Am J Physiol Heart Circ Physiol. 2025 Oct 30. doi: 10.1152/ajpheart.00801.2024. Online ahead of print.
ABSTRACT
Persistent patency of the ductus arteriosus (PDA) is less frequent among infants treated with caffeine for apnea of prematurity. Caffeine acts to inhibit A1, A2, and A3 adenosine receptors (ARs). Adenosine is typically vasodilatory, and serum adenosine levels are elevated in preterm newborns, suggesting a potential mechanism for caffeine-associated reduction in PDA. We hypothesized that caffeine has an indirect vasoconstrictive effect on the ductus by antagonizing specific ARs. The expression of AR subtypes in the mouse ductus was analyzed by RT-PCR on days 15, 17, 19 (full term) of gestation, and postnatal day 1. Pressure myography was used to examine responses of the isolated ductus to adenosine, caffeine (citrate or base), or pre-incubation with either caffeine or adenosine. AR immuno-localization and adenosine-mediated cAMP generation were evaluated in human ductus smooth muscle cells (SMCs). A1AR, A2AAR, A2BAR and A3AR were present and developmentally regulated in the mouse ductus. Adenosine promoted ductus dilation under fetal and newborn O2 conditions. Caffeine had little or no effect on ductus tone with concentrations spanning the therapeutic range and failed to augment O2-induced or cyclooxygenase inhibitor-stimulated ductus constriction. However, pre-treatment with caffeine or selective A1AR and A2AAR antagonists prevented adenosine-induced ductus dilation. Caffeine also blocked adenosine-stimulated cAMP release in human ductus SMCs. In conclusion, caffeine did not induce direct ductus constriction ex vivo. However, caffeine exposure prevented adenosine-induced ductus relaxation, suggesting inhibition of an endogenous vasodilator as a mechanism for reduction in PDA.
PMID:41165563 | DOI:10.1152/ajpheart.00801.2024
