SALBUTAMOL ATTENUATES THE ARRHYTHMOGENIC EFFECT OF AMINOPHYLLINE IN CARDIAC ORGANOIDS EXPERIMENTAL MODEL

Background: The combination of aminophylline and salbutamol is used in the treatment of obstructive lung diseases. Side effects (including arrhythmias) of the individual bronchodilator drugs were described, those of combined treatment are almost unknown. We aimed to study the arrhythmogenic potential of combined aminophylline and salbutamol in vitro. Methods: We used the established model of atomic force microscopy (AFM) coupled with cardiac organoids from human pluripotent stem cells (hPSC-CMs). We focused on the chronotropic, inotropic, and arrhythmogenic effects of salbutamol and aminofilin alone and combined. Results: Salbutamol and aminophylline had a synergistic chronotropic and inotropic effects compared to the effects of their separate application. Salbutamol reduced the arrhythmogenic effect of aminophylline, most likely mediated by endothelial nitric oxide synthase activated by beta-2 adrenergic receptors. Findings were replicated and confirmed using hPSC-CM derived from 2 cell lines (CCTL14 and CCTL12). Conclusions: Data suggest that salbutamol as an add-on therapy may not only deliver a bronchodilator effect but also increase the cardiovascular safety of aminophylline, as salbutamol reduces its arrhythmogenic potential.

Acknowledgement CarDia (EXCELES, No. LX22NPO5104) EU Next Generation and by the EC Horizon Europe MUQUABIS GA no. 101070546. and MUNI/A/1624/2023 MEYS CR  Figure  BRV analysis with combined salbutamol and aminophylline treatments. Scatter plots indicate means and SDs of SDSDs measured with mixed treatments and control (n=10 for controls, n=10,11,10,8,8,24,6,6, and 9 for treatments; ordinary one-way ANOVA test). (A) SDSD results of cardiac organoids with indicated concentrations of salbutamol and aminophylline supplemented with separate measurements of both treatments for comparison. (B) Poincaré plots of SDSD intervals.