Effects of adenosine deaminase and A1 receptor deficiency in normoxic and ischaemic mouse hearts

Laura Willems, Melissa E. Reichelt, Jose G. Molina, Chun Xiao Sun, Janci L. Chunn, Kevin J. Ashton, Jurgen Schnermann, Michael R. Blackburn, John P. Headrick

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Abstract

Objective: Adenosine deaminase (ADA) may be multifunctional, regulating adenosine levels and adenosine receptor (AR) agonism, and potentially modifying AR functionality. Herein we assess effects of ADA (and A1AR) deficiency on AR-mediated responses and ischaemic tolerance. Methods: Normoxic function and responses to 20 or 25 min ischaemia and 45 min reperfusion were studied in isolated hearts from wild-type mice and from mice deficient in ADA and/or A1ARs. Results: Neither ADA or A1AR deficiency significantly modified basal contractility, although ADA deficiency reduced resting heart rate (an effect abrogated by A1AR deficiency). Bradycardia and vasodilation in response to AR agonism (2-chloroadenosine) were unaltered by ADA deficiency, while A1AR deficiency eliminated the heart rate response. Adenosine efflux increased 10- to 20-fold with ADA deficiency (at the expense of inosine). Deletion of ADA improved outcome from 25 min ischaemia, reducing ventricular diastolic pressure (by 45%; 21 ± 4 vs. 38 ± 3 mm Hg) and lactate dehydrogenase (LDH) efflux (by 40%; 0.12 ± 0.01 vs. 0.21 ± 0.02 U/g/min ischaemia), and enhancing pressure development (by 35%; 89 ± 6 vs. 66 ± 5 mm Hg). Similar protection was evident after 20 min ischaemia, and was mimicked by the ADA inhibitor EHNA (5 μM). Deletion of ADA also enhanced tolerance in A1AR deficient hearts, though effects on diastolic pressure were eliminated. Conclusions: Deficiency of ADA does not alter sensitivities of cardiovascular A1 or A2ARs (despite markedly elevated [adenosine]), but significantly improves ischaemic tolerance. Conversely, A1AR deficiency impairs ischaemic tolerance. Effects of ADA deficiency on diastolic pressure appear solely A1AR-dependent while other ARs or processes additionally contribute to improved contractile recovery and reduced cell death.

Original languageEnglish
Pages (from-to)79-87
Number of pages9
JournalCardiovascular Research
Volume71
Issue number1
DOIs
Publication statusPublished - 1 Jul 2006
Externally publishedYes

Fingerprint

Adenosine A1 Receptors
Adenosine Deaminase
Purinergic P1 Receptors
Ischemia
Adenosine
Blood Pressure
Heart Rate
Adenosine Deaminase Inhibitors
2-Chloroadenosine
Inosine
Ventricular Pressure
Bradycardia
L-Lactate Dehydrogenase
Vasodilation
Reperfusion
Cell Death
Severe combined immunodeficiency due to adenosine deaminase deficiency
Pressure

Cite this

Willems, Laura ; Reichelt, Melissa E. ; Molina, Jose G. ; Sun, Chun Xiao ; Chunn, Janci L. ; Ashton, Kevin J. ; Schnermann, Jurgen ; Blackburn, Michael R. ; Headrick, John P. / Effects of adenosine deaminase and A1 receptor deficiency in normoxic and ischaemic mouse hearts. In: Cardiovascular Research. 2006 ; Vol. 71, No. 1. pp. 79-87.
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title = "Effects of adenosine deaminase and A1 receptor deficiency in normoxic and ischaemic mouse hearts",
abstract = "Objective: Adenosine deaminase (ADA) may be multifunctional, regulating adenosine levels and adenosine receptor (AR) agonism, and potentially modifying AR functionality. Herein we assess effects of ADA (and A1AR) deficiency on AR-mediated responses and ischaemic tolerance. Methods: Normoxic function and responses to 20 or 25 min ischaemia and 45 min reperfusion were studied in isolated hearts from wild-type mice and from mice deficient in ADA and/or A1ARs. Results: Neither ADA or A1AR deficiency significantly modified basal contractility, although ADA deficiency reduced resting heart rate (an effect abrogated by A1AR deficiency). Bradycardia and vasodilation in response to AR agonism (2-chloroadenosine) were unaltered by ADA deficiency, while A1AR deficiency eliminated the heart rate response. Adenosine efflux increased 10- to 20-fold with ADA deficiency (at the expense of inosine). Deletion of ADA improved outcome from 25 min ischaemia, reducing ventricular diastolic pressure (by 45{\%}; 21 ± 4 vs. 38 ± 3 mm Hg) and lactate dehydrogenase (LDH) efflux (by 40{\%}; 0.12 ± 0.01 vs. 0.21 ± 0.02 U/g/min ischaemia), and enhancing pressure development (by 35{\%}; 89 ± 6 vs. 66 ± 5 mm Hg). Similar protection was evident after 20 min ischaemia, and was mimicked by the ADA inhibitor EHNA (5 μM). Deletion of ADA also enhanced tolerance in A1AR deficient hearts, though effects on diastolic pressure were eliminated. Conclusions: Deficiency of ADA does not alter sensitivities of cardiovascular A1 or A2ARs (despite markedly elevated [adenosine]), but significantly improves ischaemic tolerance. Conversely, A1AR deficiency impairs ischaemic tolerance. Effects of ADA deficiency on diastolic pressure appear solely A1AR-dependent while other ARs or processes additionally contribute to improved contractile recovery and reduced cell death.",
author = "Laura Willems and Reichelt, {Melissa E.} and Molina, {Jose G.} and Sun, {Chun Xiao} and Chunn, {Janci L.} and Ashton, {Kevin J.} and Jurgen Schnermann and Blackburn, {Michael R.} and Headrick, {John P.}",
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Willems, L, Reichelt, ME, Molina, JG, Sun, CX, Chunn, JL, Ashton, KJ, Schnermann, J, Blackburn, MR & Headrick, JP 2006, 'Effects of adenosine deaminase and A1 receptor deficiency in normoxic and ischaemic mouse hearts' Cardiovascular Research, vol. 71, no. 1, pp. 79-87. https://doi.org/10.1016/j.cardiores.2006.03.006

