myocardial infarction during the early phase of reperfusion.

Animals↗
PubMed2002

Mitochondrial K(ATP) channels: role in cardioprotection.

The role of the mitochondrial ATP-sensitive potassium channel (mK(ATP)) in ischemic preconditioning and cardioprotection is reviewed. A great deal of accumulated evidence implicatese opening of this channel as an important step in the anti-infarct effect of ischemic preconditioning. Recent studies, however, reveal that channel opening can actually serve as a signal transduction element. Data indicate that mK(ATP) opening causes mitochondria to generate reactive oxygen species (ROS) which then activate downstream kinases. Opening of mK(ATP) prior to ischemia can serve as a trigger since the critical time for its opening is prior to the onset of the lethal ischemic insult. Most G(i)-coupled receptors trigger protection through the mK(ATP)/ROS pathway except for the adenosine receptor which uses some other, as yet unidentified, pathway. Possible coupling schemes between the receptors and the mK(ATP) are discussed. Protection from preconditioning can also be aborted when a mK(ATP) blocker is present only during the lethal ischemic insult (mediator phase), but a much higher concentration of the blocker is required. Thus the mK(ATP) probably serves a dual role as both a trigger and a mediator. Possible end-effectors of preconditioning's protection are discussed including the mK(ATP) itself.

Adenosine Triphosphate↗
PubMed2002

Inhibiting mitochondrial permeability transition pore opening: a new paradigm for myocardial preconditioning?

OBJECTIVE: We propose that ischemic preconditioning (IPC) and mitochondrial K(ATP) channel activation protect the myocardium by inhibiting mitochondrial permeability transition pore (MPTP) opening at reperfusion. METHODS: Isolated rat hearts were subjected to 35 min ischemia/120 min reperfusion and assigned to the following groups: (1) control; (2) IPC of 2x5 min each of preceding global ischemia; (3,4,5) 0.2 micromol/l cyclosporin A (CsA, which inhibits MPTP opening), 5 micromol/l FK506 (which inhibits the phosphatase calcineurin without inhibiting MPTP opening), or 20 micromol/l atractyloside (Atr, a MPTP opener) given at reperfusion; (6,7) pre-treatment with 30 micromol/l diazoxide (Diaz, a mitochondrial K(ATP) channel opener) or 200 nmol/l 2 chloro-N(6)-cyclopentyl-adenosine (CCPA, an adenosine A1 receptor agonist); (8) IPC+Atr; (9) Diaz+Atr; (10) CCPA+Atr. The effect of mitochondrial K(ATP) channel activation on calcium-induced MPTP opening in isolated calcein-loaded mitochondria was also assessed. RESULTS: IPC, CsA when given at reperfusion, and pre-treatment with diazoxide or CCPA all limited infarct size (19.9+/-2.6% in IPC; 24.6+/-1.9% in CsA, 18.0+/-1.7% in Diaz, 20.4+/-3.3% in CCPA vs. 44.7+/-2.0% in control, P<0.0001). Opening the MPTP with atractyloside at reperfusion abolished this cardio-protective effect (47.7+/-1.8% in IPC+Atr, 42.3+/-3.2% in Diaz+Atr, 51.2+/-1.6% in CCPA+Atr). Atractyloside and FK506, given at reperfusion, did not influence infarct size (45.7+/-2.1% in Atr and 43.1+/-3.6% in FK506 vs. 44.7+/-2.0% in control, P=NS). Diazoxide (30 micromol/l) was shown to reduce calcium-induced MPTP opening by 52.5+/-8.0% in calcein-loaded mitochondria. 5-Hydroxydecanoic acid (100 micromol/l) was able to abolish the cardio-protective effects of both diazoxide and IPC. CONCLUSION: One interpretation of these data is that IPC and mitochondrial K(ATP) channel activation may protect the myocardium by inhibiting MPTP opening at reperfusion.

