Ischaemic tolerance in aged mouse myocardium: The role of adenosine and effect of A1 adenosine receptor overexpression

John P. Headrick, Laura Willems, Kevin J. Ashton, Kirsten Holmgren, Jason Peart, G. Paul Matherne

Research output: Contribution to journalReview articleResearchpeer-review

66 Citations (Scopus)

Abstract

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 A1 adenosine receptor (A1AR) 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 μM adenosine at A1 and A2 receptors in young and aged hearts. Nonetheless, while 50 μM 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 μM diazoxide reduced ischaemic damage and arrhythmogenesis for both ages. Contractile and anti-necrotic effects of adenosine were limited by 100 μM 5-hydroxydecanoate (5-HD) and 3 μM chelerythrine. Anti-arrhythmic effects were limited by 5-HD but not chelerythrine. Non-selective (100 μM 8-sulfophenyltheophylline) and A1-selective (150 nM 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 A1AR mRNA transcription, or receptor density (∼8 fmol mg-1 protein in both age groups). However, A1AR 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 A1AR expression, and involves ineffective activation of a 5-HD-/diazoxide-sensitive process. The effects of A1AR overexpression indicate that the age-related failure in signalling can be overcome.

Original languageEnglish
Pages (from-to)823-833
Number of pages11
JournalJournal of Physiology
Volume549
Issue number3
DOIs
Publication statusPublished - 15 Jun 2003
Externally publishedYes

Fingerprint

Adenosine A1 Receptors
Adenosine
Myocardium
Diazoxide
L-Lactate Dehydrogenase
Ischemia
Adenosine A2 Receptors
Pressure
Purinergic P1 Receptors
Anti-Arrhythmia Agents
Tachycardia
Reperfusion
Real-Time Polymerase Chain Reaction
Age Groups
Phenotype
Messenger RNA
Incidence

Cite this

Headrick, John P. ; Willems, Laura ; Ashton, Kevin J. ; Holmgren, Kirsten ; Peart, Jason ; Matherne, G. Paul. / Ischaemic tolerance in aged mouse myocardium : The role of adenosine and effect of A1 adenosine receptor overexpression. In: Journal of Physiology. 2003 ; Vol. 549, No. 3. pp. 823-833.
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abstract = "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 A1 adenosine receptor (A1AR) 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 μM adenosine at A1 and A2 receptors in young and aged hearts. Nonetheless, while 50 μM 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 μM diazoxide reduced ischaemic damage and arrhythmogenesis for both ages. Contractile and anti-necrotic effects of adenosine were limited by 100 μM 5-hydroxydecanoate (5-HD) and 3 μM chelerythrine. Anti-arrhythmic effects were limited by 5-HD but not chelerythrine. Non-selective (100 μM 8-sulfophenyltheophylline) and A1-selective (150 nM 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 A1AR mRNA transcription, or receptor density (∼8 fmol mg-1 protein in both age groups). However, A1AR 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 A1AR expression, and involves ineffective activation of a 5-HD-/diazoxide-sensitive process. The effects of A1AR overexpression indicate that the age-related failure in signalling can be overcome.",
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Ischaemic tolerance in aged mouse myocardium : The role of adenosine and effect of A1 adenosine receptor overexpression. / Headrick, John P.; Willems, Laura; Ashton, Kevin J.; Holmgren, Kirsten; Peart, Jason; Matherne, G. Paul.

In: Journal of Physiology, Vol. 549, No. 3, 15.06.2003, p. 823-833.

Research output: Contribution to journalReview articleResearchpeer-review

TY - JOUR

T1 - Ischaemic tolerance in aged mouse myocardium

T2 - The role of adenosine and effect of A1 adenosine receptor overexpression

AU - Headrick, John P.

AU - Willems, Laura

AU - Ashton, Kevin J.

AU - Holmgren, Kirsten

AU - Peart, Jason

AU - Matherne, G. Paul

PY - 2003/6/15

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N2 - 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 A1 adenosine receptor (A1AR) 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 μM adenosine at A1 and A2 receptors in young and aged hearts. Nonetheless, while 50 μM 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 μM diazoxide reduced ischaemic damage and arrhythmogenesis for both ages. Contractile and anti-necrotic effects of adenosine were limited by 100 μM 5-hydroxydecanoate (5-HD) and 3 μM chelerythrine. Anti-arrhythmic effects were limited by 5-HD but not chelerythrine. Non-selective (100 μM 8-sulfophenyltheophylline) and A1-selective (150 nM 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 A1AR mRNA transcription, or receptor density (∼8 fmol mg-1 protein in both age groups). However, A1AR 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 A1AR expression, and involves ineffective activation of a 5-HD-/diazoxide-sensitive process. The effects of A1AR overexpression indicate that the age-related failure in signalling can be overcome.

AB - 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 A1 adenosine receptor (A1AR) 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 μM adenosine at A1 and A2 receptors in young and aged hearts. Nonetheless, while 50 μM 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 μM diazoxide reduced ischaemic damage and arrhythmogenesis for both ages. Contractile and anti-necrotic effects of adenosine were limited by 100 μM 5-hydroxydecanoate (5-HD) and 3 μM chelerythrine. Anti-arrhythmic effects were limited by 5-HD but not chelerythrine. Non-selective (100 μM 8-sulfophenyltheophylline) and A1-selective (150 nM 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 A1AR mRNA transcription, or receptor density (∼8 fmol mg-1 protein in both age groups). However, A1AR 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 A1AR expression, and involves ineffective activation of a 5-HD-/diazoxide-sensitive process. The effects of A1AR overexpression indicate that the age-related failure in signalling can be overcome.

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DO - 10.1113/jphysiol.2003.041541

M3 - Review article

VL - 549

SP - 823

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JO - Journal of Physiology

JF - Journal of Physiology

SN - 0022-3751

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