Adenosine A2A and A2B receptors are both required for adenosine A1 receptor-mediated cardioprotection

All four adenosine receptor subtypes have been shown to play a role in cardioprotection, and there is evidence that all four subtypes may be expressed in cardiomyocytes. There is also increasing evidence that optimal adenosine cardioprotection requires the activation of more than one receptor subtype. The purpose of this study was to determine whether adenosine A2A and/or A2B receptors modulate adenosine A1 receptor-mediated cardioprotection. Isolated perfused hearts of wild-type (WT), A2A knockout (KO), and A2BKO mice, perfused at constant pressure and constant heart rate, underwent 30 min of global ischemia and 60 min of reperfusion. The adenosine A1 receptor agonist N6-cyclohexyladenosine (CHA; 200 nM) was administrated 10 min before ischemia and for the first 10 min of reperfusion. Treatment with CHA significantly improved postischemic left ventricular developed pressure (74 ± 4% vs. 44 ± 4% of preischemic left ventricular developed pressure at 60 min of reperfusion) and reduced infarct size (30 ± 2% with CHA vs. 52 ± 5% in control) in WT hearts, effects that were blocked by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (100 nM). Treatments with the A2A receptor agonist CGS-21680 (200 nM) and the A2B agonist BAY 60-6583 (200 nM) did not exert any beneficial effects. Deletion of adenosine A2A or A2B receptor subtypes did not alter ischemia-reperfusion injury, but CHA failed to exert a cardioprotective effect in hearts of mice from either KO group. These findings indicate that both adenosine A2A and A2B receptors are required for adenosine A1 receptor-mediated cardioprotection, implicating a role for interactions among receptor subtypes.

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Protection of the reperfused heart by L-propionylcarnitine

Journal of Applied Physiology ◽

10.1152/jappl.1991.71.4.1518 ◽

1991 ◽

Vol 71 (4) ◽

pp. 1518-1522 ◽

Cited By ~ 16

Author(s):

J. A. Leipala ◽

R. Bhatnagar ◽

E. Pineda ◽

S. Najibi ◽

K. Massoumi ◽

...

Keyword(s):

Lactate Dehydrogenase ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Membrane Integrity ◽

Creatine Phosphate ◽

Left Ventricular ◽

Optimal Time ◽

Dependent Manner ◽

Cell Membrane Integrity ◽

Developed Pressure

The effects of L-propionylcarnitine on mechanical function, creatine phosphate and ATP content, and lactate dehydrogenase leakage were studied in isolated perfused rat hearts exposed to global no-flow ischemia for 30 min followed by reperfusion for 20 min. Five and 10 mM L-propionylcarnitine resulted in a 100% recovery of left ventricular-developed pressure, whereas the recovery was only 40% in the hearts perfused without this agent. Ischemia-reperfusion caused a 85% loss of creatine phosphate and a 77% loss of ATP, which was prevented by 10 mM L-propionylcarnitine. Five millimolar L-propionylcarnitine protected the heart from the loss of creatine phosphate but not from the loss of ATP. Ten millimolar L-propionylcarnitine failed to improve the postischemic left ventricular-developed pressure, when it was added to the perfusate only after ischemia. L-propionylcarnitine alleviated the decrease of coronary flow in the reperfused hearts. Lactate dehydrogenase leakage was aggravated in the beginning of the reperfusion period by 10 mM L-propionylcarnitine. This adverse effect was, however, transient. L-Propionylcarnitine provides protection for the postischemic reperfused heart in a dose-dependent manner. The optimal time for administration is before the ischemic insult. High doses of this compound may perturb cell membrane integrity. Moreover, the present data point to an intracellular, metabolic, and perhaps anaplerotic mechanism of action of L-propionylcarnitine in cardiac ischemia-reperfusion injury.

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Acute effects of 17β-estradiol on myocardial pH, Na+, and Ca2+ and ischemia-reperfusion injury

AJP Cell Physiology ◽

10.1152/ajpcell.00414.2004 ◽

2005 ◽

Vol 288 (1) ◽

pp. C57-C64 ◽

Cited By ~ 17

Author(s):

