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Selective Attenuation of Norepinephrine Release and Stress-Induced Heart Rate Increase by Partial Adenosine A(1) Agonism
The release of the neurotransmitter norepinephrine (NE) is modulated by presynaptic adenosine receptors. In the present study we investigated the effect of a partial activation of this feedback mechanism. We hypothesized that partial agonism would have differential effects on NE release in isolated...
Autores principales: | , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065468/ https://www.ncbi.nlm.nih.gov/pubmed/21464936 http://dx.doi.org/10.1371/journal.pone.0018048 |
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author | Bott-Flügel, Lorenz Bernshausen, Alexandra Schneider, Heike Luppa, Peter Zimmermann, Katja Albrecht-Küpper, Barbara Kast, Raimund Laugwitz, Karl-Ludwig Ehmke, Heimo Knorr, Andreas Seyfarth, Melchior |
author_facet | Bott-Flügel, Lorenz Bernshausen, Alexandra Schneider, Heike Luppa, Peter Zimmermann, Katja Albrecht-Küpper, Barbara Kast, Raimund Laugwitz, Karl-Ludwig Ehmke, Heimo Knorr, Andreas Seyfarth, Melchior |
author_sort | Bott-Flügel, Lorenz |
collection | PubMed |
description | The release of the neurotransmitter norepinephrine (NE) is modulated by presynaptic adenosine receptors. In the present study we investigated the effect of a partial activation of this feedback mechanism. We hypothesized that partial agonism would have differential effects on NE release in isolated hearts as well as on heart rate in vivo depending on the genetic background and baseline sympathetic activity. In isolated perfused hearts of Wistar and Spontaneously Hypertensive Rats (SHR), NE release was induced by electrical stimulation under control conditions (S1), and with capadenoson 6 · 10(−8) M (30 µg/l), 6 · 10(−7) M (300 µg/l) or 2-chloro-N(6)-cyclopentyladenosine (CCPA) 10(−6) M (S2). Under control conditions (S1), NE release was significantly higher in SHR hearts compared to Wistar (766+/−87 pmol/g vs. 173+/−18 pmol/g, p<0.01). Capadenoson led to a concentration-dependent decrease of the stimulation–induced NE release in SHR (S2/S1 = 0.90±0.08 with capadenoson 6 · 10(−8) M, 0.54±0.02 with 6 · 10(−7) M), but not in Wistar hearts (S2/S1 = 1.05±0.12 with 6 · 10(−8) M, 1.03±0.09 with 6 · 10(−7) M). CCPA reduced NE release to a similar degree in hearts from both strains. In vivo capadenoson did not alter resting heart rate in Wistar rats or SHR. Restraint stress induced a significantly greater increase of heart rate in SHR than in Wistar rats. Capadenoson blunted this stress-induced tachycardia by 45% in SHR, but not in Wistar rats. Using a [(35)S]GTPγS assay we demonstrated that capadenoson is a partial agonist compared to the full agonist CCPA (74+/−2% A(1)-receptor stimulation). These results suggest that partial adenosine A(1)-agonism dampens stress-induced tachycardia selectively in rats susceptible to strong increases in sympathetic activity, most likely due to a presynaptic attenuation of NE release. |
format | Text |
id | pubmed-3065468 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-30654682011-04-04 Selective Attenuation of Norepinephrine Release and Stress-Induced Heart Rate Increase by Partial Adenosine A(1) Agonism Bott-Flügel, Lorenz Bernshausen, Alexandra Schneider, Heike Luppa, Peter Zimmermann, Katja Albrecht-Küpper, Barbara Kast, Raimund Laugwitz, Karl-Ludwig Ehmke, Heimo Knorr, Andreas Seyfarth, Melchior PLoS One Research Article The release of the neurotransmitter norepinephrine (NE) is modulated by presynaptic adenosine receptors. In the present study we investigated the effect of a partial activation of this feedback mechanism. We hypothesized that partial agonism would have differential effects on NE release in isolated hearts as well as on heart rate in vivo depending on the genetic background and baseline sympathetic activity. In isolated perfused hearts of Wistar and Spontaneously Hypertensive Rats (SHR), NE release was induced by electrical stimulation under control conditions (S1), and with capadenoson 6 · 10(−8) M (30 µg/l), 6 · 10(−7) M (300 µg/l) or 2-chloro-N(6)-cyclopentyladenosine (CCPA) 10(−6) M (S2). Under control conditions (S1), NE release was significantly higher in SHR hearts compared to Wistar (766+/−87 pmol/g vs. 173+/−18 pmol/g, p<0.01). Capadenoson led to a concentration-dependent decrease of the stimulation–induced NE release in SHR (S2/S1 = 0.90±0.08 with capadenoson 6 · 10(−8) M, 0.54±0.02 with 6 · 10(−7) M), but not in Wistar hearts (S2/S1 = 1.05±0.12 with 6 · 10(−8) M, 1.03±0.09 with 6 · 10(−7) M). CCPA reduced NE release to a similar degree in hearts from both strains. In vivo capadenoson did not alter resting heart rate in Wistar rats or SHR. Restraint stress induced a significantly greater increase of heart rate in SHR than in Wistar rats. Capadenoson blunted this stress-induced tachycardia by 45% in SHR, but not in Wistar rats. Using a [(35)S]GTPγS assay we demonstrated that capadenoson is a partial agonist compared to the full agonist CCPA (74+/−2% A(1)-receptor stimulation). These results suggest that partial adenosine A(1)-agonism dampens stress-induced tachycardia selectively in rats susceptible to strong increases in sympathetic activity, most likely due to a presynaptic attenuation of NE release. Public Library of Science 2011-03-28 /pmc/articles/PMC3065468/ /pubmed/21464936 http://dx.doi.org/10.1371/journal.pone.0018048 Text en Bott-Flügel 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 Bott-Flügel, Lorenz Bernshausen, Alexandra Schneider, Heike Luppa, Peter Zimmermann, Katja Albrecht-Küpper, Barbara Kast, Raimund Laugwitz, Karl-Ludwig Ehmke, Heimo Knorr, Andreas Seyfarth, Melchior Selective Attenuation of Norepinephrine Release and Stress-Induced Heart Rate Increase by Partial Adenosine A(1) Agonism |
title | Selective Attenuation of Norepinephrine Release and Stress-Induced Heart Rate Increase by Partial Adenosine A(1) Agonism |
title_full | Selective Attenuation of Norepinephrine Release and Stress-Induced Heart Rate Increase by Partial Adenosine A(1) Agonism |
title_fullStr | Selective Attenuation of Norepinephrine Release and Stress-Induced Heart Rate Increase by Partial Adenosine A(1) Agonism |
title_full_unstemmed | Selective Attenuation of Norepinephrine Release and Stress-Induced Heart Rate Increase by Partial Adenosine A(1) Agonism |
title_short | Selective Attenuation of Norepinephrine Release and Stress-Induced Heart Rate Increase by Partial Adenosine A(1) Agonism |
title_sort | selective attenuation of norepinephrine release and stress-induced heart rate increase by partial adenosine a(1) agonism |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065468/ https://www.ncbi.nlm.nih.gov/pubmed/21464936 http://dx.doi.org/10.1371/journal.pone.0018048 |
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