{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T16:48:37Z","timestamp":1791564517233,"version":"4.3.4"},"reference-count":33,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,2,7]],"date-time":"2018-02-07T00:00:00Z","timestamp":1517961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/N001389\/1"],"award-info":[{"award-number":["MR\/N001389\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute for Academic Anaesthesia\/ Association of Paediatric Anaesthetists of Great Britain &amp; Ireland","award":["WKR0-2013-0032"],"award-info":[{"award-number":["WKR0-2013-0032"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Consecutive treatment of adult rat heart with isoproterenol and adenosine (Iso\/Aden), known to consecutively activate PKA\/PKC signaling, is cardioprotective against ischemia and reperfusion (I\/R). Whether this is cardioprotective in an immature heart is unknown. Langendorff\u2013perfused hearts from adult and immature (60 and 14 days old) male Wistar rats were exposed to 30 min ischemia and 120 min reperfusion, with or without prior perfusion with 5 nM Iso for 3 min followed by 30 \u03bcM Aden for 5 min. Changes in hemodynamics (developed pressure and coronary flow) and cardiac injury (Lactate Dehydrogenase (LDH) release and infarct size) were measured. Additional hearts were used to measure glycogen content. Iso induced a similar inotropic response in both age groups. Treatment with Iso\/Aden resulted in a significant reduction in time to the onset of ischemic contracture in both age groups whilst time to peak contracture was significantly shorter only in immature hearts. Upon reperfusion, the intervention reduced cardiac injury and functional impairment in adults with no protection of immature heart. Immature hearts have significantly less glycogen content compared to adult. This work shows that Iso\/Aden perfusion confers protection in an adult heart but not in an immature heart. It is likely that metabolic differences including glycogen content contribute to this difference.<\/jats:p>","DOI":"10.3390\/ijms19020494","type":"journal-article","created":{"date-parts":[[2018,2,7]],"date-time":"2018-02-07T12:20:29Z","timestamp":1518006029000},"page":"494","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Consecutive Isoproterenol and Adenosine Treatment Confers Marked Protection against Reperfusion Injury in Adult but Not in Immature Heart: A Role for Glycogen"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4410-5720","authenticated-orcid":false,"given":"Martin","family":"Lewis","sequence":"first","affiliation":[{"name":"Bristol Medical School, University of Bristol, Bristol BS8 1TH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Szobi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, 814 99 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirki","family":"Balaska","sequence":"additional","affiliation":[{"name":"School of Biochemistry, University of Bristol, Bristol BS8 1TH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Khaliulin","sequence":"additional","affiliation":[{"name":"Bristol Medical School, University of Bristol, Bristol BS8 1TH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Adameova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, 814 99 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elinor","family":"Griffiths","sequence":"additional","affiliation":[{"name":"School of Biochemistry, University of Bristol, Bristol BS8 1TH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clive","family":"Orchard","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology &amp; Neuroscience, University of Bristol, Bristol BS8 1TH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6080-480X","authenticated-orcid":false,"given":"M.-Saadeh","family":"Suleiman","sequence":"additional","affiliation":[{"name":"Bristol Medical School, University of Bristol, Bristol BS8 1TH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/S0008-6363(99)00266-7","article-title":"Metabolic aspects of programmed cell survival and cell death in the heart","volume":"45","author":"Depre","year":"2000","journal-title":"Cardiovasc. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1038\/nm.2507","article-title":"Ischemia and reperfusion\u2014From mechanism to translation","volume":"17","author":"Eltzschig","year":"2011","journal-title":"Nat. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1113\/jphysiol.2007.130369","article-title":"Temperature Preconditioning of Isolated Rat Hearts\u2014A Potent Cardioprotective Mechanism Involving a Reduction in Oxidative Stress and Inhibition of the Mitochondrial Permeability Transition Pore","volume":"581","author":"Khaliulin","year":"2007","journal-title":"J. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1093\/cvr\/cvq190","article-title":"Consecutive pharmacological activation of PKA and PKC mimics the potent cardioprotection of temperature preconditioning","volume":"88","author":"Khaliulin","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1042\/BJ20070797","article-title":"The selectivity of protein kinase inhibitors: A further update","volume":"408","author":"Bain","year":"2007","journal-title":"Biochem. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1186\/1479-5876-12-139","article-title":"Clinically-relevant consecutive treatment with isoproterenol and adenosine protects the failing heart against ischaemia and reperfusion","volume":"12","author":"Khaliulin","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Khaliulin, I., Halestrap, A.P., and Suleiman, M.S. (2011). Temperature Preconditioning is optimal at 26 \u00b0C and Confers Additional Protection to Hypothermic Cardioplegic Ischemic Arrest. Exp. Biol. Med.","DOI":"10.1258\/ebm.2011.010357"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"A4","DOI":"10.1136\/heartjnl-2013-305297.10","article-title":"10 Cell-Permeable Cyclic AMP as a Novel Cardioprotective Agent","volume":"100","author":"Dudley","year":"2014","journal-title":"Heart"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/s10863-008-9148-8","article-title":"Regulation of hexokinase binding to VDAC","volume":"40","author":"Pastorino","year":"2008","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Chiara, F., Castellaro, D., Marin, O., Petronilli, V., Brusilow, W.S., Juhaszova, M., Sollott, S.J., Forte, M., Bernardi, P., and Rasola, A. (2008). Hexokinase II detachment from mitochondria triggers apoptosis through the permeability transition pore independent of voltage-dependent anion channels. