Desensitization of cardiac β-adrenoceptor signaling with heart failure produced by myocardial infarction in the rat. Evidence for the role of Gi but not Gs or phosphorylating proteins

Andrew R. Kompa, Xin Hua Gu, Bronwyn A. Evans, Roger J. Summers

Research output: Contribution to journalArticleResearchpeer-review

Abstract

This study examined mechanisms of β-adrenergic (AR) desensitization in a myocardial infarction (MI) model of heart failure in the rat. Isotropic responses to isoproterenol (non-selective β-AR agonist) and RO 363 (selective β1-AR agonist), in left atria and left papillary muscle, were reduced by up to 65%, while chronotropic responses in right atria were unaffected. β1- and β2-AR density did not change after MI, suggesting that changes in β-AR responsiveness are due to changes occurring downstream of the receptor. Inotropic and chronotropic responses to forskolin were not altered in right and left atria and left papillary muscle after MI, suggesting changes at the level of the G-proteins. Pertussis toxin treatment of animals restored inotropic responses to isoproterenol in left atria and left papillary muscle to levels seen in the sham group, indicating that inactivation of Gi-proteins improves inotropic function in MI rats, and that β-ARs couple to Gi in cardiac failure. Expression of G-protein receptor kinase 2 (GRK2), β-arrestin1 and the regulatory subunits of cAMPdPK (RIα and RIIα), showed no change after MI. However the expression of Giα2 was significantly increased in left ventricle (sham 0.888 ± 0.140, MI 1.759 ± 0.352; P= 0.026), right ventricle (sham 0.031 ± 0.004, MI 0.037 ± 0.002; P = 0.006) and atria (sham 0.107 ± 0.006, MI 0.138 ± 0.006; P = 0.004, with no changes observed in the expression of Gsα. These results suggest that increases in Gi play an important role in the decreased β-AR responsiveness in the rat model of MI.

Original languageEnglish
Pages (from-to)1185-1201
Number of pages17
JournalJournal of Molecular and Cellular Cardiology
Volume31
Issue number6
DOIs
Publication statusPublished - 1 Jan 1999

Keywords

  • Contractile function
  • Forskolin
  • G-proteins
  • Heart failure
  • mRNA expression
  • Myocardial infarction
  • Northern blot
  • Pertussis toxin
  • β-adrenoceptors

Cite this

@article{eddc1dfe294541fe905d57a24470490b,
title = "Desensitization of cardiac β-adrenoceptor signaling with heart failure produced by myocardial infarction in the rat. Evidence for the role of Gi but not Gs or phosphorylating proteins",
abstract = "This study examined mechanisms of β-adrenergic (AR) desensitization in a myocardial infarction (MI) model of heart failure in the rat. Isotropic responses to isoproterenol (non-selective β-AR agonist) and RO 363 (selective β1-AR agonist), in left atria and left papillary muscle, were reduced by up to 65{\%}, while chronotropic responses in right atria were unaffected. β1- and β2-AR density did not change after MI, suggesting that changes in β-AR responsiveness are due to changes occurring downstream of the receptor. Inotropic and chronotropic responses to forskolin were not altered in right and left atria and left papillary muscle after MI, suggesting changes at the level of the G-proteins. Pertussis toxin treatment of animals restored inotropic responses to isoproterenol in left atria and left papillary muscle to levels seen in the sham group, indicating that inactivation of Gi-proteins improves inotropic function in MI rats, and that β-ARs couple to Gi in cardiac failure. Expression of G-protein receptor kinase 2 (GRK2), β-arrestin1 and the regulatory subunits of cAMPdPK (RIα and RIIα), showed no change after MI. However the expression of Giα2 was significantly increased in left ventricle (sham 0.888 ± 0.140, MI 1.759 ± 0.352; P= 0.026), right ventricle (sham 0.031 ± 0.004, MI 0.037 ± 0.002; P = 0.006) and atria (sham 0.107 ± 0.006, MI 0.138 ± 0.006; P = 0.004, with no changes observed in the expression of Gsα. These results suggest that increases in Gi play an important role in the decreased β-AR responsiveness in the rat model of MI.",
keywords = "Contractile function, Forskolin, G-proteins, Heart failure, mRNA expression, Myocardial infarction, Northern blot, Pertussis toxin, β-adrenoceptors",
author = "Kompa, {Andrew R.} and Gu, {Xin Hua} and Evans, {Bronwyn A.} and Summers, {Roger J.}",
year = "1999",
month = "1",
day = "1",
doi = "10.1006/jmcc.1999.0951",
language = "English",
volume = "31",
pages = "1185--1201",
journal = "Journal of Molecular and Cellular Cardiology",
issn = "0022-2828",
publisher = "Elsevier",
number = "6",

}

Desensitization of cardiac β-adrenoceptor signaling with heart failure produced by myocardial infarction in the rat. Evidence for the role of Gi but not Gs or phosphorylating proteins. / Kompa, Andrew R.; Gu, Xin Hua; Evans, Bronwyn A.; Summers, Roger J.

