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The increase in O2 tension after birth is a major factor stimulating ductus arteriosus (DA) constriction and closure. Here we. studied the role of the mitochondrial electron transport chain (ETC) as sensor, H2O2 as mediator, and voltage-gated potassium (Ky) channels and Rho kinase as effectors of O2-induced contraction in the chicken DA during fetal development. Switching from 0% to 21% O2 contracted the pulmonary side of the mature DA (mature pDA) but had no effect in immature pDA and relaxed the aortic side of the mature DA (mature aDA). This contraction of the pDA was attenuated by inhibitors of the mitochondrial ETC and by the H2O2 scavenger polyethylene glycol (PEG)-catalase. Moreover, O2 increased reactive oxygen species (ROS) production, measured with the fluorescent probes dihydroethidium and 2',7'-dichlorofluorescein, only in mature pDA. The H2O2 analog t-butyl-hydroperoxide mimicked the responses to O2 in the three vessels. In contrast to immature pDA cells, mature pDA cells exhibited high-amplitude O2-sensitive potassium currents. The Kv channel blocker 4-aminopyridine prevented the current inhibition elicited by O2. The L-type Ca2+ (CaL) channel blocker nifedipine and the Rho kinase inhibitors Y-27632 and hydroxyfasudil induced a similar relaxation when mature pDA were stimulated with O2 or H2O2. Moreover, the sensitivity to these drugs increased with maturation. Our results indicate the presence of a common mechanism for O2 sensing/signaling in mammalian and nonmammalian DA and favor the idea that, rather than a single mechanism, a parallel maturation of the sensor and effectors is critical for O2 sensitivity appearance during development. [ABSTRACT FROM AUTHOR]

Recent data suggest that diabetes is a risk factor for pulmonary hypertension. The aim of the present study was to analyze whether diabetes induces endothelial dysfunction in pulmonary arteries and the mechanisms involved. Male Sprague-Dawley rats were randomly divided into a control (saline) and a diabetic group (70 mg/kg-1 streptozotocin). After 6 wk, intrapulmonary arteries were mounted for isometric tension recording, and endothelial function was tested by the relaxant response to acetylcholine. Protein expression and localization were measured by Western blot and immunohistochemistry and superoxide production by dihydroethidium staining. Pulmonary arteries from diabetic rats showed impaired relaxant response to acetylcholine and reduced vasoconstrictor response to the nitric oxide (NO) synthase inhibitor L-NAME, whereas the response to nitroprusside and the expression of endothelial NO synthase remained unchanged. Endothelial dysfunction was reversed by addition of superoxide dismutase or the NADPH oxidase inhibitor apocynin. An increase in superoxide production and increased expression of the NADPH oxidase regulatory subunit p47phox were also found in pulmonary arteries from diabetic rats. In conclusion, the pulmonary circulation is a target for diabetes-induced endothelial dysfunction via enhanced NADPH oxidase-derived superoxide production. [ABSTRACT FROM AUTHOR]