G protein-adrenergic interactions in the heart

Abstract

Guanine nucleotide binding proteins were examined for their influence in developmental and adaptive models of adrenergic actions in the heart. In primary cultures of rat cardiac myocytes, the positive chronotropic response to the alpha-agonist, phenylephrine, changes to negative when these cells are grown with and innervated by sympathetic nerves from the paravertebral chain. Innervated cells have significantly more G protein, as determined by the ADP-ribosylation reaction catalyzed by pertussis toxin, which is linked functionally to the negative chronotropic response. Adult canine Purkinje fibers that respond to phenylephrine with a decrease in automaticity are also linked biochemically and functionally to a G protein that serves as a pertussis toxin substrate. Fibers that increase in automaticity after exposure to phenylephrine, either under control conditions (a minority of fibers) or after prior exposure to pertussis toxin (a majority of fibers), have markedly reduced levels of G. A G protein was also shown to be important in the blunted adrenergic responsiveness that characterizes congestive heart failure in human subjects. In this model, the receptor complex is beta-adrenergic and the involved G protein is a cholera toxin substrate. Gs is reduced in the lymphocytes of patients with congestive heart failure and increases toward normal after successful therapy. These observations highlight the important roles that G proteins have in adrenergic actions of the heart both with respect developmental and adaptive changes.