Caffeine-associated Reduction in Patent Ductus Arteriosus (PDA) is Mediated by Adenosine Receptor Antagonism
Patent ductus arteriosus (PDA) is a cardiac condition commonly diagnosed in preterm neonates. PDA occurs when the ductus arteriosus (DA), a muscular arterial shunt, does not close after birth as it should. This results in the mixing of oxygen-poor blood and oxygen-rich blood causing significant cardiovascular problems. Clinical studies show that PDA is less frequent in infants treated with caffeine for apnea of prematurity. Caffeine acts to inhibit A1, A2a, A2b and A3 adenosine receptors. Adenosine is typically vasodilatory, and serum adenosine levels are elevated in preterm newborns, suggesting a potential mechanism for caffeine-related reduction in PDA. We previously found that all four adenosine receptors are expressed in the mouse and human ductus arteriosus. Using pressure myography experiments, we found that caffeine can blunt the ability of adenosine to dilate the DA. Therefore, we hypothesized that caffeine has a vasoconstrictive effect on the DA by antagonizing specific adenosine receptors. To investigate this, we isolated the DA of day 19 (full term) mouse pups, which were then mounted in a chamber filled with Krebs buffer bubbled with restricted oxygen content (2%) to simulate fetal conditions. Pressurized myography recorded diameter of the DA in response to pre-established concentrations of adenosine receptor antagonists. The results of this study will identify the receptor caffeine has a predominant effect on which may help determine treatment options for PDA.