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0001852"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e005645","DOI":"10.1161\/JAHA.112.005645","article-title":"Extent of mitochondrial hexokinase II dissociation during ischemia correlates with mitochondrial cytochrome c release, reactive oxygen species production, and infarct size on reperfusion","volume":"2","author":"Pasdois","year":"2012","journal-title":"J. Am. Heart Assoc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1006\/jmcc.1998.0653","article-title":"Tolerance to ischaemia and ischaemic preconditioning in neonatal rat heart","volume":"30","author":"Ostadalova","year":"1998","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_13","first-page":"H1609","article-title":"Calcium and cardioplegia in neonates: Dose-response and time-response studies in rats","volume":"261","author":"Riva","year":"1991","journal-title":"Am. J. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s00726-003-0031-y","article-title":"Myocardial taurine, development and vulnerability to ischemia","volume":"26","author":"Modi","year":"2004","journal-title":"Amino Acids"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1139\/cjpp-2013-0498","article-title":"Developmental determinants of cardiac sensitivity to hypoxia","volume":"92","author":"Ostadal","year":"2014","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1161\/01.CIR.103.11.1551","article-title":"Age-dependent and hypoxia-related differences in myocardial protection during pediatric open heart surgery","volume":"103","author":"Imura","year":"2001","journal-title":"Circulation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1046\/j.1540-8191.2003.02031.x","article-title":"Pathology-related troponin I release and clinical outcome after pediatric open heart surgery","volume":"18","author":"Modi","year":"2003","journal-title":"J. Card. Surg."},{"key":"ref_18","first-page":"S1","article-title":"Periodization of the early postnatal development in the rat with particular attention to the weaning period","volume":"61","author":"Babicky","year":"2012","journal-title":"Physiol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1096\/fj.01-0151com","article-title":"Beta-adrenergic receptors (betaAR) regulate cardiomyocyte proliferation during early postnatal life","volume":"15","author":"Tseng","year":"2001","journal-title":"FASEB J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1006\/jmcc.1998.0875","article-title":"Ontogeny of cardiac beta-adrenoceptor desensitization mechanisms: Agonist treatment enhances receptor\/G-protein transduction rather than eliciting uncoupling","volume":"31","author":"Zeiders","year":"1999","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/0006-8993(95)00781-K","article-title":"Beta-adrenoceptor control of cardiac adenylyl cyclase during development: Agonist pretreatment in the neonate uniquely causes heterologous sensitization, not desensitization","volume":"694","author":"Giannuzzi","year":"1995","journal-title":"Brain Res."},{"key":"ref_22","first-page":"H1460","article-title":"Cross bridge-dependent activation of contraction in cardiac myofibrils at low pH","volume":"276","author":"Swartz","year":"1999","journal-title":"Am. J. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1161\/01.RES.78.3.482","article-title":"Is a high glycogen content beneficial or detrimental to the ischemic rat heart? A controversy resolved","volume":"78","author":"Cross","year":"1996","journal-title":"Circ. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1006\/jmcc.1996.0097","article-title":"Paradoxical effect of ischemic preconditioning on ischemic contracture? NMR studies of energy metabolism and intracellular pH in the rat heart","volume":"28","author":"Kolocassides","year":"1996","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1093\/oxfordjournals.bmb.a069888","article-title":"Glycogen reserves and their changes at birth and in anoxia","volume":"17","author":"Shelley","year":"1961","journal-title":"Br. Med. Bull."},{"key":"ref_26","first-page":"H998","article-title":"Effect of hypoxia and reoxygenation on mitochondrial function in neonatal myocardium","volume":"245","author":"Young","year":"1983","journal-title":"Am. J. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1161\/01.CIR.100.9.958","article-title":"Ischemic Preconditioning and the {beta}-Adrenergic Signal Transduction Pathway","volume":"100","author":"Lochner","year":"1999","journal-title":"Circulation"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1093\/cvr\/28.11.1726","article-title":"Transient beta adrenergic stimulation can precondition the rat heart against postischaemic contractile dysfunction","volume":"28","author":"Asimakis","year":"1994","journal-title":"Cardiovasc. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1016\/j.bbabio.2008.12.017","article-title":"The role of the mitochondrial permeability transition pore in heart disease","volume":"1787","author":"Halestrap","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/B978-0-12-394309-5.00006-7","article-title":"Cell Biology of Ischemia\/Reperfusion Injury","volume":"298","author":"Kalogeris","year":"2012","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1111\/bph.13709","article-title":"Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac","volume":"174","author":"Khaliulin","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_32","unstructured":"Bergmeyer, H.U. (1983). Methods of Enzymatic Analysis, NAP Inc.. [3rd ed.]."},{"key":"ref_33","unstructured":"hRiva, E., and Hearse, D.J. (1991). The Developing Myocardium, Futura Publishing Company."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/2\/494\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:54:05Z","timestamp":1760194445000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/2\/494"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,7]]},"references-count":33,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2018,2]]}},"alternative-id":["ijms19020494"],"URL":"https:\/\/doi.org\/10.3390\/ijms19020494","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,2,7]]}}}