Adenosine↗
PubMed2002

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

Reperfusion of ischemic myocardium is essential for tissue salvage but paradoxically contributes to cell death. We hypothesized that activation of potential survival pathways such as p42/p44 MAPK may prevent lethal reperfusion injury. Urocortin is a peptide factor that affects the p42/p44 MAPK signaling pathway. Both isolated and in vivo rat heart models were used to examine the potential for urocortin to prevent reperfusion injury. Isolated rat hearts underwent 35-min regional ischemia and 2-h reperfusion, with urocortin perfused for 20 min from the onset of reperfusion. In the in vivo study, urocortin was administered as an intravenous bolus 3 min before reperfusion with a protocol of 25-min regional ischemia and 2-h reperfusion. Blockade of the p42/p44 MAPK pathway with the inhibitor PD-98059 was used in both models. Urocortin attenuated lethal reperfusion-induced injury both in vitro and in vivo via a p42/p44 MAPK-dependent mechanism. Furthermore, Western blot analysis demonstrated the ability of urocortin to directly upregulate this signaling pathway. In conclusion, we believe that the p42/p44 MAPK-dependent signaling pathway represents an important survival mechanism against reperfusion injury.

Animals↗
PubMed2002

Nitric oxide as a mediator of delayed pharmacological (A(1) receptor triggered) preconditioning; is eNOS masquerading as iNOS?

BACKGROUND: Nitric oxide (NO), synthesised from the inducible isoform of nitric oxide synthase (iNOS), is implicated in mediating second window of protection (SWOP)/delayed ischemic preconditioning. However the role of NO and iNOS in delayed pharmacological protection remains unclear and is the subject of this investigation. METHODS: To test the hypothesis that iNOS is necessary for delayed pharmacological preconditioning, the adenosine A(1) receptor agonist, 2-chloro N(6) cyclopentyl adenosine (CCPA) (25 microg/kg i.v.) or saline was administered to wild type (WT) or iNOS gene knockout mice (KO). Twenty-four hours later, the hearts were isolated, Langendorff perfused and subjected to 35 min ischemia/30 min reperfusion prior to infarct size determination. RESULTS: WT and KO control hearts had identical infarct sizes of 37 +/- 3% and 37 +/- 2%, respectively. CCPA significantly reduced infarct size in WT hearts to 22 +/- 2% and also, unexpectedly, in KO hearts (27 +/- 2%). This protection was abrogated with the non-specific NOS inhibitor, N(omega) nitro L-arginine methyl ester (L-NAME, 100 microM), and could be mimicked in naïve hearts with the NO donor, donor S-nitroso N-acetyl DL penicillamine (SNAP, 1 microM). Delayed protection appeared to be mediated by NO synthesis in both WT and KO hearts. Additional studies using Western blot analysis demonstrated endothelial NOS (eNOS) upregulation and increased NO(x) release in both WT and KO hearts. CONCLUSIONS: This is the first study to demonstrate a role for eNOS in delayed A(1) receptor triggered (pharmacological) preconditioning, potentially representing a new pharmacological target for protecting the ischemic heart.

Analysis of Variance↗
PubMed2002

PI3 kinase and not p42/p44 appears to be implicated in the protection conferred by ischemic preconditioning.

Ischemic preconditioning results in an immediate phase of protection against lethal ischemia/reperfusion injury that is comprised of both irreversible necrosis and programmed cell death, apoptosis. We hypothesized that preconditioning may activate putative anti-apoptotic pathways, through the induction of either phosphatidyl inositol 3-OH kinase (PI3 kinase) or p42/p44 extracellular receptor kinase, attenuating total cell death. Isolated perfused rat hearts were preconditioned with two cycles of 5 min ischemia and 10 min reperfusion. Then they were frozen for Western blot analysis or subjected to 35 min regional ischemia and 120 min reperfusion prior to infarct size assessment. Selective PI3 kinase inhibitors, wortmannin (W, 100 n M) and LY294002 (LY, 15 microM) and the p42/p44 inhibitor, PD 98059 (PD, 10 and 50 microM), were individually infused during the preconditioning protocol. One further group of hearts received both inhibitors (W and PD). The results were expressed as percentage of infarction within the risk zone. Inhibition of PI3 kinase by either W or LY partially abrogated the infarct sparing effect of ischemic preconditioning (I/R%: 44.6+/-2.7 in C, 17.6+/-2.0 in IP, vs 32.2+/-4.2 in W, and 30.9+/-2.6 in LY, P<0.05). Inhibition of ERK phosphorylation however, had no significant effect upon infarct size reduction (17.6+/-2.0 in ischemic preconditioning vs 21.4+/-3.0 in IP+10 microM PD and 15.2+/-1.4 in IP+50 microM PD, P>0.05). Western blot analysis confirmed that PD abrogated the phosphorylation of p42/p44 and LY the phosphorylation of AKT. Combined inhibition with PD+W failed to further attenuate protection (27.6+/-1.3%, P>0.1). These data appear to demonstrate that the PI3 kinase, but not the p42/p44 cascade, is implicated in early ischemic preconditioning.

