The affinity of (--)-timolol for beta 1- and beta 2-adrenoceptors was determined on isolated atrial preparations from patients undergoing open heart surgery. The times for onset and offset of antagonism of the positive inotropic effects of (--)-adrenaline and (--)-noradrenaline by (--)-timolol were measured. 2. The antagonism of the positive inotropic effects of (--)-adrenaline and (--)-noradrenaline by (--)-timolol (0.1-100 nM) was simple competitive in human atrium tissue. The slope of Schild-plots was not significantly different from 1.0 [0.93 +/- 0.09 for (--)-adrenaline, 0.97 +/- 0.09 for (--)-noradrenaline]. 3. The inotropic effects of (--)-adrenaline were antagonized significantly more by each concentration of (--)-timolol than those of (--)-noradrenaline. KB-values (-log M) were 10.10 +/- 0.09 against (--)-adrenaline and 9.43 +/- 0.07 against (--)-noradrenaline (P < 0.001). 4. Blocking kinetics of (--)-timolol for the beta-adrenoceptor were relatively slow. Half-times for the onset of blockade by 10 times KB of (--)-timolol were approximately 30 min for both (--)-adrenaline and (--)-noradrenaline; offset times were similar. 5. It is concluded that (--)-timolol has a higher affinity for the beta 2-adrenoceptor than for the beta 1-adrenoceptor in human atrium. This property may be beneficial clinically in protecting against the beta 2-adrenoceptor hypersensitivity induced by cardiac beta 1-adrenoceptor blockade, but also explain why severe asthma can occur after administration of very low intra-ocular doses of the drug.
