Muscarinic cholinoceptors in the human heart: demonstration, subclassification, and distribution.
In human atrial and ventricular myocardium, the muscarinic cholinoceptor (M-cholinoceptor) populations were characterized by means of radioligand binding (with [N-methyl-3H]-scopolamine ([3H]-NMS) as the ligand) and functional experiments (negative inotropic effect of carbachol on isolated electrically driven right atrial and left papillary muscle preparations). (1) Binding of [3H]-NMS to human atrial and ventricular membranes was rapid, reversible and saturable (KD-values: 0.5-1.0 nmol/l). The maximal number of [3H]-NMS binding sites, however, was approximately 2.5-fold higher in right and left atrial membranes (200-250 fmol [3H]-NMS specifically bound/mg protein) than in right and left ventricular membranes (80-100 fmol/mg protein). (2) M-cholinoceptor antagonists inhibited [3H]-NMS binding to right atrial and left ventricular membranes with steep, monophasic competition curves indicating interaction with a single class of binding sites. In both tissues the order of potency was: atropine greater than AF-DX 116 greater than hexahydrosiladifenidol (HHSiD) greater than pirenzepine. (3) On isolated electrically driven right atrial and left papillary muscle preparations (with force of contraction enhanced by 10(-5) mol/l isoprenaline), carbachol (10(-8)-10(-4) mol/l) caused concentration-dependent decreases in force of contraction; the pD2-value for carbachol was 6.65 +/- 0.09 (n = 8, atria) and 6.62 +/- 0.08 (n = 10, papillary muscles). In both tissues M-cholinoceptor antagonists antagonized the negative inotropic effect of carbachol with an order of potency: atropine greater than AF-DX 116 greater than HHSiD greater than pirenzepine, identical to that obtained in radioligand binding experiments.(ABSTRACT TRUNCATED AT 250 WORDS)
Deighton
N M
NM
Medizinische Klinik und Poliklinik, Abteilung Nieren- und Hochdruckkrankheiten, Essen, Federal Republic of Germany.
Motomura
S
S
Borquez
D
D
Zerkowski
H R
HR
Doetsch
N
N
Brodde
O E
OE
D002217:Carbachol / Q000494:pharmacology; D004558:Electric Stimulation; D006321:Heart / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D019832:N-Methylscopolamine; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D011869:Radioligand Assay; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012602:Scopolamine Derivatives
D010880:Piperidines; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D010890:Pirenzepine; D002217:Carbachol; C046773:hexahydrosiladifenidol; C048593:otenzepad; D019832:N-Methylscopolamine