Steven E. Anderson ◽

Dawn M. Kirkland ◽

Andrea Beyschau ◽

Peter M. Cala

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Ovariectomized Rats ◽

Functional Coupling ◽

Cytosolic Ph ◽

Thermodynamic Effect ◽

17Β Estradiol ◽

Developed Pressure

Evidence suggests that 1) ischemia-reperfusion injury is due largely to cytosolic Ca2+ accumulation resulting from functional coupling of Na+/Ca2+ exchange (NCE) with stimulated Na+/H+ exchange (NHE1) and 2) 17β-estradiol (E2) stimulates release of NO, which inhibits NHE1. Thus we tested the hypothesis that acute E2 limits myocardial Na+ and therefore Ca2+ accumulation, thereby limiting ischemia-reperfusion injury. NMR was used to measure cytosolic pH (pHi), Na+ (Na[Formula: see text]), and calcium concentration ([Ca2+]i) in Krebs-Henseleit (KH)-perfused hearts from ovariectomized rats (OVX). Left ventricular developed pressure (LVDP) and lactate dehydrogenase (LDH) release were also measured. Control ischemia-reperfusion was 20 min of baseline perfusion, 40 min of global ischemia, and 40 min of reperfusion. The E2 protocol was identical, except that 1 nM E2 was included in the perfusate before ischemia and during reperfusion. E2 significantly limited the changes in pHi, Na[Formula: see text] and [Ca2+]i during ischemia ( P < 0.05). In control OVX vs. OVX+E2, pHi fell from 6.93 ± 0.03 to 5.98 ± 0.04 vs. 6.96 ± 0.04 to 6.68 ± 0.07; Na[Formula: see text] rose from 25 ± 6 to 109 ± 14 meq/kg dry wt vs. 25 ± 1 to 76 ± 3; [Ca2+]i changed from 365 ± 69 to 1,248 ± 180 nM vs. 293 ± 66 to 202 ± 64 nM. E2 also improved recovery of LVDP and diminished release of LDH during reperfusion. Effects of E2 were diminished by 1 μM Nω-nitro-l-arginine methyl ester. Thus the data are consistent with the hypothesis. However, E2 limitation of increases in [Ca2+]i is greater than can be accounted for by the thermodynamic effect of reduced Na[Formula: see text] accumulation on NCE.

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Hemidesmus indicusandHibiscus rosa-sinensisAffect Ischemia Reperfusion Injury in Isolated Rat Hearts

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2011/802937 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 11

Author(s):

Vinoth Kumar Megraj Khandelwal ◽

R. Balaraman ◽

Dezider Pancza ◽

Táňa Ravingerová

Keyword(s):

Infarct Size ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Moderate Increase ◽

Dependent Manner ◽

Hemidesmus Indicus ◽

Rat Hearts ◽

Perfused Rat Hearts ◽

Developed Pressure

Hemidesmus indicus(L.) R. Br. (HI) andHibiscus rosa-sinensisL. (HRS) are widely used traditional medicine. We investigated cardioprotective effects of these plants applied for 15 min at concentrations of 90, 180, and 360 μg/mL in Langendorff-perfused rat hearts prior to 25-min global ischemia/120-min reperfusion (I/R). Functional recovery (left ventricular developed pressure—LVDP, and rate of development of pressure), reperfusion arrhythmias, and infarct size (TTC staining) served as the endpoints. A transient increase in LVDP (32%–75%) occurred at all concentrations of HI, while coronary flow (CF) was significantly increased after HI 180 and 360. Only a moderate increase in LVDP (21% and 55%) and a tendency to increase CF was observed at HRS 180 and 360. HI and HRS at 180 and 360 significantly improved postischemic recovery of LVDP. Both the drugs dose-dependently reduced the numbers of ectopic beats and duration of ventricular tachycardia. The size of infarction was significantly decreased by HI 360, while HRS significantly reduced the infarct size at all concentrations in a dose-dependent manner. Thus, it can be concluded that HI might cause vasodilation, positive inotropic effect, and cardioprotection, while HRS might cause these effects at higher concentrations. However, further study is needed to elucidate the exact mechanism of their actions.

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Adenosine A2A Receptor Agonist Improves Cardiac Dysfunction From Pulmonary Ischemia-Reperfusion Injury

The Annals of Thoracic Surgery ◽

10.1016/j.athoracsur.2004.09.038 ◽

2005 ◽

Vol 79 (4) ◽

pp. 1189-1195 ◽

Cited By ~ 12

Author(s):

T. Brett Reece ◽

Victor E. Laubach ◽

Curtis G. Tribble ◽

Thomas S. Maxey ◽

Peter I. Ellman ◽

...

Keyword(s):

Reperfusion Injury ◽

Cardiac Dysfunction ◽

Receptor Agonist ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Adenosine A2a Receptor ◽

A2a Receptor ◽

Adenosine A2a ◽

Pulmonary Ischemia

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Novel soluble epoxide hydrolase inhibitor protects mitochondrial function following stress

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y2012-082 ◽

2012 ◽

Vol 90 (6) ◽

pp. 811-823 ◽

Cited By ~ 34

Author(s):

Sri N. Batchu ◽

Stephen B. Lee ◽

Victor Samokhvalov ◽

Ketul R. Chaudhary ◽

Haitham El-Sikhry ◽

...

