Beta adrenoceptor subtype binding activity in plasma and beta blockade by propranolol and beta-1 selective bisoprolol in humans. Evaluation with Schild-plots.

In the present study we investigated whether the beta adrenoceptor subtype binding activity in plasma samples can predict selective and nonselective beta blockade in humans. From the right shifts of isoprenaline dose-response curves 0 to 84 hr after administration of propranolol and the beta-1 selective bisoprolol, in vivo beta blockade was assessed. In an in vitro radioreceptor assay with membrane preparations of beta-1 or beta-2 adrenoceptors, plasma samples were assayed for subtype selective blocking activity. After propranolol administration, in vitro beta-1 and beta-2 adrenoceptor occupancy declined from initially 97% to less than 10% within 48 hr. An isoprenaline dose ratio (DR)-1 of 1 coincided with a 50% occupancy of the beta-1 or the beta-2 subtype in vitro. In Schild-plots using plasma concentrations (radioreceptor assay) and the isoprenaline DR-1 for heart rate, diastolic blood pressure and inotropy (QS2C), slopes of unity were observed. After bisoprolol administration, in vitro beta-1 occupancy shifted from initially 95% to less than 10% within 72 hr. For the beta-2 subtype, an occupancy of greater than 10% was detectable only within the first 12 hr. An isoprenaline DR-1 of 1 coincided with a 50% occupancy of beta-1 adrenoceptors. The bisoprolol Schild-plots yielded a slope of unity for inotropy, but less than unity for the heart rate and diastolic blood pressure. From an extended analysis of subtype selective antagonism in Schild-plots, the fractions of the beta-2 adrenoceptor subtype participating in the isoprenaline response were calculated: heart rate 0.45 +/- 0.12 and diastolic blood pressure 0.23 +/- 0.13. It is concluded that in vitro receptor occupancy can predict beta blockade in humans for propranolol. Beta adrenoceptor subtype-mediated effects in humans can be evaluated with a selective antagonist and a refined analysis of Schild-plot data.