Dose-response curves of pirenzepine in man in relation to M1- and M2-cholinoceptor occupancy

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Abstract
Summary The aim of the present study was to investigate the M-cholinoceptor subtype selectivity of pirenzepine in man. In parallel with effects on the heart rate and salivary flow, M-cholinoceptor subtype occupancy by antagonist present in plasma samples was detected in radioreceptor assays. Bovine cerebral cortex membranes labelled with 3H-pirenzepine (M1) and rat salivary gland membranes labelled with 3H-N-methylscopolamine (M2) were used in these in vitro assays. A half-maximal occupancy of M1-cholinoceptors in the in vitro assay of plasma samples was detected after 0.25 mg of pirenzepine i.v. The respective half-maximal M2-cholinoceptor occupancy was observed after 10 mg. Doses < 3 mg decreased the heart rate by maximally 10.7 beats/min with an ED50 of about 0.1 mg. An increase in heart rate (relative to control values) was observed at doses > 10 mg. This bivalent dose-response relationship was also observed after β-blockade. Salivary flow tended to increase at doses < 1 mg and was half-maximally inhibited after 10 mg. Combining the in vitro and in vivo results, the typical antimuscarinic effects (tachycardia and inhibition of salivary flow) can be attributed to the blockade of M2-cholinoceptors, whereas the reduction of heart rate coincides with the blockade of the M1-subtype. With respect to the typical antimuscarinic effects, pirenzepine was 70-fold less potent than atropine; in contrast, with respect to the reduction of heart rate, pirenzepine was equipotent with atropine. It is concluded that pirenzepine does not discriminate between cardiac and salivary gland M2-cholinoceptors but shows pronounced selectivity for the M1-cholinoceptors through which it mediates the decrease in heart rate. The latter effect may be explained by inhibitory M1-auto-receptors.