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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

https://doi.org/10.1006/jmcc.1999.0951Get rights and content

Abstract

This study examined mechanisms of β -adrenergic (AR) desensitization in a myocardial infarction (MI) model of heart failure in the rat. Inotropic 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- andβ2 -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 (RI α and RII α), showed no change after MI. However the expression of Gi α2was 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±0.006P =0.004), with no changes observed in the expression of Gs α . These results suggest that increases in Gi play an important role in the decreased β -AR responsiveness in the rat model of MI.

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    Secondly, to ascertain involvement of the PKC isozyme(s) in attenuating isoproterenol stimulated of adenyl cyclase activity in the cells. And, thirdly, in view of a previous report that in pulmonary artery endothelial cells pretreatment with pertussis toxin eliminates the protein kinase C activator, phorbol ester caused attenuation of isoproterenol stimulated adenyl cyclase activity [5]; and also that Gi has been shown to play an important role in decreased β-adrenergic responsiveness in a rat model of myocardial infarction [30], we tested the hypothesis that U46619 caused inhibition of isoproterenol stimulated adenyl cyclase activity occurs via phosphorylation of Gi by PKC in the pulmonary smooth muscle cells. Our present study that Tp receptor activation by U46619 caused attenuation of isoprotereol stimulated adenyl cyclase activity occurs markedly, but not completely, via PKC-ζ dependent activation of NADPH oxidase with subsequent stimulation of PKC-α activity in the smooth muscle cells.

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Please address all correspondence to: Professor Roger J. Summers, Department of Pharmacology, Monash University, Wellington Road, Clayton, Victoria, Australia, 3168. Email: [email protected]

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