Effects of A3 adenosine receptor activation and gene knock-out in ischemic-reperfused mouse heart

Glenn J. Harrison, Rachael J. Cerniway, Jason Peart, Stuart S. Berr, Kevin Ashton, Sara Regan, G. Paul Matherne, John P. Headrick

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Abstract

Objectives: To characterize effects of A3 adenosine receptor (A3AR) activation and gene knock-out on responses to ischemia-reperfusion in mouse heart. Methods: Perfused hearts from wild-type and A3AR gene knock-out (A3AR KO) mice were subjected to 20 min ischemia and 30 min reperfusion. Functional responses were assessed and changes in energy metabolism and cytosolic pH monitored via 31P-NMR spectroscopy. Results: Selective A3AR agonism with 100 nM 2-chloro-N6-(3-iodobenzyl)-adenosine-5′-N- methyluronamide (chloro-IB-MECA) enhanced post-ischemic contractile recovery without altering contracture development in wild-type hearts, an effect unrelated to non-selective activation of A1 or A2 adenosine receptors. Chloro-IB-MECA also improved recovery in hearts overexpressing A1ARs. Paradoxically, post-ischemic recovery was enhanced by A3AR KO. Developed pressure, +dP/dt, and -dP/dt all recovered to higher levels in A3AR KO (70-80% of pre-ischemia) vs. wild-type hearts (45-50% of pre-ischemia) (P<0.05). Enhanced recovery was unrelated to recoveries of ATP, phosphocreatine (PCr), inorganic phosphate (Pi), energy state ([ATP]/[ADP]. [Pi], ΔGATP) or cytosolic pH. Conclusions: Selective A3AR activation is cardioprotective in wild-type hearts and hearts overexpressing A1ARs, yet A3AR gene deletion generates an ischemia-tolerant phenotype without altering energy metabolism or pH. This may be due to compensatory changes or undefined genotypic differences in A3AR KO vs. wild-type hearts.

Original languageEnglish
Pages (from-to)147-155
Number of pages9
JournalCardiovascular Research
Volume53
Issue number1
DOIs
Publication statusPublished - 2002
Externally publishedYes

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Gene Knock-In Techniques
Adenosine A3 Receptors
Gene Knockout Techniques
Ischemia
Energy Metabolism
Reperfusion
Adenosine Triphosphate
Adenosine A2 Receptors
Phosphates
Adenosine A1 Receptors
Phosphocreatine
Gene Deletion
Contracture
Knockout Mice
Adenosine
Adenosine Diphosphate
Magnetic Resonance Spectroscopy

Cite this

Harrison, Glenn J. ; Cerniway, Rachael J. ; Peart, Jason ; Berr, Stuart S. ; Ashton, Kevin ; Regan, Sara ; Paul Matherne, G. ; Headrick, John P. / Effects of A3 adenosine receptor activation and gene knock-out in ischemic-reperfused mouse heart. In: Cardiovascular Research. 2002 ; Vol. 53, No. 1. pp. 147-155.
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abstract = "Objectives: To characterize effects of A3 adenosine receptor (A3AR) activation and gene knock-out on responses to ischemia-reperfusion in mouse heart. Methods: Perfused hearts from wild-type and A3AR gene knock-out (A3AR KO) mice were subjected to 20 min ischemia and 30 min reperfusion. Functional responses were assessed and changes in energy metabolism and cytosolic pH monitored via 31P-NMR spectroscopy. Results: Selective A3AR agonism with 100 nM 2-chloro-N6-(3-iodobenzyl)-adenosine-5′-N- methyluronamide (chloro-IB-MECA) enhanced post-ischemic contractile recovery without altering contracture development in wild-type hearts, an effect unrelated to non-selective activation of A1 or A2 adenosine receptors. Chloro-IB-MECA also improved recovery in hearts overexpressing A1ARs. Paradoxically, post-ischemic recovery was enhanced by A3AR KO. Developed pressure, +dP/dt, and -dP/dt all recovered to higher levels in A3AR KO (70-80{\%} of pre-ischemia) vs. wild-type hearts (45-50{\%} of pre-ischemia) (P<0.05). Enhanced recovery was unrelated to recoveries of ATP, phosphocreatine (PCr), inorganic phosphate (Pi), energy state ([ATP]/[ADP]. [Pi], ΔGATP) or cytosolic pH. Conclusions: Selective A3AR activation is cardioprotective in wild-type hearts and hearts overexpressing A1ARs, yet A3AR gene deletion generates an ischemia-tolerant phenotype without altering energy metabolism or pH. This may be due to compensatory changes or undefined genotypic differences in A3AR KO vs. wild-type hearts.",
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Harrison, GJ, Cerniway, RJ, Peart, J, Berr, SS, Ashton, K, Regan, S, Paul Matherne, G & Headrick, JP 2002, 'Effects of A3 adenosine receptor activation and gene knock-out in ischemic-reperfused mouse heart' Cardiovascular Research, vol. 53, no. 1, pp. 147-155. https://doi.org/10.1016/S0008-6363(01)00424-2

