The available data indicate that the
beta-adrenergic receptors that mediate positive inotropic responses undergo "down-regulation," a cellularly mediated decrease in surface receptor number, in
congestive heart failure. This decrease in
beta-adrenergic receptor number is proportional to the degree of myocardial dysfunction and the loss of contractility that occurs in
congestive heart failure. It appears to be chamber-specific, occurring to the greatest degree in the most severely affected ventricular chamber, and is specific to the beta 1-adrenergic receptor subtype.
Beta-adrenergic receptor down-regulation may be the result of the excessively high levels of plasma
catecholamines seen in
congestive heart failure, inasmuch as a similar phenomenon of
beta-adrenergic receptor down-regulation is seen in animals treated with high doses of
catecholamines. The specific down-regulation in cardiac beta receptors may be, in part, the cause of the decrease in myocardial function observed during long-term
beta-adrenergic receptor stimulation, and an actual decrease in
beta-adrenergic receptor number has been observed in myocardial tissue from patients with
congestive heart failure. Down-regulation of beta receptors in
congestive heart failure results in a decrease or loss of efficacy of
beta-adrenergic receptor agonists on long-term administration. This is especially evident for partial agonists, which are more dependent on receptor number for their positive inotropic effects than full agonists. Although beta receptors are down-regulated in
congestive heart failure, myocardial alpha 1-adrenergic receptors and
histamine H2 receptors do not appear to be subject to this same regulatory process. Inasmuch as stimulation of both of these receptors results in a positive inotropic effect, further study should be given to the potential therapeutic utility of selective stimulation of myocardial alpha 1-adrenergic receptors and
histamine H2 receptors in
congestive heart failure. It is evident that the status of specific receptor subtypes in pathophysiologic states such as
congestive heart failure must be considered when assessing the likelihood of success in treating patients with
beta-adrenergic receptor agonists.