Mechanism of subendocardial cell proliferation in the rat and relevance for understanding drug-induced valvular heart disease in humans.

摘要: Abstract A number of drugs and drug candidates, including fenfluramine ergot derivatives, are associated with valvulopathy in humans; however, these responses poorly predicted from animal studies. In vitro vivo evidence suggests that compounds exert their pathological effect through activation serotonin 2B receptor (5HT2BR) signaling. However, the variable other 5HT2BR agonists rodents has cast doubt on relevance findings to predicting human risk. Herein, a candidate compound, RO3013, induced subendocardial cell proliferation mitral tricuspid valves rats after only 3 days daily dosing. Additionally, there was treatment-related increase immunostaining marker Ki67, phosphorylated Smad3 heart indicative TGFβ signaling co-localized expression. To substantiate hypothesis RO3013-induced valvular is secondary activation, compound evaluated found bind K i 3.8 μM; it virtually devoid agonist activity functional assay cells. By contrast, RO3013 bound rat 1.2 μM activated an EC50 0.5 μM. This potency estimate good agreement free plasma concentrations at which observed. These results suggest may be susceptible 5HT2BR-mediated similar yet, significant differences between binding activities can possible explanation for observed species-selective responses.