In: Journal of Molecular and Cellular Cardiology, Vol. 31, No. 6, 01.01.1999, p. 1185-1201.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Desensitization of cardiac β-adrenoceptor signaling with heart failure produced by myocardial infarction in the rat. Evidence for the role of Gi but not Gs or phosphorylating proteins

AU - Kompa, Andrew R.

AU - Gu, Xin Hua

AU - Evans, Bronwyn A.

AU - Summers, Roger J.

PY - 1999/1/1

Y1 - 1999/1/1

N2 - This study examined mechanisms of β-adrenergic (AR) desensitization in a myocardial infarction (MI) model of heart failure in the rat. Isotropic responses to isoproterenol (non-selective β-AR agonist) and RO 363 (selective β1-AR agonist), in left atria and left papillary muscle, were reduced by up to 65%, while chronotropic responses in right atria were unaffected. β1- and β2-AR density did not change after MI, suggesting that changes in β-AR responsiveness are due to changes occurring downstream of the receptor. Inotropic and chronotropic responses to forskolin were not altered in right and left atria and left papillary muscle after MI, suggesting changes at the level of the G-proteins. Pertussis toxin treatment of animals restored inotropic responses to isoproterenol in left atria and left papillary muscle to levels seen in the sham group, indicating that inactivation of Gi-proteins improves inotropic function in MI rats, and that β-ARs couple to Gi in cardiac failure. Expression of G-protein receptor kinase 2 (GRK2), β-arrestin1 and the regulatory subunits of cAMPdPK (RIα and RIIα), showed no change after MI. However the expression of Giα2 was significantly increased in left ventricle (sham 0.888 ± 0.140, MI 1.759 ± 0.352; P= 0.026), right ventricle (sham 0.031 ± 0.004, MI 0.037 ± 0.002; P = 0.006) and atria (sham 0.107 ± 0.006, MI 0.138 ± 0.006; P = 0.004, with no changes observed in the expression of Gsα. These results suggest that increases in Gi play an important role in the decreased β-AR responsiveness in the rat model of MI.

AB - This study examined mechanisms of β-adrenergic (AR) desensitization in a myocardial infarction (MI) model of heart failure in the rat. Isotropic responses to isoproterenol (non-selective β-AR agonist) and RO 363 (selective β1-AR agonist), in left atria and left papillary muscle, were reduced by up to 65%, while chronotropic responses in right atria were unaffected. β1- and β2-AR density did not change after MI, suggesting that changes in β-AR responsiveness are due to changes occurring downstream of the receptor. Inotropic and chronotropic responses to forskolin were not altered in right and left atria and left papillary muscle after MI, suggesting changes at the level of the G-proteins. Pertussis toxin treatment of animals restored inotropic responses to isoproterenol in left atria and left papillary muscle to levels seen in the sham group, indicating that inactivation of Gi-proteins improves inotropic function in MI rats, and that β-ARs couple to Gi in cardiac failure. Expression of G-protein receptor kinase 2 (GRK2), β-arrestin1 and the regulatory subunits of cAMPdPK (RIα and RIIα), showed no change after MI. However the expression of Giα2 was significantly increased in left ventricle (sham 0.888 ± 0.140, MI 1.759 ± 0.352; P= 0.026), right ventricle (sham 0.031 ± 0.004, MI 0.037 ± 0.002; P = 0.006) and atria (sham 0.107 ± 0.006, MI 0.138 ± 0.006; P = 0.004, with no changes observed in the expression of Gsα. These results suggest that increases in Gi play an important role in the decreased β-AR responsiveness in the rat model of MI.

KW - Contractile function

KW - Forskolin

KW - G-proteins

KW - Heart failure

KW - mRNA expression

KW - Myocardial infarction

KW - Northern blot

KW - Pertussis toxin

KW - β-adrenoceptors

UR - http://www.scopus.com/inward/record.url?scp=0033153239&partnerID=8YFLogxK

U2 - 10.1006/jmcc.1999.0951

DO - 10.1006/jmcc.1999.0951

M3 - Article

VL - 31

SP - 1185

EP - 1201

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

SN - 0022-2828

IS - 6

ER -