Nitric oxide (NO) and cyclooxygenase (COX)-derived prostaglandins are critical regulators of the fetal ductus arteriosus. To examine the interaction of these pathways within the ductus wall, the ductus arteriosus of term and preterm fetal mice was evaluated by pressurized myography. The isolated preterm ductus was more sensitive to NOS inhibition than at term. Sequential NOS and COX inhibition caused 36% constriction of the preterm ductus regardless of drug order. In contrast, constriction of the term ductus was dependent on the sequence of inhibition; NOS inhibition prior to COX inhibition produced greater constriction than when inhibitors were given in reverse order (36±6% versus 23±5%). Selective COX-1 or COX-2 inhibition prior to L-NAME induced the expected degree of constriction. However, NOS inhibition followed by selective COX-2 inhibition caused unexpected ductal dilation. These findings are consistent with NO-induced activation of COX in the ductus arteriosus wall and the production of a COX-2-derived constrictor prostanoid that contributes to the balance of vasoactive forces that maintain fetal ductus arteriosus tone.

BACKGROUND Increased oxygen tension at birth regulates physiologic events that are essential to postnatal survival, but the accompanying oxidative stress may also generate isoprostanes. We hypothesized that isoprostanes regulate ductus arteriosus (DA) function during postnatal vascular transition. METHODS Isoprostanes were measured by gas chromatography–mass spectrometry. DA tone was assessed by pressure myography. Gene expression was measured by quantitative PCR. RESULTS Oxygen exposure was associated with increased 8-iso-prostaglandin (PG)F2α in newborn mouse lungs. Both 8-iso-PGE2 and 8-iso-PGF2α induced concentration-dependent constriction of the isolated term DA, which was reversed by the thromboxane A2 (TxA2) receptor antagonist SQ29548. SQ29548 pretreatment unmasked an isoprostane-induced DA dilation mediated by the EP4 PG receptor. Exposure of the preterm DA to 8-iso-PGE2 caused unexpected DA relaxation that was reversed by EP4 antagonism. In contrast, exposure to 8-iso-PGF2α caused preterm DA constriction via TxA2 receptor activation. Further investigation revealed the predominance of the TxA2 receptor at term, whereas the EP4 receptor was expressed and functionally active from mid-gestation onward. CONCLUSION This study identifies a novel physiological role for isoprostanes during postnatal vascular transition and provide evidence that oxidative stress may act on membrane lipids to produce vasoactive mediators that stimulate physiological DA closure at birth or induce pathological patency of the preterm DA.

Foods contain bioactive components that contribute to optimal health. Food-grade yeast may contain components that enhance cellular glucose metabolism. We tested the effect of brewer's yeast (Saccharomyces cerevisiae) extract (YE), in vitro on rat fat cell glucose transport, glucose metabolism to lipid, and lipolysis. YE was fractionated by reverse-phase chromatography on a C18 open column using ammonium acetate (0.05 mol/L, pH 5.8), with acetonitrile (40%) elution solvent into fraction 1 (Fx1), fraction 2 (Fx2) and fraction 3 (Fx3). Isolated rat adipocytes were preincubated with insulin (51 pmol/L), YE (10 mg/L) or both; transport of U-(14)C-glucose was measured. Adipocytes were incubated with insulin and YE fractions (10 mg/L); glucose metabolism to lipid was measured by incorporation of U-(14)C-glucose into total lipids. Lipolysis was measured by glycerol release. Insulin stimulated glucose transport to sevenfold the basal value (P < 0.05). YE did not affect glucose transport. Insulin stimulated glucose metabolism to 2.6-fold the basal value (P < 0.001); YE stimulated glucose metabolism 14% (P < 0.005). YE potentiated the action of insulin 30% (P < 0.002). YE Fx2 and Fx3 stimulated glucose metabolism 25-40% (P < 0.05). Insulin inhibited lipolysis 47% (P < 0.001). YE alone inhibited lipolysis 63% (P < 0.001). YE and insulin inhibited lipolysis 81% (P < 0.001). Fractions of YE inhibited lipolysis in the presence of insulin (P < 0.05); the order of potency was Fx2 = Fx3 >> Fx1. A novel yeast extract (YE) and its fractions affect pathways of adipocyte metabolism differentially. YE and its fractions are good candidates for in vivo study.