Biomedical subjects

Silvia Lores-Arnaiz

Publications and source records attributed to Silvia Lores-Arnaiz.

6 recordsLinked to original sources

PubMed2007

Brain nitric oxide synthases and mitochondrial function.

Nitric oxide is a small signaling molecule, which may act as a neurotransmitter and neuromodulator, exerting a regulatory effect on neuronal function. It can diffuse from its site of synthesis to different intra and extracellular compartments, being therefore present in the pre-synaptic, synaptic and post-synaptic spaces. Recently, a NOS located in the mitochondria (mtNOS) has been observed in different brain regions, responsible for the production of NO in these organelles and identified as nNOS. A regulatory effect of NO on mitochondrial function was described in brain mitochondria, where NO acts mainly by inhibiting cytochrome oxidase activity. Hippocampal mitochondrial dysfunction and decreased mtNOS activity and expression were reported in association with ultrastructural damage in an experimental model of hepatic encephalopathy. Enriched environment exposure preserved the aged animals from spatial cognition impairment; also environment and training modulated neuronal plasticity in pre-pubertal rats through NO-dependent mechanisms. In addition, brain cortical mitochondrial respiration and mtNOS activity and expression were analyzed as function of age. Mitochondrial NO production showed a decreasing tendency as a function of age. These results are in accordance with the protein expression analyzed by Western Blot of mitochondrial fractions which was 6.5 times higher in 1 month aged rats as compared with 14 old animals. Concomitant with these results, a clear increasing oxygen uptake tendency in state 3 respiration was observed, meanwhile only a slight increase was observed in state 4. All these results seems to be clearly related with the reversible and concentration-dependent attenuation of the respiratory chain by NO.

Aging↗

PubMed2005

Modulation of brain mitochondrial function by deprenyl.

The present study shows that deprenyl, a known inhibitor of monoamine oxidase B (MAO B), may generate changes in mitochondrial function. Brain submitochondrial membranes (SMP), synaptosomes and cytosolic fractions were incubated with different deprenyl concentrations and nitric oxide synthase (NOS) activity was measured. The effect of deprenyl on oxygen consumption, calcium-induced permeability transition and hydrogen peroxide (H(2)O(2)) production rates was studied in intact mitochondria. Respiratory complexes and monoamine oxidase activities were also measured in submitochondrial membranes. Incubation of brain submitochondrial membranes with deprenyl 10, 25 and 50 microM inhibited nitric oxide synthase activity in a concentration-dependent manner. The same effect was observed in cytosolic fractions and synaptosomes. Monoamine oxidase activity was inhibited at lower deprenyl concentrations (from 0.5 microM). Cytochrome oxidase (complex IV) activity was found 42% increased in the presence of 25 microM deprenyl in a condition of maximal nitric oxide synthase activity. Incubation of brain mitochondria with deprenyl 25 microM produced a 60% increase in oxygen uptake in state 3, but no significant changes were observed in state 4. Pre-incubation of brain mitochondria with deprenyl 0.5 and 1 microM inhibited calcium-induced mitochondrial permeability transition and decreased hydrogen peroxide production rates. Our results suggest that in vitro effects of deprenyl on mitochondrial function can occur through two different mechanisms, involving nitric oxide synthase inhibition and decreased hydrogen peroxide production.

Animals↗

PubMed2005

Hippocampal mitochondrial dysfunction with decreased mtNOS activity in prehepatic portal hypertensive rats.

Portal hypertension is a major complication of human cirrhosis that frequently leads to central nervous system dysfunction. In our study, rats with prehepatic portal hypertension developed hippocampal mitochondrial dysfunction as indicated by decreased respiratory rates, respiratory control and mitochondrial nitric oxide synthase (mtNOS) activity in mitochondria isolated from the whole hippocampus. Succinate-dependent respiratory rates decreased by 29% in controlled state 4 and by 42% in active state 3, and respiratory control diminished by 20%. Portal hypertensive rats showed a decreased mtNOS activity of 46%. Hippocampal mitochondrial dysfunction was associated with ultrastructural damage in the mitochondria of hippocampal astrocytes and endothelial cells. Swollen mitochondria, loss of cristae and rupture of outer and inner membrane was observed in astrocytes and endothelial cells of the blood-brain barrier in parallel with the ammonia gradient. It is concluded that the moderate increase in plasma ammonia that followed portal hypertension was the potential primary cause of the observed alterations.

