(--)-Timolol is a more potent antagonist of the positive inotropic effects of (--)-adrenaline than of those of (--)-noradrenaline in human atrium.
1. 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.
Wang
T
T
Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, UK.
Kaumann
A J
AJ
Brown
M J
MJ
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D004336:Drug Antagonism; D004837:Epinephrine / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology*; D013268:Stimulation, Chemical; D013999:Timolol / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D013999:Timolol; D009638:Norepinephrine; D004837:Epinephrine