Ergotamine Stimulates Human 5-HT(4)-Serotonin Receptors and Human H(2)-Histamine Receptors in the Heart

Ergotamine (2′-methyl-5′α-benzyl-12′-hydroxy-3′,6′,18-trioxoergotaman) is a tryptamine-related alkaloid from the fungus Claviceps purpurea. Ergotamine is used to treat migraine. Ergotamine can bind to and activate several types of 5-HT(1)-serotonin receptors. Based on the structural formula of ergotamine, we hypothesized that ergotamine might stimulate 5-HT(4)-serotonin receptors or H(2)-histamine receptors in the human heart. We observed that ergotamine exerted concentration- and time-dependent positive inotropic effects in isolated left atrial preparations in H(2)-TG (mouse which exhibits cardiac-specific overexpression of the human H(2)-histamine receptor). Similarly, ergotamine increased force of contraction in left atrial preparations from 5-HT(4)-TG (mouse which exhibits cardiac-specific overexpression of the human 5-HT(4)-serotonin receptor). An amount of 10 µM ergotamine increased the left ventricular force of contraction in isolated retrogradely perfused spontaneously beating heart preparations of both 5-HT(4)-TG and H(2)-TG. In the presence of the phosphodiesterase inhibitor cilostamide (1 µM), ergotamine 10 µM exerted positive inotropic effects in isolated electrically stimulated human right atrial preparations, obtained during cardiac surgery, that were attenuated by 10 µM of the H(2)-histamine receptor antagonist cimetidine, but not by 10 µM of the 5-HT(4)-serotonin receptor antagonist tropisetron. These data suggest that ergotamine is in principle an agonist at human 5-HT(4)-serotonin receptors as well at human H(2)-histamine receptors. Ergotamine acts as an agonist on H(2)-histamine receptors in the human atrium.