Reduction of beta-adrenergic receptors by tertatolol: an additional mechanism for beta-adrenergic blockade

Tertatolol is a potent new β-blocker with no intrinsic sympathomimetic activity or β1/β2-receptor subtype selectivity. When given at therapeutic doses (5 mg/day) to human subjects it induced a reduction in the β-adrenergic receptor number measured by 3H-CGP 12177 specific binding, without any change in the affinity on intact lymphocytes. This reduction was seen 7 hours (54%), 24 hours (35%), and 48 hours (30%) after a single drug dose. A similar receptor reduction was observed 7 hours (42%), 24 hours (37%), and 48 hours (15%) after 14 doses of the drug. In parallel, the pharmacologic efficacy of the drug was evident from the reduction in supine and upright heart rates and after submaximal exercise; heart rate was reduced to the same extent after single or repeated drug doses. The reduction of receptor number correlated well with the reduction in heart rate in the supine (P < 0.001) and upright (P < 0.01) positions and after exercise (P < 0.02). In in vitro competitive binding experiments tertatolol was found to be a competitive inhibitor of β-adrenergic receptors. However, on intact human lymphocytes preincubated with this drug, tertatolol reduced the density of β-adrenergic receptors. We conclude that tertatolol, besides competitively inhibiting β-adrenergic receptors, induced a marked and lasting decrease in the β-adrenergic receptor number. This effect may be important for its β-blocking effects. Clinical Pharmacology and Therapeutics (1986) 39, 245–254; doi:10.1038/clpt.1986.34