PO-0510 Inhibition Of Pentose Phosphate Pathway And Nadph Oxidase Impaired The Response Of Chicken Ductus Arteriosus To Oxygen

Abstract

Introduction NADPH derived from the pentose phosphate pathway (PPP) is a key system involved in maintaining the function of several important redox and antioxidant defense mechanisms. NADPH oxidases contain a catalytic NOX subunit that transfers electrons from NADPH to oxygen, thereby forming reactive oxygen species (ROS). Normoxic contraction of the ductus arteriosus (DA), such as occurs at birth, appears to be dependent upon the increase of ROS in DA smooth muscle cells. We hypothesised a role for NOX-derived ROS in the signalling pathway of oxygen-induced contraction of the DA. Methods We investigated the effects of the inhibition of PPP and NOX in the ex vivo response of chicken DA to oxygen. Experiments were performed in myograph-mounted DA rings (pulmonary and aortic sides) isolated from chicken embryos incubated for 19 days (total incubation: 21-d). Results Exposure to oxygen (21%) induced a sustained contractile response in the pulmonary but relaxation in the aortic side of 19-d DA. Incubation with the PPP inhibitor epiandrosterone or with the NOX inhibitors GKT-136901, VAS2870 and VAS3947 elicited a partial or complete impairment of oxygen-induced contraction. Phenylephrine- and KCl-induced contraction of chicken DA were impaired by epiandrosterone and VAS3947 but not by the other NOX inhibitors. Moreover, VAS3947 evoked an irreversible impairment of the contractility of the vessel. Oxygen-induced relaxation in the aortic part of the DA was not affected by NOX inhibitors. Conclusions Our data indicate that PPP and NADPH oxidase activation are events involved in the signalling cascade ofnormoxic contraction of chicken DA.