Low-dose thromboxane A2 receptor stimulation promotes closure of the rat ductus arteriosus with minimal adverse effects.
BACKGROUND
Patent ductus arteriosus (PDA) is a common life-threatening complication among premature infants. Although cyclooxygenase inhibitors are frequently used to treat PDA, as they inhibit the synthesis of prostaglandin E(2), the most potent vasodilator in the ductus arteriosus (DA), their efficacy is often limited. As thromboxane A(2) (TXA(2)) induces vascular contraction via the TXA(2) receptor (TP), we hypothesized that TP stimulation would promote DA closure.


METHODS
To measure the inner diameter of the vessels, a rapid whole-body freezing method was used.


RESULTS
Injection of the selective TP agonists U46619 and I-BOP constricted the fetal DA at embryonic day 19 (e19) and e21 in a dose-dependent manner. Of note, U46619 also exerted a vasoconstrictive effect on two different types of postnatal PDA models: premature PDA and hypoxia-induced PDA. We also found that U46619 constricted the ex vivo DA ring to a greater extent than it constricted the ex vivo aorta. Furthermore, we found that U46619 at lower concentrations (up to 0.05 mg/g of body weight) had a minimal vasoconstrictive effect on other vessels and did not induce microthrombosis in the pulmonary capillary arteries.


CONCLUSIONS
Low-dose TP stimulation constricts the DA with minimal adverse effects at least in rat neonates and our results could point to an alternative potent vasoconstrictor for PDA.
Department of Life Science and Medical Bioscience, Waseda University Graduate School of Advanced Science and Engineering, Tokyo, Japan.
Tomohiro
T
Yokota
Takashi
T
Aida
Yasuhiro
Y
Ichikawa
Takayuki
T
Fujita
Utako
U
Yokoyama
Susumu
S
Minamisawa
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002196:Capillaries / Q000473:pathology; D015925:Cryopreservation; D004305:Dose-Response Relationship, Drug; D004373:Ductus Arteriosus / Q000187:drug effects / Q000254:growth & development*; D004374:Ductus Arteriosus, Patent / Q000517:prevention & control*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005333:Fetus; D011650:Pulmonary Alveoli / Q000098:blood supply; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000819:agonists*; D014661:Vasoconstriction / Q000187:drug effects*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C061750:7-(3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo(2.2.1)heptan-2-yl)-5-heptenoic acid; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid