Abstract P115: Selective Vasoconstriction of the Ductus Arteriosus in the Rat by Stimulation of Thromboxane A2 Receptor
Objective: Patent ductus arteriosus (PDA) is a common life-threatening complication of premature infants. Cyclooxygenase inhibitors are frequently used for pharmacologic therapy of PDA to inhibit the synthesis of prostaglandin E2 (PGE2) that is the most potent vasodilator in the DA. However, they often cause severe side-effects. Thromboxane A2 (TXA2), a vasoconstrictive lipid mediator, induces vascular contraction via TXA2 receptor (TP). TXA2 is also known to counteract prostacycline, a vasodilative lipid mediator. Therefore, we hypothesized that TXA2-TP stimulation can be an alternative strategy to induce DA closure by counteracting PGE2.
Methods and Results: Quantitative RT-PCR analysis revealed that the expression of TP mRNA was higher in the DA than in the aorta during fetal periods. When the selective TP agonist U46619 was intraperitoneally injected into Wister rat fetuses at embryonic day 19th (e19) and e21, we found that U46619 selectively constricted the fetal DA in a dose-dependent manner even though the level of circulating PGE2 was supposed to be high. The vasoconstrictive effect of U46619 was weaker at e19 than at e21 in the DA, suggesting that immature DA is less sensitive to TP stimulation. Importantly, U46619 also showed vasoconstrictive effect on two different types of postnatal PDA models: immature PDA and hypoxia-induced PDA. These effects of U46619 were stronger than the effect of indomethacin that is the most common cyclooxygenase inhibitor. In addition, we found that U46619 exhibited little vasoconstrictive effect on other vessels such as the aorta, pulmonary arteirs, carotid arteries, renal arteries, and portal veins. Furthermore, U46619 was not likely to induce microthrombosis in the pulmonary capillary arteries. These results suggest that TP agonists could selectively promote the DA constriction without severe complications and be an alternative potent vasoconstrictor for patients with PDA.
- © 2011 by American Heart Association, Inc.