[Subtypes of muscarinic receptors--aspects of their physiologic significance for controlling heart rate in the human].

The cDNAs for five different muscarinic cholinoceptors have been cloned. The biochemical and physiological relevance of the m1, m2 and m3 receptors is understood in many aspects. The pharmacological defined M1, M2 and M3 related to antagonists binding studies closely correspond with those cloned. We compared effects of atropine and of the subtype selective M-cholinoceptor antagonists pirenzepine and AF-DX 116 in humans. Dose- or time-response curves have been established for heart rate. Plasma samples were drawn in parallel with the effect measurements and analysed for drug concentrations. Subtype-selective radioceptor assays of the samples served to estimate the respective receptor occupancy in vivo. After low dosis of pirenzepine (M1-selective blockade) a negative chronotropic effect on heart rate could be observed. After high doses of pirenzepine or atropine (M-unselective blockade) the wellknown tachycardia appeared in parallel with occupancy of both the M2 and M3 subtypes. AF-DX 116 induced a tachycardia without a decrease of salivary flow in agreement with its selectivity profile (M2 > M1 > M3). Gastric emptying was only slightly inhibited by AF-DX 116 but nearly completely by a very high dose of pirenzepine blocking M1-, M2- and M3-cholinoceptors. The negative chronotropic effect on heart rate of a low dose of pirenzepine (M1 selective) was multi-folded by pretreatment with isoprenaline but disappeared during bicycle exercise. The implications of the functional M cholinoceptor heterogeneity in humans revealed by antagonists are discussed according to its possible importance for the control of autonomous nerve system.