Adenosine A<sub>1</sub>/A<sub>2a</sub> receptor agonist AMP-579 induces acute and delayed preconditioning against in vivo myocardial stunning

Kristo, Gentian; Yoshimura, Yukihiro; Keith, Byron J.; Stevens, Randy; Jahania, Salik; Mentzer, Robert M.; Lasley, Robert D.

doi:10.1152/ajpheart.00493.2004

Cited by 10 publications

(11 citation statements)

References 33 publications

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“…The animal was then euthanized with a pentobarbital overdose, the heart was excised, and the atria and great vessels were removed. The heart was sliced into three to four pieces (Ͼ2 mm thickness) from base to apex for staining with triphenyltetrazolium chloride solution to measure infarct size as previously described (12). The AAR was devoid of Evans blue dye while the infarcted tissue within the AAR was the triphenyltetrazolium chloride -negative stained region.…”

Section: Allmentioning

confidence: 99%

In vivo adenosine receptor preconditioning reduces myocardial infarct size via subcellular ERK signaling

Reid

Kristo

Yoshimura

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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. In vivo adenosine receptor preconditioning reduces myocardial infarct size via subcellular ERK signaling. Am J Physiol Heart Circ Physiol 288: H2253-H2259, 2005. First published January 14, 2005 doi:10.1152/ajpheart.01009.2004.-The protective effects of adenosine receptor acute preconditioning (PC) are well known; however, the signaling mechanism mediating this effect has not been determined in in vivo models. The purpose of this study was to determine the role of the extracellular signal-regulated kinase (ERK) pathway in mediating adenosine PC in in vivo rat myocardium. Open-chest rats were submitted to 25 min of coronary artery occlusion and 2 h of reperfusion. ERK activation was assessed by measuring total and dually phosphorylated p44/42 ERK isoforms in nuclear and/or myofilament, mitochondrial, cytosolic, and membrane fractions. Adenosine receptor PC with the A1/A2a agonist 1S-[1a,2b,3b,4acyclopentane carboxamide (AMP-579) reduced infarct size from 49 Ϯ 3% to 29 Ϯ 3%, an effect that was blocked by the mitogen-activated protein kinase-ERK inhibitor U-0126. ERK isoforms were present in all fractions, with the greatest expression in the cytosolic fraction and the least in the mitochondrial fraction. AMP-579 treatment increased preischemic p44/42 ERK phosphorylation in all fractions 2.7-to 6.9-fold. Reperfusion increased ERK isoform activation in all fractions, but there were no differences between control and AMP-579 hearts. Preischemic increases in phospo-p44/p42 ERK with AMP-579 were blunted by U-0126, although only in mitochondrial and membrane compartments. The PC effects of AMP-579 on infarct size and ERK were blunted by both the A 1 antagonist 8-cyclopentyl-1,3-dipropylxanthine and, surprisingly, the A2a antagonist ZM-241385. These results indicate that the unique adenosine receptor agonist AMP-579 exerts its beneficial effects in vivo via both A1 and A2a receptor modulation of subcellular ERK isoform signaling.

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Section: Allmentioning

confidence: 99%

In vivo adenosine receptor preconditioning reduces myocardial infarct size via subcellular ERK signaling

Reid

Kristo

Yoshimura

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…Treatment with AMP579, both prior to ischemia and during reperfusion, reduces in vivo infarct size in several species [26][27][28][29][30][31], due to its ability to activate both adenosine A 1 and A 2A receptors. We have recently reported that pretreatment with AMP579 dose-dependently attenuated in vivo myocardial stunning, with only minor, transient reductions in HR and MAP [10]. This anti-stunning effect of AMP579 was completely blocked by the adenosine A 1 receptor antagonist DPCPX, indicating that this cardioprotective effect was mediated via A 1 receptor activation.…”

Section: Discussionmentioning

confidence: 91%

“…On the other hand, AMP579 is a unique agent with high affinity for both adenosine A 1 and A 2A receptors, and it has been shown to exert much less hemodynamic effects in vivo [10,[26][27][28][29]. Treatment with AMP579, both prior to ischemia and during reperfusion, reduces in vivo infarct size in several species [26][27][28][29][30][31], due to its ability to activate both adenosine A 1 and A 2A receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Although the cardioprotective effects of preischemic adenosine are thought to be mediated via the activation of adenosine A 1, and possibly A 3 receptors [6,7], there have been few reports of adenosine A 1 receptor mediated attenuation of stunning in in vivo models [8,9]. Recently, we reported that preischemic treatment with the adenosine A 1 /A 2A receptor agonist AMP579 attenuated myocardial stunning in an in vivo porcine model via the activation of adenosine A 1 receptors [10].…”

Section: Introductionmentioning

confidence: 94%

“…The slices were incubated in a 1% 2,3,5-triphenyltetrazolium chloride (TTC) solution (Sigma) in phosphate-buffered saline solution at 37 • C for 15 min to determine whether any infarction occurred. We have previously reported that this model of myocardial stunning does not produce any necrosis [10,[22][23][24][25]. The region at risk was calculated by dividing the area at risk by the total left ventricular area (e.g., the sum of the area at risk and the area of the remainder of the left ventricle).…”

