Dual, Constrictor-to-Dilator, Response of the Mouse Ductus Arteriosus to the Microsomal Prostaglandin E Synthase-1 Inhibitor, 2-(6-Chloro-1H-phenanthro[9,10<i>d</i>]imidazole- 2-yl)isophthalonitrile

Abstract

Background: Microsomal prostaglandin E synthase-1 (mPGES1) is critical for prostaglandin E₂ 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). Objective: 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). Methods: 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. Results: 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). Conclusions: 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.

Therapeutic manipulation of the ductus arteriosus: current options and future prospects

“…Hence, this selectivity has been sought by testing either an antagonist of the PGE 2 receptor subtype EP 4 48 or an inhibitor of the terminal mPGES1 enzyme in the synthetic cascade. 21 As expected, both treatments constrict the ductus with the distinct advantage over COX inhibition of leaving PGI 2 (prostacyclin) function unaffected. 21,48 In truth, there has been some inconsistency in the response to the mPGES1 inhibitor, but its cause is likely connected to the particular compound used.…”

“…Conversely, as discussed below, a promising lead may be found in the PGE synthase complex when considering that one of its constituents, microsomal PGE synthase-1 (mPGES1), is the prime source for PGE 2 in the ductus 20 and that mPGES1 suppression, unlike suppression of either COX, 13,14 is not followed by NO upregulation. 20,21 Postnatal closure The functional closure of the ductus rests on 2 complementary events, the contractile effect of oxygen on the muscle cells and the lesser influence of relaxant PGE 2 that follows the abrupt cessation of the placental function (i.e., the major source for blood-borne compound) and the waning expression of local PGE 2 receptors including the critical EP 4 subtype. 22,23 A considerable effort has been devoted over the years to identify the oxygen sensor and elucidate the mechanism by which its activation is translated into sustained contraction.…”

“…21 As expected, both treatments constrict the ductus with the distinct advantage over COX inhibition of leaving PGI 2 (prostacyclin) function unaffected. 21,48 In truth, there has been some inconsistency in the response to the mPGES1 inhibitor, but its cause is likely connected to the particular compound used. 21 On the other hand, the absence with mPGES1 inhibition of any rebound upregulation of NO is quite advantageous.…”

“…21,48 In truth, there has been some inconsistency in the response to the mPGES1 inhibitor, but its cause is likely connected to the particular compound used. 21 On the other hand, the absence with mPGES1 inhibition of any rebound upregulation of NO is quite advantageous.21 On the downside, however, both agents still have opposing effects on ductus closure -i.e., subsidence of muscle relaxation along with inhibition of tissue remodeling -because this dual feature is intrinsic to PGE 2 action via the EP 4 receptor. Nevertheless, the therapeutic potential of these agents warrants further investigation.…”

Understanding the pathobiology in patent ductus arteriosus in prematurity—beyond prostaglandins and oxygen

“…112 A single study in mice with a microsomal PGE synthase type 1 inhibitor showed dual effects on DA tone, ranging from vasoconstriction to vasodilation. 143 However, since there was no reciprocal increase in the NO pathway, further research regarding this enzyme might be worthwhile. Recently it was found that neonatal EP 4 inhibition with a EP 4 antagonist contracted the DA, with fewer adverse effects due to the selective expression of EP 4 in the rat DA.…”