Diphenhydramine Arrhythmogenicity Testing Using Monolayers of Human iPSC-derived Cardiomyocytes

Diphenhydramine is a first-generation antihistamine, local anesthetic that prolongs QT-interval, causes Torsade de pointes and toxic when using in high dosage. It blocks rapid and slow delayed rectifier potassium currents, inward rectifier potassium current of cardiomyocytes. Also, diphenhydramine has a potency to block sodium voltage-gated ion channels and gap junctions in cardiomyocytes but the factual concentrations of these effects for human cardiac tissue models remain unclear. In this study conduction velocity, maximum capture rate and the number of re-entry occurrence on the standard linear obstacle in human induced pluripotent stem cell-derived cardiomyocyte monolayer from 2 healthy individuals were evaluated under 0.3, 2.6, 10, 16 μM diphenhydramine by earlier proposed method of testing. Obtained conduction velocity decrease shows probable blocking effect of diphenhydramine on sodium voltage-gated ion channels and gap junctions in cardiomyocytes under 16 μM diphenhydramine. Dose-dependent maximum capture rate reduction was observed and proved diphenhydramine action on voltage-gated potassium channels. Re-entry formation under 2.6 μM diphenhydramine was in 50% of tested samples and provided the third evidence for diphenhydramine arrhythmogenicity in vitro.