Keyword(s):

Mitochondrial Function ◽

Epoxide Hydrolase ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Soluble Epoxide Hydrolase ◽

Left Ventricular ◽

Ros Generation ◽

The Novel ◽

Active Metabolites ◽

Developed Pressure

Epoxyeicosatrienoic acids (EETs) are active metabolites of arachidonic acid that are inactivated by soluble epoxide hydrolase enzyme (sEH) to dihydroxyeicosatrienoic acid. EETs are known to render cardioprotection against ischemia reperfusion (IR) injury by maintaining mitochondrial function. We investigated the effect of a novel sEH inhibitor (sEHi) in limiting IR injury. Mouse hearts were perfused in Langendorff mode for 40 min and subjected to 20 min of global no-flow ischemia followed by 40 min of reperfusion. Hearts were perfused with 0.0, 0.1, 1.0 and 10.0 µmol·L–1 of the sEHi N-(2-chloro-4-methanesulfonyl-benzyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide (BI00611953). Inhibition of sEH by BI00611953 significantly improved postischemic left-ventricular-developed pressure and reduced infarct size following IR compared with control hearts, and similar to hearts perfused with 11,12-EETs (1 µmol·L–1) and sEH–/– mice. Perfusion with the putative EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, 10 µmol·L–1), or the plasma membrane KATP channels (pmKATP) inhibitor (glibenclamide, 10 µmol·L–1) abolished the improved recovery by BI00611953 (1 µmol·L–1). Mechanistic studies in H9c2 cells demonstrated that BI0611953 decreased ROS generation, caspase-3 activity, proteasome activity, increased HIF-1∝ DNA binding, and delayed the loss of mitochondrial membrane potential (ΔΨm) caused by anoxia–reoxygenation. Together, our data demonstrate that the novel sEHi BI00611953, a nicotinamide-based compound, provides significant cardioprotection against ischemia reperfusion injury.

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Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts

Journal of Endocrinology ◽

10.1530/joe-14-0067 ◽

2014 ◽

Vol 222 (2) ◽

pp. 289-299 ◽

Cited By ~ 5

Author(s):

Takuya Yoshino ◽

Tomohisa Nagoshi ◽

Ryuko Anzawa ◽

Yusuke Kashiwagi ◽

Keiichi Ito ◽

...

Keyword(s):

Ischemia Reperfusion Injury ◽

Diastolic Pressure ◽

Heart Diseases ◽

Ischemia Reperfusion ◽

Wistar Rat ◽

Left Ventricular ◽

Ventricular Contractility ◽

Independent Manner ◽

Beneficial Effects ◽

Physiological Dose

Although persistent excessive actions of aldosterone have unfavorable effects on the cardiovascular system, primarily via mineralocorticoid receptor (MR)-dependent pathways, the pathophysiological significance of aldosterone cascade activation in heart diseases has not yet been fully clarified. We herein examined the effects of short-term aldosterone stimulation at a physiological dose on cardiac function during ischemia–reperfusion injury (IRI). In order to study the effects of aldosterone preconditioning, male Wistar rat Langendorff hearts were perfused with 10−9 mol/l of aldosterone for 10 min before ischemia, and the response to IRI was assessed. Although aldosterone did not affect the baseline hemodynamic parameters, preconditioning actions of aldosterone significantly improved the recovery in left ventricular contractility and left ventricular end-diastolic pressure associated with a reduced activity of creatine phosphokinase released into the perfusate after ischemia–reperfusion. Notably, the MR inhibitor eplerenone did not abrogate these beneficial effects. Biochemical analyses revealed that p38MAPK phosphorylation was significantly increased during aldosterone preconditioning before ischemia, whereas its phosphorylation was substantially attenuated during sustained ischemia–reperfusion, compared with the results for in the non-preconditioned control hearts. This dual regulation of p38MAPK was not affected by eplerenone. The phosphorylation levels of other MAPKs were not altered by aldosterone preconditioning. In conclusion, the temporal induction of the aldosterone cascade, at a physiological dose, has favorable effects on cardiac functional recovery and injury following ischemia–reperfusion in a MR-independent manner. Phasic dynamism of p38MAPK activation may play a key role in the physiological compensatory pathway of aldosterone under severe cardiac pathological conditions.

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Pretreatment with adenosine and adenosine A1 receptor agonist protects against intestinal ischemia-reperfusion injury in rat

World Journal of Gastroenterology ◽

10.3748/wjg.v13.i4.538 ◽

2007 ◽

Vol 13 (4) ◽

pp. 538 ◽

Cited By ~ 7

Author(s):

V Haktan Ozacmak

Keyword(s):

Reperfusion Injury ◽

Receptor Agonist ◽

Intestinal Ischemia ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Adenosine A1 Receptor ◽

Adenosine A1 ◽

A1 Receptor ◽

Intestinal Ischemia Reperfusion

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Abstract 374: Targeted Deletion of A 2B Adenosine Receptors Attenuates the Protective Effects of Myocardial Postconditioning

Circulation ◽

10.1161/circ.118.suppl_18.s_293-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Xinglin Tan ◽

Stephen L Tilley ◽

Thomas Krahn ◽

Bunyen Teng ◽

S. J Mustafa ◽

...