Androstadienes↗
PubMed2002

Cardiotrophin-1 (CT-1) can protect the adult heart from injury when added both prior to ischaemia and at reperfusion.

OBJECTIVES: To determine whether the cytokine cardiotrophin-1 (CT-1) can protect the adult heart against ischaemia/reperfusion when added either prior to ischaemia or at reperfusion. BACKGROUND: CT-1 has previously been shown to protect cultured embryonic or neonatal cardiocytes from cell death. To assess the therapeutic potential of CT-1, it is necessary to determine whether this effect can be observed in adult cardiac cells both in culture and most importantly in the intact heart. METHODS: We examined the protective effect of CT-1 both in cultured adult rat cardiocytes and in the rat intact heart. In both cases, the cardiac cells were exposed to hypoxia/ischaemia followed by reoxygenation/reperfusion and CT-1 was administered either prior to hypoxia/ischaemia or at reoxygenation/reperfusion. RESULTS: CT-1 has a protective effect in reducing ischaemic damage in the intact heart ex vivo as assayed by infarct size to area at risk ratio (20% compared to 35%). Similar protective effects against cell death were noted in adult cells in vitro. Both in vitro and ex vivo CT-1 can exert a protective effect when added at the time of reoxygenation/reperfusion as well as prior to the hypoxic/ischaemic stimulus (cell death reduced from 50 to 20% in TUNEL assay, infarct size to zone at risk ratio reduced from 35 to 20%). These protective effects are blocked by an inhibitor of the p42/p44 MAPK pathway. CONCLUSION: CT-1 can protect adult cardiac cells both in vitro and in vivo when added both prior to or after the hypoxic/ischaemic stimulus. The potential therapeutic benefit of CT-1 when added at the time of reperfusion following ischaemic damage is discussed.

Age Factors↗
PubMed2002

Adenosine A(3) receptor activation protects the myocardium from reperfusion/reoxygenation injury.

Ischemia-reperfusion induces both necrotic and apoptotic cell death. The ability of adenosine to attenuate reperfusion-induced injury (RI) and the role played by adenosine receptors are unclear. We therefore studied the role of the A(3) receptor (A(3)R) in ameliorating RI using the specific A(3)R agonist 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxi-N-methyl-b-D-ribofuranuronamide (2-Cl-IB-MECA). Isolated rat hearts and cardiomyocytes were subjected to ischemia or simulated ischemia, followed by reperfusion/reoxygenation. The end points were percent infarction/risk zone and annexin-V (apoptosis) and/or propidium iodide positivity (necrosis), respectively. In isolated hearts, 2-Cl-IB-MECA significantly limited infarct size (44.2 +/- 2.7% in control vs. 21.9 +/- 2.4% at 1 nM and 35.8 +/- 3.3% at 0.1 nM, P < 0.05). In isolated myocytes, apoptosis and necrosis were significantly reduced compared with controls (5.7 +/- 2.6% vs. 17.1 +/- 1.3% and 13.7 +/- 2.0% vs. 23.1 +/- 1.5%, respectively, P < 0.0001). In both models, the beneficial effects were abrogated using the A(3)R antagonist MRS-1191. The involvement of A(2a) receptor activation was also examined. This is the first study to demonstrate that A(3)R activation at reperfusion limits myocardial injury in the isolated rat heart and improves survival in isolated myocytes, possibly by antiapoptotic and antinecrotic mechanisms.

Adenosine↗