No abstract

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.

Previously we have reported that association of cigarette smoke (CS) and chronic hypoxia (CH) interact positively to physiopathologically remodel pulmonary circulation. In present study we have exposed guinea pigs to CS smoke (four cigarettes/day; 3 months; CS) and to chronic hypoxia (12% O(2), 15 days; CH) alone or in combination (CSCH animals) and evaluated airways remodeling and resistance assessed as Penh (enhance pause). We measured Penh while animals breathe air, 10% O(2) and 5% CO(2) and found that CS and CH animals have higher Penh than controls; Penh was even larger in CSCH animals. A rough parallelism between Penh and thickness of bronchiolar wall and muscular layer and Goblet cell number was noticed. We conclude that CS and CH association accelerates CS-induced respiratory system damage, evidenced by augmented airway resistance, bronchial wall thickness and muscularization and Goblet cell number. Our findings would suggest that appearance of hypoxia would aggravate any preexisting pulmonary pathology by increasing airways resistance and reactivity.

Obstructive sleep apnoea syndrome (OSAS) is a disorder characterized by repetitive episodes of complete (apnoea) or partial (hypopnoea) obstruction of airflow during sleep. The severity of OSAS is defined by the apnoea hypopnoea index (AHI) or number of obstructive episodes. An AHI greater than 30 is considered severe, but it can reach values higher than 100 in some patients. Associated to the OSA there is high incidence of cardiovascular and neuro-psychiatric pathologies including systemic hypertension, stroke, cardiac arrhythmias and atherosclerosis, diurnal somnolence, anxiety and depression. In the present study we have used a model of intermittent hypoxia (IH) of moderately high intensity (30 episodes/h) to evaluate arterial blood gases and plasma catecholamines as main effectors in determining arterial blood pressure. Male rats were exposed toIH with a regime of 80s, 20% O(2) // 40s, 10%O(2), 8 h/day, 8 or 15 days.Lowering the breathing atmosphere to 10% O(2) reduced arterial blood PO(2) to 56.9 mmHg (nadir HbO(2) 86, 3%). Plasma epinephrine (E) and norepinephrine (NE) levels at the end of 8 and 15 days of IH showed a tendency to increase, being significant the increase of norepinephrine (NE) levels in the group exposed to intermittent hypoxia during 15 days. We conclude that IH causes an increase in sympathetic activity and a concomitant increase in NE levels which in turn would generate an increase in vascular tone and arterial blood pressure.

No abstract

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 of Glial cells can be activated to endogenously produce ⅐ NO through the induction of the inducible NOS isoform (iNOS) (9 -13). Within the brain, free L-arginine is predominantly located in astrocytes (14), which produce large amounts of ⅐ NO upon iNOS (15) and L-arginine transporter (7) induction. However, unlike in astrocytes, L-arginine content in neurons is very low and is limiting for nNOS activity (16,17). Consistent with this, glial-derived L-arginine has been shown to be increased upon activation of ionotropic glutamate (non-N-methyl-Daspartate) receptors (18) and peroxynitrite (19), suggesting a neuronal-astrocytic signaling transduction pathway focused to provide NOS substrate for the neurons. However, direct demonstration of such a pathway and the elucidation of the precise transport system involved remain elusive.Plasma membrane L-arginine transport is brought about by two families of cationic amino acid transport proteins: Cat (cationic amino acid transporter) and Bat (broad scope amino acid transporter). The Cat family of transporters comprises three different genes encoding four isoform proteins (Cat1, Cat2, Cat2a, and Cat3) (20, 21), commonly referred to as the system y ϩ (22), which is mostly selective for cationic amino acids, although it does show a weak interaction with neutral amino acids in the presence of Na ϩ (23). Glial cells mainly, but not exclusively, express the high affinity (k t for L-arginine ϭ 40 -250 M) (24) 67-kDa Cat1 (constitutive) (25) and the 71.8-kDa Cat2 (inducible) (26) system y ϩ proteins (7, 27). The Bat family of constitutive transporter proteins is found in systems b o,ϩ , B o,ϩ , and y ϩ L (y ϩ Lat1 and y ϩ Lat2), which are mainly expressed in kidney and intestine, except for y ϩ Lat2, which is expressed in astrocytes (28).We have reported previously that the neurotoxic ⅐ NO derivative, peroxynitrite anion (ONOO Ϫ ), specifically stimulates Larginine release from astrocytes (19). Although the ONOO Ϫ -mediated stimulatory effect was inhibited by L-lysine, hence suggesting the involvement of system y ϩ (19), an in-depth study focused on elucidating the precise mechanism responsible for L-arginine transport activation has not yet been carried out. In view of the potential critical role of glial cells as neuronal L-arginine suppliers for ⅐ NO biosynthesis (8,18,29), we were prompted to investigate the mechanism through which ONOO Ϫ modulates L-arginine transport across the glial cell plasma membrane as well as the potential relevance of such modulation for neuronal L-arginine uptake.* This work was funded by grants from the Ministerio de Ciencia y Tecnología (Grant SAF2001-1961), the Junta de Castilla y León (Grant SA065/01) and Fundación Ramón Areces (to J. P. B.), and Grant RO1 DK53307-01 (to M. H.).§ The recipient of a fellowship from the Fundación Miguel Casado...