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Caffeine Acts via A1 Adenosine Receptors to Disrupt Embryonic Cardiac Function
BACKGROUND: Evidence suggests that adenosine acts via cardiac A1 adenosine receptors (A1ARs) to protect embryos against hypoxia. During embryogenesis, A1ARs are the dominant regulator of heart rate, and A1AR activation reduces heart rate. Adenosine action is inhibited by caffeine, which is widely co...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229565/ https://www.ncbi.nlm.nih.gov/pubmed/22164264 http://dx.doi.org/10.1371/journal.pone.0028296 |
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author | Buscariollo, Daniela L. Breuer, Gregory A. Wendler, Christopher C. Rivkees, Scott A. |
author_facet | Buscariollo, Daniela L. Breuer, Gregory A. Wendler, Christopher C. Rivkees, Scott A. |
author_sort | Buscariollo, Daniela L. |
collection | PubMed |
description | BACKGROUND: Evidence suggests that adenosine acts via cardiac A1 adenosine receptors (A1ARs) to protect embryos against hypoxia. During embryogenesis, A1ARs are the dominant regulator of heart rate, and A1AR activation reduces heart rate. Adenosine action is inhibited by caffeine, which is widely consumed during pregnancy. In this study, we tested the hypothesis that caffeine influences developing embryos by altering cardiac function. METHODOLOGY/PRINCIPAL FINDINGS: Effects of caffeine and adenosine receptor-selective antagonists on heart rate were studied in vitro using whole murine embryos at E9.5 and isolated hearts at E12.5. Embryos were examined in room air (21% O(2)) or hypoxic (2% O(2)) conditions. Hypoxia decreased heart rates of E9.5 embryos by 15.8% and in E12.5 isolated hearts by 27.1%. In room air, caffeine (200 µM) had no effect on E9.5 heart rates; however, caffeine increased heart rates at E12.5 by 37.7%. Caffeine abolished hypoxia-mediated bradycardia at E9.5 and blunted hypoxia-mediated bradycardia at E12.5. Real-time PCR analysis of RNA from isolated E9.5 and E12.5 hearts showed that A1AR and A2aAR genes were expressed at both ages. Treatment with adenosine receptor-selective antagonists revealed that SCH-58261 (A2aAR-specific antagonist) had no affects on heart function, whereas DPCPX (A1AR-specific antagonist) had effects similar to caffeine treatment at E9.5 and E12.5. At E12.5, embryonic hearts lacking A1AR expression (A1AR−/−) had elevated heart rates compared to A1AR+/− littermates, A1AR−/− heart rates failed to decrease to levels comparable to those of controls. Caffeine did not significantly affect heart rates of A1AR−/− embryos. CONCLUSIONS/SIGNIFICANCE: These data show that caffeine alters embryonic cardiac function and disrupts the normal cardiac response to hypoxia through blockade of A1AR action. Our results raise concern for caffeine exposure during embryogenesis, particularly in pregnancies with increased risk of embryonic hypoxia. |
format | Online Article Text |
id | pubmed-3229565 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-32295652011-12-07 Caffeine Acts via A1 Adenosine Receptors to Disrupt Embryonic Cardiac Function Buscariollo, Daniela L. Breuer, Gregory A. Wendler, Christopher C. Rivkees, Scott A. PLoS One Research Article BACKGROUND: Evidence suggests that adenosine acts via cardiac A1 adenosine receptors (A1ARs) to protect embryos against hypoxia. During embryogenesis, A1ARs are the dominant regulator of heart rate, and A1AR activation reduces heart rate. Adenosine action is inhibited by caffeine, which is widely consumed during pregnancy. In this study, we tested the hypothesis that caffeine influences developing embryos by altering cardiac function. METHODOLOGY/PRINCIPAL FINDINGS: Effects of caffeine and adenosine receptor-selective antagonists on heart rate were studied in vitro using whole murine embryos at E9.5 and isolated hearts at E12.5. Embryos were examined in room air (21% O(2)) or hypoxic (2% O(2)) conditions. Hypoxia decreased heart rates of E9.5 embryos by 15.8% and in E12.5 isolated hearts by 27.1%. In room air, caffeine (200 µM) had no effect on E9.5 heart rates; however, caffeine increased heart rates at E12.5 by 37.7%. Caffeine abolished hypoxia-mediated bradycardia at E9.5 and blunted hypoxia-mediated bradycardia at E12.5. Real-time PCR analysis of RNA from isolated E9.5 and E12.5 hearts showed that A1AR and A2aAR genes were expressed at both ages. Treatment with adenosine receptor-selective antagonists revealed that SCH-58261 (A2aAR-specific antagonist) had no affects on heart function, whereas DPCPX (A1AR-specific antagonist) had effects similar to caffeine treatment at E9.5 and E12.5. At E12.5, embryonic hearts lacking A1AR expression (A1AR−/−) had elevated heart rates compared to A1AR+/− littermates, A1AR−/− heart rates failed to decrease to levels comparable to those of controls. Caffeine did not significantly affect heart rates of A1AR−/− embryos. CONCLUSIONS/SIGNIFICANCE: These data show that caffeine alters embryonic cardiac function and disrupts the normal cardiac response to hypoxia through blockade of A1AR action. Our results raise concern for caffeine exposure during embryogenesis, particularly in pregnancies with increased risk of embryonic hypoxia. Public Library of Science 2011-12-02 /pmc/articles/PMC3229565/ /pubmed/22164264 http://dx.doi.org/10.1371/journal.pone.0028296 Text en Buscariollo et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Buscariollo, Daniela L. Breuer, Gregory A. Wendler, Christopher C. Rivkees, Scott A. Caffeine Acts via A1 Adenosine Receptors to Disrupt Embryonic Cardiac Function |
title | Caffeine Acts via A1 Adenosine Receptors to Disrupt Embryonic Cardiac Function |
title_full | Caffeine Acts via A1 Adenosine Receptors to Disrupt Embryonic Cardiac Function |
title_fullStr | Caffeine Acts via A1 Adenosine Receptors to Disrupt Embryonic Cardiac Function |
title_full_unstemmed | Caffeine Acts via A1 Adenosine Receptors to Disrupt Embryonic Cardiac Function |
title_short | Caffeine Acts via A1 Adenosine Receptors to Disrupt Embryonic Cardiac Function |
title_sort | caffeine acts via a1 adenosine receptors to disrupt embryonic cardiac function |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229565/ https://www.ncbi.nlm.nih.gov/pubmed/22164264 http://dx.doi.org/10.1371/journal.pone.0028296 |
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