Selective antagonists reveal different functions of M cholinoceptor subtypes in humans

Effects of atropine and of the subtype selective mAChR antagonists pirenzepine (PZ) and AF-DX 116 were studied in humans. Dose- or time-response curves were established for heart rate and salivary flow. Plasma samples were drawn in parallel with the effect measurements and analysed for drug concentrations. Subtype-selective radioreceptor assays of the samples served to estimate the respective receptor occupancy in vivo. It is shown that low doses of PZ (M1-selective blockade) cause cholinomimetic effects indicated by bradycardia and increase in salivary flow. After high doses of PZ or atropine, tachycardia and inhibition of salivary flow are observed in parallel with occupancy of both the M2 and M3 subtypes. AF-DX 116 induces a tachycardia together with an increased salivary flow in agreement with its selectivity profile (M2 greater than M1 greater than M3). The diagnostic and therapeutic applications of M1- or M2-selective blockade by low dose PZ or AF-DX 116 respectively are discussed.