Effects of A3 adenosine receptor activation and gene knock-out in ischemic-reperfused mouse heart. / Harrison, Glenn J.; Cerniway, Rachael J.; Peart, Jason; Berr, Stuart S.; Ashton, Kevin; Regan, Sara; Paul Matherne, G.; Headrick, John P.

In: Cardiovascular Research, Vol. 53, No. 1, 2002, p. 147-155.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Effects of A3 adenosine receptor activation and gene knock-out in ischemic-reperfused mouse heart

AU - Harrison, Glenn J.

AU - Cerniway, Rachael J.

AU - Peart, Jason

AU - Berr, Stuart S.

AU - Ashton, Kevin

AU - Regan, Sara

AU - Paul Matherne, G.

AU - Headrick, John P.

PY - 2002

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N2 - Objectives: To characterize effects of A3 adenosine receptor (A3AR) activation and gene knock-out on responses to ischemia-reperfusion in mouse heart. Methods: Perfused hearts from wild-type and A3AR gene knock-out (A3AR KO) mice were subjected to 20 min ischemia and 30 min reperfusion. Functional responses were assessed and changes in energy metabolism and cytosolic pH monitored via 31P-NMR spectroscopy. Results: Selective A3AR agonism with 100 nM 2-chloro-N6-(3-iodobenzyl)-adenosine-5′-N- methyluronamide (chloro-IB-MECA) enhanced post-ischemic contractile recovery without altering contracture development in wild-type hearts, an effect unrelated to non-selective activation of A1 or A2 adenosine receptors. Chloro-IB-MECA also improved recovery in hearts overexpressing A1ARs. Paradoxically, post-ischemic recovery was enhanced by A3AR KO. Developed pressure, +dP/dt, and -dP/dt all recovered to higher levels in A3AR KO (70-80% of pre-ischemia) vs. wild-type hearts (45-50% of pre-ischemia) (P<0.05). Enhanced recovery was unrelated to recoveries of ATP, phosphocreatine (PCr), inorganic phosphate (Pi), energy state ([ATP]/[ADP]. [Pi], ΔGATP) or cytosolic pH. Conclusions: Selective A3AR activation is cardioprotective in wild-type hearts and hearts overexpressing A1ARs, yet A3AR gene deletion generates an ischemia-tolerant phenotype without altering energy metabolism or pH. This may be due to compensatory changes or undefined genotypic differences in A3AR KO vs. wild-type hearts.

AB - Objectives: To characterize effects of A3 adenosine receptor (A3AR) activation and gene knock-out on responses to ischemia-reperfusion in mouse heart. Methods: Perfused hearts from wild-type and A3AR gene knock-out (A3AR KO) mice were subjected to 20 min ischemia and 30 min reperfusion. Functional responses were assessed and changes in energy metabolism and cytosolic pH monitored via 31P-NMR spectroscopy. Results: Selective A3AR agonism with 100 nM 2-chloro-N6-(3-iodobenzyl)-adenosine-5′-N- methyluronamide (chloro-IB-MECA) enhanced post-ischemic contractile recovery without altering contracture development in wild-type hearts, an effect unrelated to non-selective activation of A1 or A2 adenosine receptors. Chloro-IB-MECA also improved recovery in hearts overexpressing A1ARs. Paradoxically, post-ischemic recovery was enhanced by A3AR KO. Developed pressure, +dP/dt, and -dP/dt all recovered to higher levels in A3AR KO (70-80% of pre-ischemia) vs. wild-type hearts (45-50% of pre-ischemia) (P<0.05). Enhanced recovery was unrelated to recoveries of ATP, phosphocreatine (PCr), inorganic phosphate (Pi), energy state ([ATP]/[ADP]. [Pi], ΔGATP) or cytosolic pH. Conclusions: Selective A3AR activation is cardioprotective in wild-type hearts and hearts overexpressing A1ARs, yet A3AR gene deletion generates an ischemia-tolerant phenotype without altering energy metabolism or pH. This may be due to compensatory changes or undefined genotypic differences in A3AR KO vs. wild-type hearts.

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DO - 10.1016/S0008-6363(01)00424-2

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