Section: Determination Of the Region At Riskmentioning

confidence: 99%

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The p38 MAPK Inhibitor SB203580 Blocks Adenosine A1 Receptor-Induced Attenuation of In Vivo Myocardial Stunning

Yoshimura

Kristo

Keith

et al. 2004

Cardiovasc Drugs Ther

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There is considerable evidence implicating a key role for p38 mitogen-activated protein kinase (MAPK) in ischemic and pharmacological preconditioning against myocardial infarction. However, there have been few, if any, studies examining the role of p38 MAPK in the protection of stunned myocardium. The purpose of this study was to determine whether p38 MAPK plays a role in the adenosine A(1) receptor anti-stunning effect in in vivo porcine myocardium. Regional myocardial stunning in anesthetized, open-chest pigs was induced by 15 min of left anterior descending coronary artery (LAD) occlusion and 3 h of reperfusion (RP). Animals were treated with either vehicle (n = 5), AMP579 (70 microg/kg i.v.; 25 microg/kg bolus + 1.5 microg/kg/min for 30 min prior to ischemia, n = 5), the p38 MAPK inhibitor SB203580 (0.25 mg/kg i.v. bolus, n = 4) or a combination of SB203580 plus AMP579 (n = 5). Regional ventricular function was monitored by measurements of segment shortening and load insensitive parameters including preload recruitable stroke work (PRSW) and PRSW area (PRSWA). The ischemic area at risk was similar in all groups and there was no necrosis in any heart. Treatment with AMP579 significantly improved reperfusion regional PRSW and PRSWA compared to vehicle controls. The p38 inhibitor SB203580 alone did not alter the extent of myocardial stunning, but it abolished the beneficial effect of AMP579 pretreatment. These results provide the first evidence that p38 MAPK activation may play an important role in the mechanism by which adenosine agonists attenuate myocardial stunning.

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Adenosine Receptors and Reperfusion Injury of the Heart

Headrick

Lasley

2009

Adenosine Receptors in Health and Disease

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Adenosine, a catabolite of ATP, exerts numerous effects in the heart, including modulation of the cardiac response to stress, such as that which occurs during myocardial ischemia and reperfusion. Over the past 20 years, substantial evidence has accumulated that adenosine, administered either prior to ischemia or during reperfusion, reduces both reversible and irreversible myocardial injury. The latter effect results in a reduction of both necrosis or myocardial infarction (MI) and apoptosis. These effects appear to be mediated via the activation of one or more G-protein-coupled receptors (GPCRs), referred to as A 1 , A 2A , A 2B and A 3 adenosine receptor (AR) subtypes. Experimental studies in different species and models suggest that activation of the A 1 or A 3 ARs prior to ischemia is cardioprotective. Further experimental studies reveal that the administration of A 2A AR agonists during reperfusion can also reduce MI, and recent reports suggest that A 2B ARs may also play an important role in modulating myocardial reperfusion injury. Despite convincing experimental evidence for AR-mediated cardioprotection, there have been only a limited number of clinical trials examining the beneficial effects of adenosine or adenosine-based therapeutics in humans, and the results of these studies have been equivocal. This review summarizes our current knowledge of AR-mediated cardioprotection, and the roles of the four known ARs in experimental models of ischemia-reperfusion. The chapter concludes with an examination of the clinical trials to date assessing the safety and efficacy of adenosine as a cardioprotective agent during coronary thrombolysis in humans.

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Adenosine A₁/A_2a receptor agonist AMP-579 induces acute and delayed preconditioning against in vivo myocardial stunning

Cited by 10 publications

References 33 publications

In vivo adenosine receptor preconditioning reduces myocardial infarct size via subcellular ERK signaling

In vivo adenosine receptor preconditioning reduces myocardial infarct size via subcellular ERK signaling

The p38 MAPK Inhibitor SB203580 Blocks Adenosine A1 Receptor-Induced Attenuation of In Vivo Myocardial Stunning

Adenosine Receptors and Reperfusion Injury of the Heart

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Adenosine A1/A2a receptor agonist AMP-579 induces acute and delayed preconditioning against in vivo myocardial stunning

Cited by 10 publications

References 33 publications

In vivo adenosine receptor preconditioning reduces myocardial infarct size via subcellular ERK signaling

In vivo adenosine receptor preconditioning reduces myocardial infarct size via subcellular ERK signaling

The p38 MAPK Inhibitor SB203580 Blocks Adenosine A1 Receptor-Induced Attenuation of In Vivo Myocardial Stunning

Adenosine Receptors and Reperfusion Injury of the Heart

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Adenosine A₁/A_2a receptor agonist AMP-579 induces acute and delayed preconditioning against in vivo myocardial stunning