Effects of adenosine deaminase and A1 receptor deficiency in normoxic and ischaemic mouse hearts. / Willems, Laura; Reichelt, Melissa E.; Molina, Jose G.; Sun, Chun Xiao; Chunn, Janci L.; Ashton, Kevin J.; Schnermann, Jurgen; Blackburn, Michael R.; Headrick, John P.

In: Cardiovascular Research, Vol. 71, No. 1, 01.07.2006, p. 79-87.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Effects of adenosine deaminase and A1 receptor deficiency in normoxic and ischaemic mouse hearts

AU - Willems, Laura

AU - Reichelt, Melissa E.

AU - Molina, Jose G.

AU - Sun, Chun Xiao

AU - Chunn, Janci L.

AU - Ashton, Kevin J.

AU - Schnermann, Jurgen

AU - Blackburn, Michael R.

AU - Headrick, John P.

PY - 2006/7/1

Y1 - 2006/7/1

N2 - Objective: Adenosine deaminase (ADA) may be multifunctional, regulating adenosine levels and adenosine receptor (AR) agonism, and potentially modifying AR functionality. Herein we assess effects of ADA (and A1AR) deficiency on AR-mediated responses and ischaemic tolerance. Methods: Normoxic function and responses to 20 or 25 min ischaemia and 45 min reperfusion were studied in isolated hearts from wild-type mice and from mice deficient in ADA and/or A1ARs. Results: Neither ADA or A1AR deficiency significantly modified basal contractility, although ADA deficiency reduced resting heart rate (an effect abrogated by A1AR deficiency). Bradycardia and vasodilation in response to AR agonism (2-chloroadenosine) were unaltered by ADA deficiency, while A1AR deficiency eliminated the heart rate response. Adenosine efflux increased 10- to 20-fold with ADA deficiency (at the expense of inosine). Deletion of ADA improved outcome from 25 min ischaemia, reducing ventricular diastolic pressure (by 45%; 21 ± 4 vs. 38 ± 3 mm Hg) and lactate dehydrogenase (LDH) efflux (by 40%; 0.12 ± 0.01 vs. 0.21 ± 0.02 U/g/min ischaemia), and enhancing pressure development (by 35%; 89 ± 6 vs. 66 ± 5 mm Hg). Similar protection was evident after 20 min ischaemia, and was mimicked by the ADA inhibitor EHNA (5 μM). Deletion of ADA also enhanced tolerance in A1AR deficient hearts, though effects on diastolic pressure were eliminated. Conclusions: Deficiency of ADA does not alter sensitivities of cardiovascular A1 or A2ARs (despite markedly elevated [adenosine]), but significantly improves ischaemic tolerance. Conversely, A1AR deficiency impairs ischaemic tolerance. Effects of ADA deficiency on diastolic pressure appear solely A1AR-dependent while other ARs or processes additionally contribute to improved contractile recovery and reduced cell death.

AB - Objective: Adenosine deaminase (ADA) may be multifunctional, regulating adenosine levels and adenosine receptor (AR) agonism, and potentially modifying AR functionality. Herein we assess effects of ADA (and A1AR) deficiency on AR-mediated responses and ischaemic tolerance. Methods: Normoxic function and responses to 20 or 25 min ischaemia and 45 min reperfusion were studied in isolated hearts from wild-type mice and from mice deficient in ADA and/or A1ARs. Results: Neither ADA or A1AR deficiency significantly modified basal contractility, although ADA deficiency reduced resting heart rate (an effect abrogated by A1AR deficiency). Bradycardia and vasodilation in response to AR agonism (2-chloroadenosine) were unaltered by ADA deficiency, while A1AR deficiency eliminated the heart rate response. Adenosine efflux increased 10- to 20-fold with ADA deficiency (at the expense of inosine). Deletion of ADA improved outcome from 25 min ischaemia, reducing ventricular diastolic pressure (by 45%; 21 ± 4 vs. 38 ± 3 mm Hg) and lactate dehydrogenase (LDH) efflux (by 40%; 0.12 ± 0.01 vs. 0.21 ± 0.02 U/g/min ischaemia), and enhancing pressure development (by 35%; 89 ± 6 vs. 66 ± 5 mm Hg). Similar protection was evident after 20 min ischaemia, and was mimicked by the ADA inhibitor EHNA (5 μM). Deletion of ADA also enhanced tolerance in A1AR deficient hearts, though effects on diastolic pressure were eliminated. Conclusions: Deficiency of ADA does not alter sensitivities of cardiovascular A1 or A2ARs (despite markedly elevated [adenosine]), but significantly improves ischaemic tolerance. Conversely, A1AR deficiency impairs ischaemic tolerance. Effects of ADA deficiency on diastolic pressure appear solely A1AR-dependent while other ARs or processes additionally contribute to improved contractile recovery and reduced cell death.

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U2 - 10.1016/j.cardiores.2006.03.006

DO - 10.1016/j.cardiores.2006.03.006

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