AF-DX 116 discriminates heart from gland M2-cholinoceptors in man.
The M2-cholinoceptor subtype selective antagonist AF-DX 116 was compared with atropine with respect to effects on heart rate and salivary flow in healthy volunteers. These effects were related with in vitro occupancy of M-cholinoceptor subtypes in radioreceptor assays of plasma samples. Radioreceptor assays comprised M1-cholinoceptors in bovine cerebral cortex and M2-cholinoceptors in pig heart and rat salivary gland membranes. 3H-pirenzepine served as a label in the cerebral cortex 3H-N-methyl-scopolamine in the heart and gland preparations. Oral administration of 240 mg AF-DX 116 led to a time dependent increase in heart rate with a maximum effect comparable to atropine 40 micrograms/kg i.v. The effects of both drugs on heart rate were matched by a greater than 80% occupancy of heart M2-cholinoceptors in the radioreceptor assay of plasma samples. In contrast to the complete inhibition of salivary flow after atropine, AF-DX 116 induced an increase of salivation. The effects on salivary flow coincided with a greater than 80% occupancy of glandular M2-cholinoceptors after atropine but no detectable occupancy after AF-DX 116. Occupancy of the M1-subtype amounted to 61.7% after AF-DX 116 and a blockade of inhibitory, presynaptic M1-autoreceptors at missing postsynaptic blockade of glandular M2-cholinoceptors might explain the hypersalivation induced by AF-DX 116.
Kerckhoff Klinik der Max-Planck-Gesellschaft, Bad Nauhelm, FRG.
H F
HF
Pitschner
B
B
Schulte
M
M
Schlepper
D
D
Palm
A
A
Wellstein
D000328:Adult; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D019832:N-Methylscopolamine; D009928:Organ Specificity; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D012016:Reference Values; D012463:Saliva / Q000187:drug effects / Q000378:metabolism*; D012469:Salivary Glands / Q000378:metabolism*; D012602:Scopolamine Derivatives / Q000378:metabolism; D013552:Swine
D011950:Receptors, Cholinergic; D012602:Scopolamine Derivatives; D010890:Pirenzepine; D001285:Atropine; D011433:Propranolol; C048593:otenzepad; D019832:N-Methylscopolamine