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We have recently shown that diabetes induces PA endothelial dysfunction secondary to enhanced NADPH oxidase-derived superoxide production in Sprague�CDawley rats (Lopez-Lopez et al. 2008). Likewise, diabetes significantly (P www.selleckchem.com/products/MLN8237.html Diabetic plus hypoxic animals showed similar relaxations to those of normoxic diabetic animals. Thus, diabetes reduced the Emax from 60 �� 6 to 40 �� 9% in normoxia and from 65 �� 6 to 44 �� 11% in moderate hypoxia, without significant changes in the sensitivity of the vessels to acetylcholine (pD2 values of 7.7 �� 0.2, 7.3 �� 0.3, 7.8 �� 0.4 and 7.4 �� 0.2, in control, diabetic, hypoxic and diabetic plus hypoxic groups respectively). In freshly isolated PA smooth muscle cells, membrane capacitance, an estimate of membrane surface, was similar in the four groups (inset in Fig. 2B). As expected, Aldosterone a significant decrease in the amplitude of the KV currents was observed in moderately hypoxic animals (Fig. 2A and B). However, diabetes did not produce any significant effect on the KV currents. Diabetic plus hypoxic animals showed similar KV currents to those of hypoxic control animals. As BMPR2 is a key protein involved in PH, we examined its expression in diabetic lungs and found that BMPR2 was strongly downregulated both by diabetes and by moderate hypoxia (Fig. 3). Small pulmonary arteries (25�C300 ��m) in lung sections were classified as muscular, partly muscular and non-muscular arteries (Fig. 4A). Both diabetes and hypoxia increased the percentage of muscular arteries, with a corresponding decrease in partly muscular and non-muscular arteries. No further increase in arterial muscularization was found in lungs from diabetic animals exposed to hypoxia. Likewise, both diabetes and hypoxia increased the medial wall thickness of pulmonary arteries (25�C75��m), but no additive effect was found with the combination of both factors. In several sections from diabetic rats exposed to either normoxia or hypoxia, there was apparent infiltration of inflammatory cells (e.g. Fig. 4Bd). Therefore, we analysed the MPO activity in lung tissue homogenates as a marker of neutrophil and macrophage parenchymal infiltration. As expected, diabetes increased MPO activity two- to threefold www.selleckchem.com/products/wnt-c59-c59.html in both normoxia and hypoxia (Fig. 5A), while hypoxia alone had no significant effect. Immunohistochemistry demonstrated that pulmonary infiltration in diabetic animals corresponded to CD68-positive macrophages, and it was markedly increased by exposure to moderate hypoxia (Fig. 5B and C). We found no significant changes in RVSP, SPAP, DPAP or MPAP or in the ratios of the free wall of the right ventricle (RV) to body weight (BW) and free wall of the left ventricle (LV) plus septum (S) to BW in rats exposed to moderate hypoxia or diabetes (Fig. 6). The Fulton index [i.e.