Existence of functional M3-muscarinic receptors in the human heart.
It has been recently shown that, in adult rat ventricular cardiomyocytes, functional muscarinic receptors (M-receptors) of the M(3)-subtype exist that mediate inositol phosphate (IP) formation. The aim of this study was to characterize the M-receptor subtype mediating IP formation in the human heart. For this purpose in [3H]-myo-inositol labeled slices of human right atria, carbachol-induced [3H]-IP formation and its inhibition by several M-receptor antagonists was assessed. Carbachol (0.1 microM-100 microM) increased [3H]-IP formation; maximal increase at 100 microM was 93+/-16% above basal ( n=20); the pEC(50)-value for carbachol was 5.56. Atropine (1 microM) completely suppressed 100 microM carbachol-induced [3H]-IP formation. Among the M-receptor subtype "selective" antagonists himbacine (1 microM) and pirenzepine (1 microM) only marginally affected carbachol-induced [3H]-IP formation whereas the M(3)-receptor antagonist darifenacin (1 nM-1 microM) concentration-dependently inhibited carbachol-induced [3H]-IP formation with a pK(i)-value of 8.49. We conclude that in human right atrium there exist functional M(3)-receptors that couple to IP formation.
Willmy-Matthes
Pia
P
Institute of Pharmacology, University of Halle, 06097 Halle, Germany.
Leineweber
Kirsten
K
Wangemann
Thekla
T
Silber
Ralf-Edgar
RE
Brodde
Otto-Erich
OE
D000368:Aged; D002217:Carbachol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D043587:Receptor, Muscarinic M3 / Q000187:drug effects*
D007295:Inositol Phosphates; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3; D002217:Carbachol