Reduced β-adrenergic receptor activation decreases G-protein expression and β-adrenergic receptor kinase activity in porcine heart

To determine whether β-adrenergic receptor agonist activation influences guanosine 5'-triphosphate-binding protein (G-protein) expression and β- adrenergic receptor kinase activity in the heart, we examined the effects of chronic β₁-adrenergic receptor antagonist treatment (bisoprolol, 0.2 mg/kg per d i.v., 35 d) on components of the myocardial β-adrenergic receptor-G- protein-adenylyl cyclase pathway in porcine myocardium. Three novel alterations in cardiac adrenergic signaling associated with chronic reduction in β-adrenergic receptor agonist activation were found. First, there was coordinate downregulation of Giα₂ and Gsα mRNA and protein expression in the left ventricle; reduced G-protein content was also found in the right atrium. Second, in the left ventricle, there was a twofold increase in β- adrenergic receptor-dependent stimulation of adenylyl cyclase and a persistent high affinity state of the β-adrenergic receptor. Finally, there was a reduction in left ventricular β-adrenergic receptor kinase activity, suggesting a previously unrecognized association between the degree of adrenergic activation and myocardial β-adrenergic receptor kinase expression. The heart appears to adapt in response to chronic β-adrenergic receptor antagonist administration in a manner that would be expected to offset reduced agonist stimulation. The mechanisms for achieving this extend beyond β-adrenergic receptor upregulation and include alterations in G- protein expression, β-adrenergic receptor-Gs interaction, and myocardial β- adrenergic receptor kinase activity.