Myocardial Preconditioning Produced by Ischemia, Hypoxia, and a KATPChannel Opener: Effects on Interstitial Adenosine in Dogs

Mei, David A.; Nithipatikom, Kasem; Lasley, Robert D.; Gross, Garrett J.

doi:10.1006/jmcc.1998.0687

Cited by 24 publications

(12 citation statements)

References 2 publications

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“…Moreover, it was shown in a heart model that hypoxia leads to the accumulation of adenosine by the inhibition of the enzyme adenosine kinase which under physiological conditions recycles adenosine by phosphorylation to AMP(31). In agreement with earlier studies, demonstrating an increase in extracellular tissue concentrations of adenosine after a hypoxic challenge in the heart muscle(11) or in the hippocampus(12), adenosine plasma concentrations doubled after 10 minutes of breathing 10%oxygen for hypoxic preconditioning. Increased levels of adenosine are consistent with the parallel rise in its degradation products inosine and hypoxanthine(7).…”

Section: Discussionsupporting

confidence: 92%

“…organ hypoxia, we asked whether short, non-ischemic general hypoxia may also protect against hepatic IRI. It has been suggested that the protection by ischemic preconditioning against IRI may be mediated by the action of adenosine, and this may also be true for the protection by hypoxic preconditioning(11, 12). Like ischemia, hypoxia alone results in the hydrolysis of ATP leading to the accumulation of adenosine and its metabolites inosine and hypoxanthine (13).…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Hypoxic Preconditioning Protects From Warm Liver Ischemia-Reperfusion Injury Through the Adenosine A2B Receptor

Choukèr

Ohta

Martignoni³

et al. 2012

Transplantation

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BACKGROUND Liver ischemia(I)/reperfusion(R) injury(I) is a known risk factor for the postoperative outcome of patients undergoing liver surgery/transplantation. Attempts to protect from organ damage require multidisciplinary strategies and are of emerging interest in view of patients with higher age and ASA-status. Ischemic preconditioning has been successfully applied to prevent from IRI during liver resections/transplantation. Since even short periods of ischemia during preconditioning inevitably lead to hypoxia and formation of anti-inflammatory/ cytoprotective acting adenosine, we reasoned that short non-ischemic hypoxia also protects against hepatic IRI. METHODS Mice underwent hypoxic preconditioning(HPC) by breathing 10%-oxygen for 10 minutes, followed by 10 minutes of 21%-oxygen prior to left-liver-lobe-ischemia(45 min) and reperfusion(4 hrs). The interactions of hypoxia->adenosine->adenosine-receptors were tested by pharmacologic antagonism at adenosine receptor(AR) sites in wild type mice and in mice with genetic deletions at the A1-;A2A-;A2B- and A3-ARs. Hepatocellular damage, inflammation and metabolic effects were quantified by enzyme activities, cytokines, liver-myeloperoxidase(MPO), blood adenosine and tissue-adenosinemonophosphate(AMP), respectively. RESULTS Hepatoprotection by HPC was significant in wild type and A1-, A2A-and A3 AR-knock-out mice as quantified by lower ALT serum activities, cytokine levels, histological damage-scores, tissue-myeloperoxidase-concentrations and as well as preserved AMP-concentrations. Protection by HPC was blunted in mice pretreated with the A2B-AR-antagonist MRS1754 or in A2B-AR“knock-outs”. CONCLUSION Because liver protective effects of HPC are negated when the A2B receptor is non-functional, the "hypoxia->adenosine->A2B receptor" pathway plays a critical role in the prevention of warm ischemia reperfusion injury in vivo. Hypoxic activation of this pathway warrants use of selective A2B-AR-agonists or even intermittent hypoxia (e.g. in deceased organ donors) to protect from liver ischemia/reperfusion injury.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

In Vivo Hypoxic Preconditioning Protects From Warm Liver Ischemia-Reperfusion Injury Through the Adenosine A2B Receptor

Choukèr

Ohta

Martignoni³

et al. 2012

Transplantation

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“…This controversy also arises in large part from the fact that if ecto-5Ј-nucleotidase played a major role in mediating preconditioning, one would expect it to cause an elevation of adenosine levels in myocardial tissue, whereas an opposite pattern (ie, a decrease in tissue adenosine) has been reported during classic ischemic preconditioning, 20 as well as after pharmacological preconditioning with isoflurane 21 or potassium channel openers. 22 In turn, one could argue that because of the predominantly endothelial location of ecto-5Ј-nucleotidase, 18,20 endothelium-derived adenosine may be preferentially released into the vascular compartment and thus escape interstitial fluid sampling with microdialysis techniques (indeed, a reduction in ischemic changes occurring with repeated balloon occlusions during angioplasty procedures correlates with an increased release of adenosine in the coronary venous effluent). 23 Together, these considerations suggest that it is important to make a clear distinction between ecto-5Ј-nucleotidase, taken as a surrogate marker of PKC activation, which sounds acceptable, and ecto-5Ј-nucleotidase, taken as an intrinsically cardioprotective compound mediating the preconditioning response, which remains more uncertain.…”

