Simvastatin and dehydroepiandrosterone sulfate effects against hypoxic pulmonary hypertension are not additive.

Pulmonary hypertension is a group of disorders characterized by elevated mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance. To test our hypothesis that combining two drugs useful in experimental pulmonary hypertension, statins and dehydroepiandrosterone sulfate (DHEA S), is more effective than either agent alone, we induced pulmonary hypertension in adult male rats by exposing them to hypoxia (10%O2) for 3 weeks. We treated them with simvastatin (60 mg/l) and DHEA S (100 mg/l) in drinking water, either alone or in combination. Both simvastatin and DHEA S reduced mPAP (froma mean±s.d. of 34.4±4.4 to 27.6±5.9 and 26.7±4.8 mmHg, respectively), yet their combination was not more effective (26.7±7.9 mmHg). Differences in the degree of oxidative stress (indicated by malondialdehydeplasma concentration),the rate of superoxide production (electron paramagnetic resonance), or blood nitric oxide levels (chemiluminescence) did not explain the lack of additivity of the effect of DHEA S and simvastatin on pulmonary hypertension. We propose that the main mechanism of both drugs on pulmonary hypertension could be their inhibitory effect on 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, which could explain their lack of additivity.

Nitric oxide elevation in polytrauma is driven by oxygen radicals.

A common problem in management of polytrauma - a simultaneous injury to more than one organ or organ system, at least one of them lethal without intervention - is a discrepancy between a relatively good initial state and a serious subsequent development. Since nitric oxide (NO) is produced in high quantities during tissue injury, we assumed that serum levels of NO (and its oxidation products, NOx) might serve as a prognostic marker of polytrauma severity. However, we found recently that NOx was increased in polytrauma, but not in the most severe cases. The present study was undertaken to test the hypothesis that serum NOx is reduced in severe polytrauma by concomitant overproduction of reactive oxygen species (ROS). Polytrauma was induced in rats under anesthesia by bilateral fracture of femurs and tibiae plus incision of the right liver lobe through laparotomy. Serum NOx was measured by chemiluminescence after hot acidic reduction. The role of ROS was assessed by treatment with an antioxidant, N-acetyl-L-cysteine (NAC). Experimental polytrauma elevated NOx from 11.0+/-0.7 to 23.8+/-4.5 ppb. This was completely prevented by NAC treatment (9.1+/-2.2 ppb). Serum NOx is elevated in severe polytrauma, and this is not reduced by ROS. On the contrary, ROS are necessary for the NOx elevation, probably because ROS produced by inflammatory cells activated by the polytrauma induce massive NO production.

Nitric oxide as an indicator for severity of injury in polytrauma.

BACKGROUND: Patients with injuries to multiple organs or organ systems are in a serious risk of shock, multiorgan failure and death. Although there are scoring systems available to assess the extent of polytrauma and guide the prognosis, their usefulness is limited by their considerably subjective nature. As the production of nitric oxide (NO) by many cell types is elevated in tissue injury, we hypothesized that serum concentration of NO (and its oxidation products, NOx) represents a suitable marker of polytrauma correlating with prognosis. We wanted to prove that nitric oxide could serve as an indicator for severity of injury in polytrauma. METHODS: We measured serum NOx and standard biochemical parameters in 93 patients with various degrees of polytrauma, 15 patients with minor injuries and 20 healthy volunteers. RESULTS: On admission, serum NOx was higher in patients with moderate polytrauma than both in controls and patients with minor injury, and it was even higher in patients with severe polytrauma. Surprisingly, NOx on admission was normal in the group of patients that required cardiopulmonary resuscitation or died within 48 hours after admission. In the groups, where it was elevated on admission, serum NOx dropped to normal values within 12 hours. Blood lactate levels on admission were elevated in proportion to the severity of subsequent clinical course. CONCLUSION: Elevated serum NOx and blood lactate in patients with polytrauma are markers of serious clinical course, while normal NOx combined with a very high lactate may signal a fatal prognosis (Fig. 4, Ref. 8).

The effect of plant cytokinin hormones on the production of ethylene, nitric oxide, and protein nitrotyrosine in ageing tobacco leaves.

Transgenic plants with genetically increased or decreased levels of cytokinins were used to investigate the effect of cytokinin level on the production of ethylene, a plant hormone with suggested role in senescence, and the production of nitric oxide, potentially important signalling and regulatory molecule. The production of these gases was followed during the course of leaf development and senescence. The production of ethylene and nitric oxide is under genetic control of genes other than those involved in regulation of senescence. The difference in basic ethylene and NO levels in different tobacco cultivars was higher than their changes in senescence. The results of this study did not indicate a direct link between ethylene production and cytokinin levels. However, there was a decreased production of NO in senescent leaves. Low cytokinins level was associated with increased NO production during leaf development. Protein nitrotyrosine proved to be a better indicator of the reactive nitrogen species than measuring of the NO production. Higher nitrotyrosine concentrations were found in insoluble proteins than in the soluble ones, pointing to membrane proteins as the primary targets of the reactive nitrogen species. In plants with elevated cytokinin levels the content of nitrated proteins decreased both in soluble and insoluble fractions. This finding indicates an antioxidative function of cytokinins against reactive nitrogen species.

Hyperoxia attenuated nitrotyrosine concentration in the lung tissue of rats with experimental pneumonia.

Although nitrated proteins have been repeatedly used as markers of lung injury, little is known about their formation and metabolism under hyperoxia. We therefore measured 3-nitrotyrosine (3NTYR) concentrations in lung tissue and serum of rats with carrageenan-induced pneumonia exposed to hyperoxia. Twenty-nine Wistar male rats were assigned to one of 4 groups. Two experimental groups were treated by intratracheal application of carrageenan (0.5 ml of 0.7 % solution) and then one was exposed to hyperoxia for 7 days (FIO2 0.8), the other to air. Rats of two control groups breathed either hyperoxic gas mixture or air for 7 days. At the end of exposure the ventilation was determined in anesthetized, intubated animals in which 3NTYR concentrations were measured in the lung tissue and nitrites and nitrates (NOx) were estimated in the serum. Carrageenan instillation increased 3NTYR concentrations in lung tissue (carrageenan-normoxic group 147+/-7 pmol/g protein, control 90+/-10 pmol/g protein) and NOx concentration in the serum (carrageenan-normoxic group 126+/-13 ppb, control 78+/-9 ppb). Hyperoxia had no effect on lung tissue 3NTYR concentration in controls (control-hyperoxic 100+/-14 pmol/g protein) but blocked the increase of lung tissue 3NTYR in carrageenan-treated rats (carrageenan-hyperoxic 82+/-13 pmol/g protein), increased NOx in serum (control-hyperoxic 127+/-19 ppb) and decreased serum concentration of 3NTYR in both hyperoxic groups (carrageenan-hyperoxic 51+/-5 pmol/g protein, control-hyperoxic 67+/-7 pmol/g protein, carrageenan-normoxic 82+/-9 pmol/g protein, control 91+/-7 pmol/g protein). The results suggest that hyperoxia affects nitration of tyrosine residues, probably by increasing 3NTYR degradation.

[Pachydermoperiostosis--development of bone changes 25 years after disease onset]. / Pachydermoperiostóza--vývoj kostních zmen po 25 letech od pocátku nemoci.

Pachydermoperiostosis-hyperostosis generalisata cum pachydermia is considered a sex-linked hereditary pathological disposition of the mesenchyme with a favourable course of the dominant form; it is, however, progressively malignant in the recessive type of heredity. As a rule men affected. The author describes the case of a patient where the disease was diagnosed 25 years previously.