Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 906, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2021.174206
Keywords
serotonin; 5-HT(4)a receptor; Hypothermia; Hyperthermia; Arrhythmia; Inotropy; Chronotropy; Transgenic mice; Hypokalaemia; Sotalol; Erythromycin
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The study revealed that lowering temperature can increase arrhythmias in mice overexpressing the human 5-HT4 receptor in their cardiac myocytes, suggesting a potential link between 5-HT4 receptors and hypothermia-induced arrhythmias in human patients.
We investigated whether hypothermia would be arrhythmogenic in mice that overexpress the human 5-HT4 receptor only in their cardiac myocytes (5-HT4-TG). Contractile studies were performed in isolated, electrically driven (1 Hz) left and spontaneously beating right atrial preparations of 5-HT4-TG and littermate wild-type control mice (WT). Hypothermia (23 degrees C) decreased the force of contraction in the mouse right and left atrial preparations. Moreover, the concentration-dependent positive inotropic effects of 5-HT were blunted but still shifted to lower 5-HT concentrations in the left 5-HT4-TG atria in hypothermia compared to normothermia (37 degrees C). Furthermore, hypothermia increased the incidence of right atrial arrhythmias in 5-HT4-TG more than in WT mice. In contrast, at 37 degrees C, lowering the potassium concentration from 5.2 to 2.0 mM also induced arrhythmias in the right atrium, but with a similar incidence in WT and 5-HT4-TG mice. In contrast, 10 mu M d,lsotalol and 300 mu M erythromycin did not induce arrhythmias. Hypothermia was accompanied by the increased expression of heat shock protein 70 (HSP70) in WT but not in 5-HT4-TG mice. We concluded that without the stimulation of 5-HT4-receptors by exogenous agonists, a simple temperature reduction can increase arrhythmias in 5-HT4-TG mice. It is tempting to speculate that in human patients, 5-HT4 receptors might contribute to potentially deadly hypothermia-induced arrhythmias.
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