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 [H-3]-myo-inositol labeled slices of human right atria, carbachol-induced [H-3]-IP formation and its inhibition by several M-receptor antagonists was assessed. Carbachol (0.1 muM-100 muM) increased [H-3]-IP formation; maximal increase at 100 muM was 93+/-16% above basal (n=20); the pEC(50)-value for carbachol was 5.56. Atropine (1 muM) completely suppressed 100 muM carbachol-induced [H-3]-IP formation. Among the M-receptor subtype "selective" antagonists himbacine (1 muM) and pirenzepine (1 muM) only marginally affected carbachol-induced [H-3]-IP formation whereas the M-3-receptor antagonist darifenacin (1 nM-1 muM) concentration-dependently inhibited carbachol-induced [H-3]-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.