phenanthrenes and Ductus-Arteriosus--Patent

Microsomal prostaglandin E synthase-1 (mPGES1) is critical for prostaglandin E(2) formation in ductus arteriosus (DA) and, accordingly, in its patency. We previously reported that mPGES1 deletion, unlike cyclo-oxygenase (COX) suppression, is not followed by upregulation of relaxant nitric oxide (NO). Consequently, we proposed that a mPGES1 inhibitor may be better than currently used COX inhibitors in managing premature infants with persistent DA (PDA).. To assess the effect of the mPGES1 inhibitor, 2-(6-chloro-1H-phenanthro[9,10d]imidazole-2-yl)isophthalonitrile (MF63) on DA ex vivo and in vivo (p.o. to the mother).. Experiments were carried out with mice bearing human mPGES1. We utilized isolated, wire-mounted DA for isometric recording and a whole-body freezing technique to assess the DA caliber as it occurs in vivo.. MF63 (10 μM) contracted the isolated DA. DA constriction was also seen in vivo after a single 10-mg kg(-1) dose. Conversely, a 30-mg kg(-1) dose gave inconsistent results, combining constriction with no effect. DA dilatation followed instead a repeated lower dose (twice daily for 3 days), and postnatal closure of the vessel was also delayed. Chronic pretreatment had no effect on endothelial NO synthase mRNA expression in fetal DA, nor did it modify the contraction to NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (100 μM).. MF63 has a dual action on DA, the constriction being associated with accessory dilatation. The latter effect should be explained before considering further a mPGES1 inhibitor for management of PDA.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Ductus Arteriosus; Ductus Arteriosus, Patent; Enzyme Inhibitors; Female; Gene Knock-In Techniques; Humans; Imidazoles; Intramolecular Oxidoreductases; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type III; Phenanthrenes; Pregnancy; Prostaglandin-E Synthases; Vasoconstriction; Vasodilation