Increase of the 40,000-mol wt pertussis toxin substrate (G protein) in the failing human heart

Human heart failure is associated with a diminished contractile response to β-adrenergic agonists. We hypothesized that alterations in the activity of a guanine nucleotide-binding regulatory protein (G protein) might be partially responsible for this abnormality. We therefore measured the activity of G proteins in failing human myocardium utilizing bacterial toxin-catalyzed ADP ribosylation. The activity of a 40,000-mol wt pertussis toxin substrate (αG₄₀) was increased by 36% in failing human hearts when compared with nonfailing controls. In contrast, there was no change in the level of the stimulatory regulatory subunit (G(s)). The increased activity in αG₄₀ was associated with a 30% decrease in basal as well as 5'-guanylyl imidodiphosphate-stimulated adenylate cyclase activity. These data suggest that increased αG₄₀ activity is a new marker for failing myocardium and may account at least in part for the diminished responsiveness to β₁-adrenergic agonists in the failing human heart.