Ergotamine Stimulates Human 5-HT4-Serotonin Receptors and Human H2-Histamine Receptors in the Heart

Abstract

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-HT1-serotonin receptors. Based on the structural formula of ergotamine, we hypothesized that ergotamine might stimulate 5-HT4-serotonin receptors or H2-histamine receptors in the human heart. We observed that ergotamine exerted concentration- and time-dependent positive inotropic effects in isolated left atrial preparations in H2-TG (mouse which exhibits cardiac-specific overexpression of the human H2-histamine receptor). Similarly, ergotamine increased force of contraction in left atrial preparations from 5-HT4-TG (mouse which exhibits cardiac-specific overexpression of the human 5-HT4-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-HT4-TG and H2-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 H2-histamine receptor antagonist cimetidine, but not by 10 µM of the 5-HT4-serotonin receptor antagonist tropisetron. These data suggest that ergotamine is in principle an agonist at human 5-HT4-serotonin receptors as well at human H2-histamine receptors. Ergotamine acts as an agonist on H2-histamine receptors in the human atrium.

Studies on the mechanisms of action of MR33317

“…This cardiac effect of metoclopramide is an off-target effect of metoclopramide because the intended use of metoclopramide is in the gastric tract where it stimulates gastric 5-HT 4 -serotonin receptors. In similar way, we have recently noted that some hallucinogenic drugs like psilocin or lysergic acid diethylamide (LSD) can stimulate cardiac 5-HT 4 -serotonin receptors in the 5-HT 4 -TG (Dimov et al 2023;Jacob et al 2023). Hence, there is precedence for unintended cardiac effect of drugs with an intended action on other organs (gut, brain) and our approach seems reasonable, though speculative.…”

“…Only in the presence of a phosphodiesterase we noted a positive inotropic effect. We used cilostamide as a phosphodiesterase inhibitor as before (Jacob et al 2023). This was done because cilostamide inhibits PDE III and because PDE III is the main PDE in the human heart (Movsesian et al 2009).…”

Effects of hallucinogenic drugs on the human heart

“…Ergotamine acts on many G-protein coupled receptors (Silberstein and McCrory, 2003). However, In isolated human right atrial preparations ergotamine increased force of contraction only via H 2 -histamine receptors (Jacob et al, 2023b). As with LSD, one noted with ergotamine alone a time-and concentration-dependent negative inotropic effect.…”

“…Interestingly, ergotamine was an agonist at the human H 2histamine and serotonin 5-HT 4 -receptors in the transgenic mouse atrium (Jacob et al, 2023b;Table 4). This is not without precedence.…”

Hydroalkoxylation of Enamides Catalyzed by N-Heteroarenium Iodides

“…For example, as shown in Scheme , Cefmetazole is a cephalosporin antibiotic used to treat various bacterial infections . Ergotamine is an α-1-selective adrenergic agonist vasoconstrictor used to treat migraines with or without aura and cluster headaches . Ketazolam is a long-acting benzodiazepine used to manage anxiety and insomnia .…”