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Ischaemic Tolerance in Aged Mouse Myocardium: The Role of Adenosine and Effects of A 1 Adenosine Receptor Overexpression
Author(s) -
Headrick John P.,
Willems Laura,
Ashton Kevin J.,
Holmgren Kirsten,
Peart Jason,
Matherne G. Paul
Publication year - 2003
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2003.041541
Subject(s) - adenosine , medicine , chelerythrine , contractility , diazoxide , endocrinology , adenosine receptor , diastole , ischemia , cardioprotection , cardiology , receptor , chemistry , blood pressure , agonist , signal transduction , biochemistry , protein kinase c , insulin
The genesis of the ischaemia intolerant phenotype in aged myocardium is poorly understood. We tested the hypothesis that impaired adenosine‐mediated protection contributes to ischaemic intolerance, and examined whether this is countered by A 1 adenosine receptor (A 1 AR) overexpression. Responses to 20 min ischaemia and 45 min reperfusion were assessed in perfused hearts from young (2–4 months) and moderately aged (16–18 months) mice. Post‐ischaemic contractility was impaired by ageing with elevated ventricular diastolic (32 ± 2 vs . 18 ± 2 mmHg in young) and reduced developed (37 ± 3 vs . 83 ± 6 mmHg in young) pressures. Lactate dehydrogenase (LDH) loss was exaggerated (27 ± 2 vs . 16 ± 2 IU g − 1 in young ) whereas the incidence of tachyarrhythmias was similar in young (15 ± 1 %) and aged hearts (16 ± 1 %). Functional analysis confirmed equipotent effects of 50 μ m adenosine at A 1 and A 2 receptors in young and aged hearts. Nonetheless, while 50 μ m adenosine improved diastolic (5 ± 1 mmHg) and developed pressures (134 ± 7 mmHg) and LDH loss (6 ± 2 IU g − 1 ) in young hearts, it did not alter these variables in the aged group. Adenosine did attenuate arrhythmogenesis for both ages (to ∼10 %). In contrast to adenosine, 50 μ m diazoxide reduced ischaemic damage and arrhythmogenesis for both ages. Contractile and anti‐necrotic effects of adenosine were limited by 100 μ m 5‐hydroxydecanoate (5‐HD) and 3 μ m chelerythrine. Anti‐arrhythmic effects were limited by 5‐HD but not chelerythrine. Non‐selective (100 μ m 8‐sulfophenyltheophylline) and A 1 ‐selective (150 n m 8‐cyclopentyl‐1,3‐dipropylxanthine) adenosine receptor antagonism impaired ischaemic tolerance in young but not aged hearts. Quantitative real‐time PCR and radioligand analysis indicated that impaired protection is unrelated to changes in A 1 AR mRNA transcription, or receptor density (∼8 fmol mg − 1 protein in both age groups). However, A 1 AR overexpression improved tolerance for both ages, restoring adenosine‐mediated protection. These data reveal impaired protection via exogenous and endogenous adenosine contributes to ischaemic intolerance with ageing. This is independent of A 1 AR expression, and involves ineffective activation of a 5‐HD‐/diazoxide‐sensitive process. The effects of A 1 AR overexpression indicate that the age‐related failure in signalling can be overcome.