Cigarette smoke (CS) and chronic hypoxia (CH) can produce pulmonary hypertension. Similarities and differences between both exposures and their interaction have not been explored. The aim of the present study was to investigate the effects of CS and CH, as single factors or in combination, on the pulmonary circulation in the guinea pig.51 guinea pigs were exposed to CS for 12 weeks and 32 were sham-exposed. 50% of the animals in each group were additionally exposed to CH for the final 2 weeks. We measured pulmonary artery pressure (P_pa), and the weight ratio between the right ventricle (RV) and left ventricle plus the septum. Pulmonary artery contractility in response to noradrenaline (NA), endothelium-dependent vasodilatation and distensibility were evaluated in organ bath chambers. The number of small intrapulmonary vessels showing immunoreactivity to smooth muscle (SM) α-actin and double elastic laminas was assessed microscopically.CS and CH induced similar increases ofP_paand RV hypertrophy (p<0.05 for both), effects that were further enhanced when both factors were combined. CH increased the contractility to NA (p<0.01) and reduced the distensibility (p<0.05) of pulmonary arteries. Animals exposed to CS showed an increased number of small vessels with positive immunoreactivity to SM α-actin (p<0.01) and those exposed to CH a greater proportion of vessels with double elastic laminas (p<0.05).We conclude that CH amplifies the detrimental effects of CS on the pulmonary circulation by altering the mechanical properties of pulmonary arteries and enhancing the remodelling of pulmonary arterioles.

Superoxide anion is the most important reactive oxygen species (ROS) primarily generated in cells. The main cellular constituents with capabilities to generate superoxide anion are NADPH oxidases and mitochondrial respiratory chain. The emphasis of our article is centered in critically examining hypotheses proposing that ROS generated by NADPH oxidase and mitochondria are key elements in O(2)-sensing and hypoxic responses generation in carotid body chemoreceptor cells. Available data indicate that chemoreceptor cells express a specific isoform of NADPH oxidase that is activated by hypoxia; generated ROS acting as negative modulators of the carotid body (CB) hypoxic responses. Literature is also consistent in supporting that poisoned respiratory chain can produce high amounts of ROS, making mitochondrial ROS potential triggers-modulators of the CB activation elicited by mitochondrial venoms. However, most data favour the notion that levels of hypoxia, capable of strongly activating chemoreceptor cells, would not increase the rate of ROS production in mitochondria, making mitochondrial ROS unlikely triggers of hypoxic responses in the CB. Finally, we review recent literature on heme oxygenases from two perspectives, as potential O(2)-sensors in chemoreceptor cells and as generators of bilirubin which is considered to be a ROS scavenger of major quantitative importance in mammalian cells.

Background: Cardiovascular (CV) diseases are a leading cause of mortality and they are frequent in patients with the obstructive sleep apnea syndrome (OSAS). Objectives: In this study we investigated if OSAS influences CV function independently of other CV risk factors frequently present in these patients (e.g. obesity, high blood pressure). Methods: We compared plasma markers of endothelial dysfunction, asymmetric dimethylarginine (ADMA) and endothelin-1 (ET-1), and atherosclerosis progression (soluble fraction of the CD40 ligand, sCD40L) in OSAS patients with (n = 23) and without (n = 18) concurrent CV risk factors, as well as in healthy subjects (n = 23). Results: Plasma ADMA (p < 0.01) and sCD40L (p < 0.05) were abnormally increased in patients with OSAS versus healthy controls, but they were not influenced by the presence or absence of CV risk factors in OSAS. ET-1 levels were not different between the three groups of subjects studied. Conclusions: OSAS is associated with endothelial injury and atherosclerosis progression independently of other CV risk factors.

We have reported previously that peroxynitrite stimulates l-arginine release from astrocytes, but the mechanism responsible for such an effect remains elusive. To explore this issue, we studied the regulation ofl-[³H]arginine transport by either exogenous or endogenous peroxynitrite in glial cells. A 2-fold peroxynitrite-mediated stimulation of l-arginine release in C6 cells was found to be Na⁺-independent, was prevented by 5 mm l-arginine and, although only in the presence of Na⁺, was blocked by 5 mm l-alanine or l-leucine. Peroxynitrite-mediated stimulation of l-arginine uptake was trans-stimulated by 10 mm l-arginine and was inhibited in a dose-dependent fashion (k _i of ∼40 μm) by the system y ⁺ inhibitorN-ethylmaleimide in C6 cells. Endogenous production of peroxynitrite in lipopolysaccharide-treated astrocytes triggered an increased l-arginine transport activity without affectingCat1 l-arginine transporter mRNA levels. However, Western blot analyses of peroxynitrite-treated astrocytes and C6 glial cells revealed a 3-nitrotyrosinated anti-Cat1-immunopositive band, strongly suggesting peroxynitrite-mediated Cat1 nitration. Furthermore, peroxynitrite stimulation of l-arginine release was abolished in fibroblast cells homozygous for a targeted inactivation of the Cat1 gene. Finally, peroxynitrite-triggered l-arginine released from astrocytes was efficiently taken up by neurons in an insert-based co-culture system. These results strongly suggest that peroxynitrite-mediated activation of the Cat1 transporter in glial cells may serve as a mechanism focused to replenish l-arginine in the neighboring neurons.