Cargando…
The Adenylate Cyclase Activator Forskolin Potentiates the Positive Inotropic Effect of the Phosphodiesterase Inhibitor Milrinone But Not of the Calcium Sensitizer Levosimendan nor of Its Hemodynamically Active Metabolites: An Apparent Conundrum
OR-1855 and OR-1896 are 2 hemodynamically active metabolites of the inodilator levosimendan, with calcium sensitizing activity, but their mechanism of action is still not fully understood. It has been previously reported that the positive inotropic effect of levosimendan is not potentiated by the ad...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Journal of Cardiovascular Pharmacology
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9162272/ https://www.ncbi.nlm.nih.gov/pubmed/35170487 http://dx.doi.org/10.1097/FJC.0000000000001235 |
_version_ | 1784719663156953088 |
---|---|
author | Levijoki, Jouko Pollesello, Piero Grossini, Elena Papp, Zoltán |
author_facet | Levijoki, Jouko Pollesello, Piero Grossini, Elena Papp, Zoltán |
author_sort | Levijoki, Jouko |
collection | PubMed |
description | OR-1855 and OR-1896 are 2 hemodynamically active metabolites of the inodilator levosimendan, with calcium sensitizing activity, but their mechanism of action is still not fully understood. It has been previously reported that the positive inotropic effect of levosimendan is not potentiated by the adenylate cyclase activator forskolin, whereas forskolin does potentiate the effects of the phosphodiesterase (PDE) inhibitor milrinone. To ascertain whether the active metabolites follow the same pattern of levosimendan, the positive inotropic effects of OR- 1855 and OR-1896 were studied in guinea-pig-isolated papillary muscle in the presence and absence of forskolin. OR-1855 and OR-1896 were also tested as inhibitors of PDE-III and PDE-IV. Our results show that 0.1 µM forskolin did not potentiate the positive inotropic effect of OR-1855 or OR-1896, as in the case of the parent compound levosimendan. As in previous studies, the positive inotropic effect of milrinone was markedly potentiated in the presence of forskolin. From these data, we propose an explanation for the divergent behavior of the calcium sensitizing drugs and PDE inhibitors. |
format | Online Article Text |
id | pubmed-9162272 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Journal of Cardiovascular Pharmacology |
record_format | MEDLINE/PubMed |
spelling | pubmed-91622722022-06-08 The Adenylate Cyclase Activator Forskolin Potentiates the Positive Inotropic Effect of the Phosphodiesterase Inhibitor Milrinone But Not of the Calcium Sensitizer Levosimendan nor of Its Hemodynamically Active Metabolites: An Apparent Conundrum Levijoki, Jouko Pollesello, Piero Grossini, Elena Papp, Zoltán J Cardiovasc Pharmacol Original Article OR-1855 and OR-1896 are 2 hemodynamically active metabolites of the inodilator levosimendan, with calcium sensitizing activity, but their mechanism of action is still not fully understood. It has been previously reported that the positive inotropic effect of levosimendan is not potentiated by the adenylate cyclase activator forskolin, whereas forskolin does potentiate the effects of the phosphodiesterase (PDE) inhibitor milrinone. To ascertain whether the active metabolites follow the same pattern of levosimendan, the positive inotropic effects of OR- 1855 and OR-1896 were studied in guinea-pig-isolated papillary muscle in the presence and absence of forskolin. OR-1855 and OR-1896 were also tested as inhibitors of PDE-III and PDE-IV. Our results show that 0.1 µM forskolin did not potentiate the positive inotropic effect of OR-1855 or OR-1896, as in the case of the parent compound levosimendan. As in previous studies, the positive inotropic effect of milrinone was markedly potentiated in the presence of forskolin. From these data, we propose an explanation for the divergent behavior of the calcium sensitizing drugs and PDE inhibitors. Journal of Cardiovascular Pharmacology 2022-06 2022-02-16 /pmc/articles/PMC9162272/ /pubmed/35170487 http://dx.doi.org/10.1097/FJC.0000000000001235 Text en Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. |
