Doxorubicin alters G-protein coupled receptor-mediated vasocontraction in rat coronary arteries

Caroline Lozahic; Helen Maddock; Mark Wheatley; Hardip Sandhu

doi:10.1007/s00210-024-02988-x

Doxorubicin alters G-protein coupled receptor-mediated vasocontraction in rat coronary arteries

Caroline Lozahic, Helen Maddock, Mark Wheatley, Hardip Sandhu

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Abstract

Doxorubicin (Doxo)-associated cardio-and vasotoxicity has been recognised as a serious complication of cancer chemotherapy. The purpose of this novel paper was to determine the effect of Doxo on G-protein coupled receptor (GPCR)-mediated vasocontraction located on vascular smooth muscle cells. Rat left anterior descending artery segments were incubated for 24 h with 0.5 µM Doxo. The vasocontractile responses by activation of endothelin receptor type A (ET_A) and type B (ET_B), serotonin receptor 1B (5-HT_1B) and thromboxane A2 prostanoid receptor (TP) were investigated by a sensitive myography using specific agonists, while the specificity of the GPCR agonists was verified by applying selective antagonists (i.e. ET_A and ET_B agonist = 10^− 14-10^− 7.5 M endothelin-1 (ET-1); ET_A antagonist = 10 µM BQ123; ET_B agonists = 10^− 14-10^− 7.5 M sarafotoxin 6c (S6c) and ET-1; ET_B antagonist = 0.1 µM BQ788; 5-HT_1B agonist = 10^− 12-10^− 5.5 M 5-carboxamidotryptamine (5-CT); 5-HT_1B antagonist = 1 µM GR55562; TP agonist = 10^− 12-10^− 6.5 M U46619; TP antagonist = 1 µM Seratrodast). Our results show that 0.5 µM Doxo incubation of LAD segments leads to an increased VSMC vasocontraction through the ET_B, 5-HT_1B and TP GPCRs, with a 2.2-fold increase in ET_B-mediated vasocontraction at 10^− 10.5 M S6c, a 2.0-fold increase in 5-HT_1B-mediated vasocontraction at 10^− 5.5 M 5-CT, and a 1.3-fold increase in TP-mediated vasocontraction at 10^− 6.5 M U46619. Further studies unravelling the involvement of intracellular GPCR signalling pathways will broaden our understanding of the Doxo-induced vasotoxicity, and thus pave the way to mitigate the adverse effects by potential implementation of adjunct therapy options.

Original language	English
Pages (from-to)	5831-5845
Number of pages	15
Journal	Naunyn-Schmiedeberg's Archives of Pharmacology
Volume	397
Early online date	8 Feb 2024
DOIs	https://doi.org/10.1007/s00210-024-02988-x
Publication status	Published - Aug 2024

Bibliographical note

Copyright © and Moral Rights are retained by the author(s) and/ or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders.

This document is the author’s post-print version, incorporating any revisions agreed during the peer-review process. Some differences between the published version and this version may remain and you are advised to consult the published version if you wish to cite from it.

Funding

This research was supported by Coventry University, Research Centre for Health & Life Sciences, Coventry University.

Funders	Funder number
Coventry University

Keywords

G-protein coupled receptors
Doxorubicin
Cancer therapy adverse effect
Vasotoxicity
Cardiotoxicity
Coronary microvascular function

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s00210-024-02988-x

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Cite this

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title = "Doxorubicin alters G-protein coupled receptor-mediated vasocontraction in rat coronary arteries",

abstract = "Doxorubicin (Doxo)-associated cardio-and vasotoxicity has been recognised as a serious complication of cancer chemotherapy. The purpose of this novel paper was to determine the effect of Doxo on G-protein coupled receptor (GPCR)-mediated vasocontraction located on vascular smooth muscle cells. Rat left anterior descending artery segments were incubated for 24 h with 0.5 µM Doxo. The vasocontractile responses by activation of endothelin receptor type A (ETA) and type B (ETB), serotonin receptor 1B (5-HT1B) and thromboxane A2 prostanoid receptor (TP) were investigated by a sensitive myography using specific agonists, while the specificity of the GPCR agonists was verified by applying selective antagonists (i.e. ETA and ETB agonist = 10− 14-10− 7.5 M endothelin-1 (ET-1); ETA antagonist = 10 µM BQ123; ETB agonists = 10− 14-10− 7.5 M sarafotoxin 6c (S6c) and ET-1; ETB antagonist = 0.1 µM BQ788; 5-HT1B agonist = 10− 12-10− 5.5 M 5-carboxamidotryptamine (5-CT); 5-HT1B antagonist = 1 µM GR55562; TP agonist = 10− 12-10− 6.5 M U46619; TP antagonist = 1 µM Seratrodast). Our results show that 0.5 µM Doxo incubation of LAD segments leads to an increased VSMC vasocontraction through the ETB, 5-HT1B and TP GPCRs, with a 2.2-fold increase in ETB-mediated vasocontraction at 10− 10.5 M S6c, a 2.0-fold increase in 5-HT1B-mediated vasocontraction at 10− 5.5 M 5-CT, and a 1.3-fold increase in TP-mediated vasocontraction at 10− 6.5 M U46619. Further studies unravelling the involvement of intracellular GPCR signalling pathways will broaden our understanding of the Doxo-induced vasotoxicity, and thus pave the way to mitigate the adverse effects by potential implementation of adjunct therapy options.",

keywords = "G-protein coupled receptors, Doxorubicin, Cancer therapy adverse effect, Vasotoxicity, Cardiotoxicity, Coronary microvascular function",

author = "Caroline Lozahic and Helen Maddock and Mark Wheatley and Hardip Sandhu",

note = "Copyright {\textcopyright} and Moral Rights are retained by the author(s) and/ or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders. This document is the author{\textquoteright}s post-print version, incorporating any revisions agreed during the peer-review process. Some differences between the published version and this version may remain and you are advised to consult the published version if you wish to cite from it. ",