Animals↗

PubMed2004

Brain mitochondrial nitric oxide synthase: in vitro and in vivo inhibition by chlorpromazine.

Mouse brain mitochondria have a nitric oxide synthase (mtNOS) of 147 kDa that reacts with anti-nNOS antibodies and that shows an enzymatic activity of 0.31-0.48 nmol NO/min mg protein. Addition of chlorpromazine to brain submitochondrial membranes inhibited mtNOS activity (IC50 = 2.0 +/- 0.1 microM). Brain mitochondria isolated from chlorpromazine-treated mice (10 mg/kg, i.p.) show a marked (48%) inhibition of mtNOS activity and a markedly increased state 3 respiration (40 and 29% with malate-glutamate and succinate as substrates, respectively). Respiration of mitochondria isolated from control mice was 16% decreased by arginine and 56% increased by NNA (Nomega-nitro-L-arginine) indicating a regulatory activity of mtNOS and NO on mitochondrial respiration. Similarly, mitochondrial H2O2 production was 55% decreased by NNA. The effect of NNA on mitochondrial respiration and H2O2 production was significantly lower in chlorpromazine-added mitochondria and absent in mitochondria isolated from chlorpromazine-treated mice. Results indicate that chlorpromazine inhibits brain mtNOS activity in vitro and can exert the same action in vivo.

Animals↗

PubMed2003

Enalapril increases mitochondrial nitric oxide synthase activity in heart and liver.

Heart and liver mitochondria isolated from rats treated with enalapril, 3-30 mg/kg/day in the drinking water for 7-120 days, showed a time- and dose-dependent increased nitric oxide (NO) production in the range of 14-250%. Heart and liver mitochondria from control rats produced 0.69 and 0.50 nmol of NO/min/mg of protein, respectively, as determined by dual wavelength spectrophotometry (577-591 nm) following hemoglobin oxidation to methemoglobin. The response to enalapril treatment, attributed to a gene-mediated up-regulation of mitochondrial nitric oxide synthase (mtNOS) activity, was half-maximal at 5-6 days and was maintained up to 120 days. Enalapril-treated animals showed an increased mtNOS functional activity in heart mitochondria that inhibited state 3 O(2) uptake (from 22% in control rats to 43%) and increased state 4 hydrogen peroxide (H(2)O(2)) production (from 30% in control rats to 52%). Calculated heart intramitochondrial NO and H(2)O(2) steady-state concentrations were increased 66% and 20%, respectively, by enalapril treatment. Signaling pathways dependent on mitochondrial NO and H(2)O(2) may account for the beneficial effects of enalapril in aging mammals.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2002

Long-term angiotensin II inhibition increases mitochondrial nitric oxide synthase and not antioxidant enzyme activities in rat heart.

OBJECTIVE: To provide insight into the subcellular mechanisms involved in the improvement of cardiovascular structure and function by long-term inhibition of the renin-angiotensin system. DESIGN: The activities of antioxidant enzymes and mitochondrial free radical production were determined in the heart of control (C), enalapril-treated (E), and losartan-treated (L) rats to test the hypothesis of increased antioxidant enzyme activities and participation of mitochondria in the effects of chronic treatments with angiotensin II inhibitors. METHODS: At 6 and 18 months of treatment, superoxide dismutases (SOD), Se-glutathione peroxidase, and catalase activities were determined in left ventricle homogenates by spectrophotometric methods and nitric oxide (NO) production in submitochondrial membranes by the oxyhemoglobin oxidation assay. The maximal rate of hydrogen peroxide (H2O2) production by submitochondrial membranes was also evaluated at 18 months by the scopoletin-horseradish peroxidase method. RESULTS: No significant increase was found in the antioxidant enzymes measured. At 6 months, Mn-SOD was actually decreased in E and catalase in both E and L, whereas at 18 months Se-glutathione peroxidase was decreased in L. Production of NO by submitochondrial particles was 64% higher at 6 months in E and 105% higher at 18 months in E and L. Maximal hydrogen peroxide production was lower at 18 months in both groups. CONCLUSIONS: Results do not support the hypothesis of an increase in antioxidant enzyme activity by long-term treatment with angiotensin II inhibitors as previously suggested and point towards a role for the NO produced by mitochondrial nitric oxide synthase (mtNOS) in the protective effect of these drugs.

Angiotensin II↗