spellingShingle | Original Article Levijoki, Jouko Pollesello, Piero Grossini, Elena Papp, Zoltán The Adenylate Cyclase Activator Forskolin Potentiates the Positive Inotropic Effect of the Phosphodiesterase Inhibitor Milrinone But Not of the Calcium Sensitizer Levosimendan nor of Its Hemodynamically Active Metabolites: An Apparent Conundrum |
title | The Adenylate Cyclase Activator Forskolin Potentiates the Positive Inotropic Effect of the Phosphodiesterase Inhibitor Milrinone But Not of the Calcium Sensitizer Levosimendan nor of Its Hemodynamically Active Metabolites: An Apparent Conundrum |
title_full | The Adenylate Cyclase Activator Forskolin Potentiates the Positive Inotropic Effect of the Phosphodiesterase Inhibitor Milrinone But Not of the Calcium Sensitizer Levosimendan nor of Its Hemodynamically Active Metabolites: An Apparent Conundrum |
title_fullStr | The Adenylate Cyclase Activator Forskolin Potentiates the Positive Inotropic Effect of the Phosphodiesterase Inhibitor Milrinone But Not of the Calcium Sensitizer Levosimendan nor of Its Hemodynamically Active Metabolites: An Apparent Conundrum |
title_full_unstemmed | The Adenylate Cyclase Activator Forskolin Potentiates the Positive Inotropic Effect of the Phosphodiesterase Inhibitor Milrinone But Not of the Calcium Sensitizer Levosimendan nor of Its Hemodynamically Active Metabolites: An Apparent Conundrum |
title_short | The Adenylate Cyclase Activator Forskolin Potentiates the Positive Inotropic Effect of the Phosphodiesterase Inhibitor Milrinone But Not of the Calcium Sensitizer Levosimendan nor of Its Hemodynamically Active Metabolites: An Apparent Conundrum |
title_sort | adenylate cyclase activator forskolin potentiates the positive inotropic effect of the phosphodiesterase inhibitor milrinone but not of the calcium sensitizer levosimendan nor of its hemodynamically active metabolites: an apparent conundrum |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9162272/ https://www.ncbi.nlm.nih.gov/pubmed/35170487 http://dx.doi.org/10.1097/FJC.0000000000001235 |
work_keys_str_mv | AT levijokijouko theadenylatecyclaseactivatorforskolinpotentiatesthepositiveinotropiceffectofthephosphodiesteraseinhibitormilrinonebutnotofthecalciumsensitizerlevosimendannorofitshemodynamicallyactivemetabolitesanapparentconundrum AT pollesellopiero theadenylatecyclaseactivatorforskolinpotentiatesthepositiveinotropiceffectofthephosphodiesteraseinhibitormilrinonebutnotofthecalciumsensitizerlevosimendannorofitshemodynamicallyactivemetabolitesanapparentconundrum AT grossinielena theadenylatecyclaseactivatorforskolinpotentiatesthepositiveinotropiceffectofthephosphodiesteraseinhibitormilrinonebutnotofthecalciumsensitizerlevosimendannorofitshemodynamicallyactivemetabolitesanapparentconundrum AT pappzoltan theadenylatecyclaseactivatorforskolinpotentiatesthepositiveinotropiceffectofthephosphodiesteraseinhibitormilrinonebutnotofthecalciumsensitizerlevosimendannorofitshemodynamicallyactivemetabolitesanapparentconundrum AT levijokijouko adenylatecyclaseactivatorforskolinpotentiatesthepositiveinotropiceffectofthephosphodiesteraseinhibitormilrinonebutnotofthecalciumsensitizerlevosimendannorofitshemodynamicallyactivemetabolitesanapparentconundrum AT pollesellopiero adenylatecyclaseactivatorforskolinpotentiatesthepositiveinotropiceffectofthephosphodiesteraseinhibitormilrinonebutnotofthecalciumsensitizerlevosimendannorofitshemodynamicallyactivemetabolitesanapparentconundrum AT grossinielena adenylatecyclaseactivatorforskolinpotentiatesthepositiveinotropiceffectofthephosphodiesteraseinhibitormilrinonebutnotofthecalciumsensitizerlevosimendannorofitshemodynamicallyactivemetabolitesanapparentconundrum AT pappzoltan adenylatecyclaseactivatorforskolinpotentiatesthepositiveinotropiceffectofthephosphodiesteraseinhibitormilrinonebutnotofthecalciumsensitizerlevosimendannorofitshemodynamicallyactivemetabolitesanapparentconundrum |