Norepinephrine and
epinephrine stimulate alpha- and
beta-adrenergic receptors which, in turn, modulate force of contraction in heart muscle cells. However, chronic stimulation may be associated with growth-promoting effects and modulation of the cardiac phenotype. Sympathetic tone is chronically enhanced in chronic
heart failure and results in a selective down regulation of
beta 1 adrenergic receptors, most likely due to local mechanisms. Beyond reduced beta 1 receptor density and increased levels of inhibitory Gi
proteins, there is now evidence that NO can modulate the beta-
adrenergic stimulation in the human myocardium. Increased NO activity generated by an inducible
NO synthase is associated with a reduced positive inotropic response to beta-agonists, a mechanism which may play an important role in inflammatory states such as
myocarditis or
sepsis. Experimental data suggests that stimulation of
alpha-adrenergic receptors of cardiomyocytes results in cardiac growth and changes in phenotype which, in turn, may affect the functional properties of the myocardium. For example,
phenylephrine can upregulate the expression of the
sodium/calcium exchanger, while the expression SR
Ca2+ ATPase may be reduced. The latter is also affected by
angiotensin II. Similar changes in the expression of these crucial
proteins for the cardiac
calcium homeostasis have been reported in the failing human heart, raising the possibility that the increased sympathetic tone and the activated renin-angiotensin system may be involved in these changes.