Preconditioning limits myocardial infarct size and attenuates myocardial stunning via adenosine receptor activation

Adenosine-enhanced ischemic preconditioning (APC) extends the cardioprotection of ischemic preconditioning (IPC) by both significantly decreasing myocardial infarct size and significantly enhancing postischemic functional recovery. In this study, the role of adenosine receptors during ischemia-reperfusion was determined. Rabbit hearts ( n = 92) were used for Langendorff perfusion. Control hearts were perfused for 180 min, global ischemia hearts received 30-min ischemia and 120-min reperfusion, and IPC hearts received 5-min ischemia and 5-min reperfusion before ischemia. APC hearts received a bolus injection of adenosine coincident with IPC. Adenosine receptor (A1, A2, and A3) antagonists were used with APC before ischemia and/or during reperfusion. GR-69019X (A1/A3) and MRS-1191/MRS-1220 (A3) significantly increased infarct size in APC hearts when administered before ischemia and significantly decreased functional recovery when administered during both ischemia and reperfusion ( P < 0.05 vs. APC). DPCPX (A1) administered either before ischemia and/or during reperfusion had no effect on APC cardioprotection. APC-enhanced infarct size reduction is modulated by adenosine receptors primarily during ischemia, whereas APC-enhanced postischemic functional recovery is modulated by adenosine receptors during both ischemia and reperfusion.

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Limitation of myocardial infarct size by adenosine A1 receptor activation is abolished by protein kinase C inhibitors in the rabbit

Cardiovascular Research ◽

10.1016/s0008-6363(96)88641-x ◽

1995 ◽

Vol 29 (5) ◽

pp. 682-688 ◽

Cited By ~ 19

Author(s):

Jun Sakamoto ◽

Tetsuji Miura ◽

Mahiko Goto ◽

Osamu Iimura

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Infarct Size ◽

Myocardial Infarct ◽

Receptor Activation ◽

Myocardial Infarct Size ◽

Protein Kinase C Inhibitors ◽

Kinase C ◽

Adenosine A1 ◽

A1 Receptor

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Phosphodiesterase-3 inhibition augments the myocardial infarct size-limiting effects of exenatide in mice with type 2 diabetes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00609.2012 ◽

2013 ◽

Vol 304 (1) ◽

pp. H131-H141 ◽

Cited By ~ 17

Author(s):

Yumei Ye ◽

Jinqiao Qian ◽

Alexander C. Castillo ◽

Shukuan Ling ◽

Hongmei Ye ◽

...

Keyword(s):

Infarct Size ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Receptor Activation ◽

Intracellular Camp ◽

Myocardial Infarct Size ◽

Activity Levels ◽

Additive Effects ◽

Phosphodiesterase 3 ◽

Camp Levels

Glucagon-like peptide (GLP)-1 receptor activation increases intracellular cAMP with downstream activation of PKA. Cilostazol (CIL), a phosphodiesterase-3 inhibitor, prevents cAMP degradation. We assessed whether CIL amplifies the exenatide (EX)-induced increase in myocardial cAMP levels and PKA activity and augments the infarct size (IS)-limiting effects of EX in db/ db mice. Mice fed a Western diet received oral CIL (10 mg/kg) or vehicle by oral gavage 24 h before surgery. One hour before surgery, mice received EX (1 μg/kg sc) or vehicle. Additional mice received H-89, a PKA inhibitor, alone or with CIL + EX. Mice underwent 30 min of coronary artery occlusion and 24 h of reperfusion. Both EX and CIL increased myocardial cAMP levels and PKA activity. Levels were significantly higher in the EX + CIL group. Both EX and CIL reduced IS. IS was the smallest in the CIL + EX group. H-89 completely blocked the IS-limiting effects of EX + CIL. EX + CIL decreased phosphatase and tensin homolog on chromosome 10 upregulation and increased Akt and ERK1/2 phosphorylation after ischemia-reperfusion. These effects were blocked by H-89. In conclusion, EX and CIL have additive effects on IS limitation in diabetic mice. The additive effects are related to cAMP-induced PKA activation, as H-89 blocked the protective effect of CIL + EX.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01009.2004 ◽

2005 ◽

Vol 288 (5) ◽

pp. H2253-H2259 ◽

Cited By ~ 40

Author(s):

Easton A. Reid ◽

Gentian Kristo ◽

Yukihiro Yoshimura ◽

Cherry Ballard-Croft ◽

Byron J. Keith ◽

...

Keyword(s):

Infarct Size ◽

Adenosine Receptor ◽

Myocardial Infarct ◽

Mitogen Activated Protein Kinase ◽

Myocardial Infarct Size ◽

Protective Effects ◽

In Vivo Models ◽

Receptor Modulation ◽

Adenosine Receptor Agonist

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 1 S-[1a,2b,3b,4a( S*)]-4-[7-[[2-(3-chloro-2-thienyl)-1-methylpropyl]amino]-3H-imidazo[4,5-b]pyridyl-3-yl]cyclopentane carboxamide (AMP-579) reduced infarct size from 49 ± 3% to 29 ± 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 A1 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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