Section: Discussionmentioning

confidence: 99%

Evidence for Preconditioning by Isoflurane in Coronary Artery Bypass Graft Surgery

Belhomme¹,

Peynet²,

Louzy³

et al. 1999

Circulation

207

106

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Background-Experimentally, isoflurane, a commonly used volatile anesthetic agent, mimics the cardioprotective effects of ischemic preconditioning via a mechanism that could involve the activation of protein kinase C. The present study was designed to assess the clinical relevance of this observation in patients undergoing elective CABG. Methods and Results-Twenty patients were included in the study. In 10 of them, preconditioning was elicited after the onset of cardiopulmonary bypass via a 5-minute exposure to isoflurane (2.5 minimum alveolar concentration), followed by a 10-minute washout before aortic cross-clamping and cardioplegic arrest. Ten case-matched control patients underwent an equivalent period (15 minutes) of prearrest isoflurane-free bypass. Outcome measurements included troponin I and creatine kinase-MB isoenzyme (until the third postoperative day) levels and the activity of ecto-5Ј-nucleotidase, which contributes to adenosine production and is considered to be a reporter of protein kinase C activation, as assessed in right atrial biopsy samples taken before bypass and at the end of the preconditioning protocol (or after 15 minutes of bypass in control patients Key Words: ischemia Ⅲ bypass Ⅲ anesthesia I schemic preconditioning is recognized as one of the most effective means of reducing cellular necrosis. As such, its implementation during cardiac surgery might be clinically relevant, particularly in high-risk patients in whom any additional myocardial ischemic injury induced with cardiopulmonary bypass and superimposed cardioplegic arrest can adversely affect postoperative outcome. Because in this setting it is particularly desirable to avoid an ischemic-type preconditioning stimulus, 1-3 extensive research is targeted toward identifying the pharmacological mediators of the preconditioning phenomenon in an attempt to exploit them therapeutically.There is compelling evidence that the preconditioning signal activates various membrane receptors, which triggers a signaling pathway leading to the activation of several kinases, 4 in particular, protein kinase C (PKC), 5 and the subsequent opening of ATP-dependent potassium channels, possibly at the mitochondrial level. 6,7 How opening of these channels elicits cardioprotection is not yet established but might involve the limitation of calcium influx, better control of cellular volume, or both. This scheme provides a framework for rationalizing interventions targeted at mimicking preconditioning and, in this perspective, makes logical the use, among other drugs, of potassium channel openers.Within this class of drugs, only nicorandil is currently available for human use. However, aside from the fact that nicorandil cannot be administered intravenously, this compound has marked nitrovasodilatory properties, which can be Circulation is available at http://www.circulationaha.org II-340by guest on May 10, 2018http://circ.ahajournals.org/ Downloaded from of concern. Alternatively, isoflurane is a volatile anesthetic agent that has been reported in animal mo...

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“…Mei et al (37) determined the role of adenosine in mediating the cardioprotective effects of PC produced by 5 min of ischemia, hypoxia, or by a 5-min intracoronary (i.c.) infusion of bimakalim (1 mg/min).…”

Section: Cardioprotective Actionmentioning

confidence: 99%

Bimakalim: A Promising K_ATP Channel Activating Agent

Puddu

Garlid

Monti

et al. 2000

Cardiovascular Drug Reviews

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Myocardial Preconditioning Produced by Ischemia, Hypoxia, and a KATPChannel Opener: Effects on Interstitial Adenosine in Dogs

Cited by 24 publications

References 2 publications

In Vivo Hypoxic Preconditioning Protects From Warm Liver Ischemia-Reperfusion Injury Through the Adenosine A2B Receptor

In Vivo Hypoxic Preconditioning Protects From Warm Liver Ischemia-Reperfusion Injury Through the Adenosine A2B Receptor

Evidence for Preconditioning by Isoflurane in Coronary Artery Bypass Graft Surgery

Bimakalim: A Promising K_ATP Channel Activating Agent

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Myocardial Preconditioning Produced by Ischemia, Hypoxia, and a KATPChannel Opener: Effects on Interstitial Adenosine in Dogs

Cited by 24 publications

References 2 publications

In Vivo Hypoxic Preconditioning Protects From Warm Liver Ischemia-Reperfusion Injury Through the Adenosine A2B Receptor

In Vivo Hypoxic Preconditioning Protects From Warm Liver Ischemia-Reperfusion Injury Through the Adenosine A2B Receptor

Evidence for Preconditioning by Isoflurane in Coronary Artery Bypass Graft Surgery

Bimakalim: A Promising KATP Channel Activating Agent

Contact Info

Product

Resources

About

Bimakalim: A Promising K_ATP Channel Activating Agent