Keyword(s):

Adenosine Receptor ◽

Troponin I ◽

Diastolic Pressure ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Heart Weight ◽

Receptor Subtypes ◽

Protective Effects ◽

Targeted Deletion ◽

Beneficial Effects

Endogenous adenosine is an important ligand trigger for the cardioprotective effects of postconditioning (PostCon). To assess the hypothesis that A 2B adenosine receptor (A 2B AR) activation contributes to PostCon-induced protection, global ischemia-reperfusion was performed with and without PostCon or the selective A 2B agonist, BAY 60 – 6583 (BAY), in isolated wild-type (WT) and A 2B AR knockout (A 2B KO) mouse hearts. In WT hearts, PostCon improved post-ischemic recovery of left ventricular developed pressure (LVDP) to 63.3±1.6 % of pre-ischemic baseline vs. 49.9±1.6 % in non-PostCon controls (CTL), lowered end diastolic pressure (EDP) to 15.8±1.5 mmHg vs. 27.9±1.6 mmHg in CTL, and reduced coronary efflux of cardiac troponin I (cTnI) to 2507±359 ng/g heart weight vs. 4693±343 ng/g in CTL (n=12 both groups, p <0.05 each comparison). Treatment with BAY in the first two min of reperfusion mimicked beneficial effects of PostCon in WT hearts (LVDP: 64.7±2.0 % baseline, EDP: 16.2±2.0 mmHg, cTnI: 3311±366; n=13, not significant compared to respective PostCon values). Real-time PCR confirmed absence of A 2B AR in A 2B KO hearts and demonstrated no changes in expression of other adenosine receptor subtypes compared with WT hearts. In A 2B KO hearts, neither PostCon nor BAY improved recovery of LVDP (50.8±1.6 % baseline for CTL vs. 54.5±1.7 % with PostCon vs. 53.0±1.4 with BAY; n=6 each group), and neither affected EDP or release of cTnI. During reperfusion, both PostCon and BAY increased survival kinase signaling through Akt and ERK1/2 phosphorylation in WT but not A 2B KO hearts. In non-ischemic WT hearts, Akt and ERK1/2 phosphorylation was increased by both BAY treatment and application of the PostCon stimulus. These data demonstrate that the protective effects of PostCon are attenuated by targeted deletion of A 2B AR and are mimicked by selective A 2B AR activation, suggesting A 2B AR activation is an important trigger leading to PostCon-induced myocardial protection.

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Effects of the AT1 Receptor Blocker Candesartan on Myocardial Ischemia/Reperfusion in Isolated Rat Hearts

The Heart Surgery Forum ◽

10.1532/hsf98.2014400 ◽

2014 ◽

Vol 17 (5) ◽

pp. 263 ◽

Cited By ~ 1

Author(s):

C. Murat Songur ◽

Merve Ozenen Songur ◽

Sinan Sabit Kocabeyoglu ◽

Bilgen Basgut

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Relaxation Rates ◽

Cardioplegic Solution ◽

Rat Hearts ◽

Developed Pressure ◽

Contraction And Relaxation ◽

Isolated Rat

Background: We sought to investigate the effects of the angiotension II receptor blocker candesartan on ischemia-reperfusion injury using a cardioplegia arrested isolated rat heart model.Methods: Ischemia-reperfusion injury was induced in isolated rat hearts with 40 minutes of global ischemia followed by a 30-minute reperfusion protocol. Throughout the experiment, constant pressure perfusion was achieved using a Langendorff apparatus. Cardioplegic solution alone, and in combination with candesartan, was administered before ischemia and 20 minutes after ischemia. Post-ischemic recovery of contractile function, left ventricular developed pressure, left ventricular end-diastolic pressure and contraction and relaxation rates were evaluated.Results: In the control group, left ventricular developed pressure, rate pressure product, contraction and relaxation rates and coronary flow significantly decreased but coronary resistance increased following reperfusion. With the administration of candesartan alone, parameters did not differ compared to controls. Contractile parameters improved in the group that received candesartan in combination with the cardioplegia compared to the group that received cardioplegia alone; however, the difference between these two groups was insignificant.Conclusion: In this study, the addition of candesartan to a cardioplegic arrest protocol routinely performed during cardiac surgery did not provide a significant advantage in protection against ischemia-reperfusion injury compared with the administration of cardioplegic solution alone.

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