Decrease In Number Of Beta-adrenergic Receptors Research Articles

Effect of Transforming Growth Factor Beta-1 on the Intracellular Calcium in Cardiac Fibroblasts.

We attempted to determine the effects of transforming growth factor beta-1 on intracellular Ca2+ concentration changes in the presence of isoproterenol in cardiac fibroblasts. Transforming growth factor beta-1 inhibited the increase of intracellular Ca2+ concentration in the presence of isoproterenol in fibroblasts. It also inhibited the production of cyclic-AMP in fibroblasts in the presence of isoproterenol. Islet-activating protein did not block these reactions of transforming growth factor beta-1. Forskolin did not affect the intracellular calcium concentration change resulting from treatment with transforming growth factor beta-1. Binding of [3H]CGP-12177 was decreased to 47% of control preincubated for 24 hours with transforming growth factor beta-1 in fibroblasts. Scatchard plots suggested a decrease in beta-adrenergic receptor number without specific change in receptor affinity. These results suggested that transforming growth factor beta-1 modulates the signal transduction through beta-adrenergic receptor and intracellular Ca2+ concentration by regulating the number of receptors in fibroblasts.

Importance of receptor regulation in the pathophysiology and therapy of congestive heart failure

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-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 H 2 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 H 2 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.

Beta-adrenergic receptor changes during tertatolol treatment in healthy volunteers: relevance for beta-blocking therapy.

Tertatolol is a new potent beta-blocker without intrinsic sympathomimetic activity and lacking beta 1/beta 2 receptor subtype selectivity. Tertatolol was found in vitro to be a competitive inhibitor of beta-adrenergic receptors in competitive binding experiments. However, the density of beta-adrenergic receptors on intact human lymphocytes preincubated with tertatolol was reduced. When given at therapeutic doses (5 mg/day) to human volunteers, it induced a reduction in the number of beta-adrenergic receptors (Bmax) without any change in the affinity (KD) for intact lymphocytes (beta-adrenergic receptors were measured by the specific binding of 3H-CGP 12177). This effect was seen 7 h (-54%), 24 h (-35%) and 48 h (-30%) after a single drug dose. A similar receptor reduction was observed 7 h (-42%), 24 h (-37%) and 48 h (-15%) after 14 daily doses of the drug. In parallel, the pharmacological efficacy of the drug was evident from the reduction in heart rate in supine and upright positions and after submaximal exercise; heart rate was reduced to the same extent after single or repeated drug doses. The reduction in receptor number correlated with the reduction in heart rate in both the supine (p less than 0.001) and upright (p less than 0.01) positions and after exercise (p less than 0.02). We conclude that tertatolol, besides competitively inhibiting beta-adrenergic receptors, induces a marked and lasting decrease in beta-adrenergic receptor number. This effect may be important for the beta-blocking effects of this drug.