DOSE-EFFECT AND KINETIC-DYNAMIC RELATIONSHIPS OF THE BETA-ADRENOCEPTOR BLOCKING PROPERTIES OF VARIOUS DOSES OF TALINOLOL IN HEALTHY HUMANS

Twelve healthy subjects were investigated on six separate occasions at least 1 week apart when they either received a single oral dose of 80 mg propranolol; 25, 50, 100, or 400 mg talinolol; or placebo (double- blinded, period-balanced six-way cross-over design). The subjects were investigated during supine rest and performed supine bicycle ergometr y 0200, 0500, 0730, 1000, and 2400 h after dosing. Isoprenaline (ISO) and epinephrine (EPI) were infused intravenously (i.v.) at a constant infusion rate of 1 mu g/min for 10 min, at 0315 and 0400 h after dosin g, respectively. At various timepoints, blood was drawn for the high-p erformance liquid chromatography (HPLC) determination of the plasma co ncentrations of talinolol's enantiomers and for the ex vivo in vitro d etermination of beta(1)- and beta(2)-adrenoceptor binding and related concentrations by radioreceptor assay (RRA). Talinolol was confirmed t o bind to beta-adrenoceptors with moderate affinity but to act as a hi ghly selective and efficient beta(1)-adrenoceptor antagonist in terms of the relative degree and duration of its ergometric effects. At dose s less than or equal to 100 mg talinolol hardly altered the reduction of estimated vascular total peripheral resistance (TPR) in response to the intravenous infusion of ISO and EPI. Only at doses of 400 mg did talinolol more closely approximate the effects of propranolol, which l ead to a loss of the vasodilatory actions of EPI (''EPI reversal''). O n the average, there was a smoothly linear relationship between the er gometric treatment effects and log-transformed dose, the logtransforme d concentrations of the S(-)-enantiomer measured by HPLC, and the RRA- derived estimated occupancies of beta(1)-adrenoceptors.