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

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.