Abstract
In the broad field of cardiology, pediatric research has lagged behind in establishing appropriate models to study the developing heart. Human cardiomyocytes exhibit a limited life span and immortalized cell lines lack physiologically relevant automaticity. Pediatric animal models include caveats related to action potential morphology, ion channel expression, and excitation-contraction coupling. Changes that occur in these parameters as the animal transition from neonate to adult are relatively unknown, especially as it may be translated to a human model. In quantifying the toxicological effect of plasticizer exposure in a pediatric population, we first sought to establish the limits of using hearts from developing neonatal rats as a viable model. This study aimed to quantify the advantages and limitations associated with using neonatal rat hearts as a model for pharmacology screening. The heart from rats ranging in age from 2 days old, up to adult were excised, and the aorta was cannulated. It was placed on a Langendorff system and retrograde perfused. Calcium and voltage sensitive dyes were used to stain the heart for imaging via a single sensor, single excitation, dual emission system. It was mechanically uncoupled with blebbistatin to eliminate motion artifacts. Compared with adults, isolated neonatal rat hearts displayed a longer action potential duration (APD80: adult= 61.28ms n=9, neonatal=109.4ms n=34, P<0.05) associated with delayed repolarization as also evidenced by an increased in triangulation. Calcium handling was also slower in the neonatal heart (Cad80: Adults: 126.8ms n=12, neonatal=170.1 n=30, P<0.05), likely due to immature expression and localization of key calcium handling proteins. The developing excitation-contraction coupling machinery will be further probed using pharmacological tools, and this newly established pediatric model will be used for toxicological screening.
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