Complex dose-response curves of atropine in man explained by different functions of M1- and M2-cholinoceptors

In the present study we set out to explain the complex atropine dose-response curves in man in relation to M-cholinoceptor subtype occupancy. In healthy volunteers the effects of atropine on heart rate and salivary flow were quantified. M-cholinoceptor subtype occupancy by antagonist present in plasma samples was detected in an in vitro radioreceptor assay. Atropine effects were studied without and after propranolol (240 mg oral dose) and without and after pirenzepine (1.1 mg i.v.) to differentiate beta-adrenoceptor and M-cholinoceptor subtype mediated effects. 1. In receptor binding studies, M-cholinoceptors in bovine cerebral cortex membranes were labelled with 3H-pirenzepine (pKd = 8.05), M-cholinoceptors in rat salivary gland membranes with 3H-N-methylscopolamine (pKd = 9.02). Atropine competed for binding of these ligands with a small (2.1-fold) preferential selectivity via the cerebral in comparison to the glandular receptors (pKi = 9.18 versus 8.86). Pirenzepine showed a marked selectivity (40-fold) in this respect with pKi-values of 8.05 (M1: cerebral cortex) and 6.45 (M2: salivary glands). 2. At heart rate and at salivary flow, bivalent dose-response curves of atropine were observed with opposite effect vectors. The typical antagonist effects at M-cholinoceptors (i.e. an increase of heart rate and an inhibition of salivary flow) were observed at doses greater than 1 microgram/kg, whereas "paradoxical" cholinomimetic effects of atropine became apparent at lower doses. From a superposition of two isotherms with opposite effect vectors ED50-values were calculated, which were in the range of half-maximal M-cholinoceptor occupancy in the in vitro radioreceptor assay of plasma samples.(ABSTRACT TRUNCATED AT 250 WORDS)