Beta-Adrenergic Receptor Changes during Tertatolol Treatment in Healthy Volunteers: Relevance for Beta-Blocking Therapy

Tertatolol is a new potent β-blocker without intrinsic sympathomimetic activity and lacking β1/β2 receptor subtype selectivity. Tertatolol was found in vitro to be a competitive inhibitor of β-adrenergic receptors in competitive binding experiments. However, the density of β-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 β-adrenergic receptors (Bmax) without any change in the affinity (KD) for intact lymphocytes (β-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