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language = "English",

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TY - JOUR

T1 - Doxorubicin alters G-protein coupled receptor-mediated vasocontraction in rat coronary arteries

AU - Lozahic, Caroline

AU - Maddock, Helen

AU - Wheatley, Mark

AU - Sandhu, Hardip

N1 - Copyright © and Moral Rights are retained by the author(s) and/ or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders. This document is the author’s post-print version, incorporating any revisions agreed during the peer-review process. Some differences between the published version and this version may remain and you are advised to consult the published version if you wish to cite from it.

PY - 2024/8

Y1 - 2024/8

N2 - Doxorubicin (Doxo)-associated cardio-and vasotoxicity has been recognised as a serious complication of cancer chemotherapy. The purpose of this novel paper was to determine the effect of Doxo on G-protein coupled receptor (GPCR)-mediated vasocontraction located on vascular smooth muscle cells. Rat left anterior descending artery segments were incubated for 24 h with 0.5 µM Doxo. The vasocontractile responses by activation of endothelin receptor type A (ETA) and type B (ETB), serotonin receptor 1B (5-HT1B) and thromboxane A2 prostanoid receptor (TP) were investigated by a sensitive myography using specific agonists, while the specificity of the GPCR agonists was verified by applying selective antagonists (i.e. ETA and ETB agonist = 10− 14-10− 7.5 M endothelin-1 (ET-1); ETA antagonist = 10 µM BQ123; ETB agonists = 10− 14-10− 7.5 M sarafotoxin 6c (S6c) and ET-1; ETB antagonist = 0.1 µM BQ788; 5-HT1B agonist = 10− 12-10− 5.5 M 5-carboxamidotryptamine (5-CT); 5-HT1B antagonist = 1 µM GR55562; TP agonist = 10− 12-10− 6.5 M U46619; TP antagonist = 1 µM Seratrodast). Our results show that 0.5 µM Doxo incubation of LAD segments leads to an increased VSMC vasocontraction through the ETB, 5-HT1B and TP GPCRs, with a 2.2-fold increase in ETB-mediated vasocontraction at 10− 10.5 M S6c, a 2.0-fold increase in 5-HT1B-mediated vasocontraction at 10− 5.5 M 5-CT, and a 1.3-fold increase in TP-mediated vasocontraction at 10− 6.5 M U46619. Further studies unravelling the involvement of intracellular GPCR signalling pathways will broaden our understanding of the Doxo-induced vasotoxicity, and thus pave the way to mitigate the adverse effects by potential implementation of adjunct therapy options.

AB - Doxorubicin (Doxo)-associated cardio-and vasotoxicity has been recognised as a serious complication of cancer chemotherapy. The purpose of this novel paper was to determine the effect of Doxo on G-protein coupled receptor (GPCR)-mediated vasocontraction located on vascular smooth muscle cells. Rat left anterior descending artery segments were incubated for 24 h with 0.5 µM Doxo. The vasocontractile responses by activation of endothelin receptor type A (ETA) and type B (ETB), serotonin receptor 1B (5-HT1B) and thromboxane A2 prostanoid receptor (TP) were investigated by a sensitive myography using specific agonists, while the specificity of the GPCR agonists was verified by applying selective antagonists (i.e. ETA and ETB agonist = 10− 14-10− 7.5 M endothelin-1 (ET-1); ETA antagonist = 10 µM BQ123; ETB agonists = 10− 14-10− 7.5 M sarafotoxin 6c (S6c) and ET-1; ETB antagonist = 0.1 µM BQ788; 5-HT1B agonist = 10− 12-10− 5.5 M 5-carboxamidotryptamine (5-CT); 5-HT1B antagonist = 1 µM GR55562; TP agonist = 10− 12-10− 6.5 M U46619; TP antagonist = 1 µM Seratrodast). Our results show that 0.5 µM Doxo incubation of LAD segments leads to an increased VSMC vasocontraction through the ETB, 5-HT1B and TP GPCRs, with a 2.2-fold increase in ETB-mediated vasocontraction at 10− 10.5 M S6c, a 2.0-fold increase in 5-HT1B-mediated vasocontraction at 10− 5.5 M 5-CT, and a 1.3-fold increase in TP-mediated vasocontraction at 10− 6.5 M U46619. Further studies unravelling the involvement of intracellular GPCR signalling pathways will broaden our understanding of the Doxo-induced vasotoxicity, and thus pave the way to mitigate the adverse effects by potential implementation of adjunct therapy options.

KW - G-protein coupled receptors

KW - Doxorubicin

KW - Cancer therapy adverse effect

KW - Vasotoxicity

KW - Cardiotoxicity

KW - Coronary microvascular function

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U2 - 10.1007/s00210-024-02988-x

DO - 10.1007/s00210-024-02988-x

M3 - Article

SN - 0028-1298

VL - 397

SP - 5831

EP - 5845

JO - Naunyn-Schmiedeberg's Archives of Pharmacology

JF - Naunyn-Schmiedeberg's Archives of Pharmacology

ER -

Doxorubicin alters G-protein coupled receptor-mediated vasocontraction in rat coronary arteries

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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