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 M3-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 μM–100 μM) increased [3H]-IP formation; maximal increase at 100 μM was 93±16% above basal (n=20); the pEC50-value for carbachol was 5.56. Atropine (1 μM) completely suppressed 100 μM carbachol-induced [3H]-IP formation. Among the M-receptor subtype “selective” antagonists himbacine (1 μM) and pirenzepine (1 μM) only marginally affected carbachol-induced [3H]-IP formation whereas the M3-receptor antagonist darifenacin (1 nM–1 μM) concentration-dependently inhibited carbachol-induced [3H]-IP formation with a pKi-value of 8.49. We conclude that in human right atrium there exist functional M3-receptors that couple to IP formation.